Cancers

13 pages, 948 KiB

Open AccessArticle

Surgical Techniques and Outcomes of Colorectal Anastomosis after Left Hemicolectomy with Low Anterior Rectal Resection for Advanced Ovarian Cancer

by Kyoko Nishikimi, Shinichi Tate, Ayumu Matsuoka, Satoyo Otsuka and Makio Shozu

Cancers 2021, 13(16), 4248; https://doi.org/10.3390/cancers13164248 - 23 Aug 2021

Cited by 2 | Viewed by 3719

Abstract

Extended colon resection is often performed in advanced ovarian cancer. Restoring intestinal continuity and avoiding stoma creation improve patients’ quality of life postoperatively. We tried to minimize the number of anastomoses, restore intestinal continuity, and avoid stoma creation for 295 patients with stage [...] Read more.

Extended colon resection is often performed in advanced ovarian cancer. Restoring intestinal continuity and avoiding stoma creation improve patients’ quality of life postoperatively. We tried to minimize the number of anastomoses, restore intestinal continuity, and avoid stoma creation for 295 patients with stage III/IV ovarian cancer who underwent low anterior rectal resection (LAR) with or without colon resection during cytoreductive surgery. When the remaining colon could not reach the rectal stump after left hemicolectomy with LAR, we used the following techniques for tension-free anastomosis: right colonic transposition, retro-ileal anastomosis through an ileal mesenteric defect, or an additional colic artery division. Rates of stoma creation and rectal anastomotic were 3% (9/295) and 6.6% (19/286), respectively. Among 21 patients in whom the remaining colon did not reach the rectal stump after left hemicolectomy with LAR, 20 underwent tension-free anastomosis, including eight, six, and six patients undergoing right colonic transposition, retro-ileal anastomosis through an ileal mesenteric defect, and an additional colic artery division, respectively. Colorectal anastomosis is feasible for patients with extended colonic resection. Low anastomotic leakage and stoma rates can be achieved with careful attention to colonic mobilization and tension-free anastomosis. Full article

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22 pages, 15220 KiB

Open AccessArticle

Hot Spot Analysis of YAP-TEAD Protein-Protein Interaction Using the Fragment Molecular Orbital Method and Its Application for Inhibitor Discovery

by Jongwan Kim, Hocheol Lim, Sungho Moon, Seon Yeon Cho, Minhye Kim, Jae Hyung Park, Hyun Woo Park and Kyoung Tai No

Cancers 2021, 13(16), 4246; https://doi.org/10.3390/cancers13164246 - 23 Aug 2021

Cited by 24 | Viewed by 4772

Abstract

The Hippo pathway is an important signaling pathway modulating growth control and cancer cell proliferation. Dysregulation of the Hippo pathway is a common feature of several types of cancer cells. The modulation of the interaction between yes-associated protein (YAP) and transcriptional enhancer associated [...] Read more.

The Hippo pathway is an important signaling pathway modulating growth control and cancer cell proliferation. Dysregulation of the Hippo pathway is a common feature of several types of cancer cells. The modulation of the interaction between yes-associated protein (YAP) and transcriptional enhancer associated domain (TEAD) in the Hippo pathway is considered an attractive target for cancer therapeutic development, although the inhibition of PPI is a challenging task. In order to investigate the hot spots of the YAP and TEAD1 interacting complex, an ab initio Fragment Molecular Orbital (FMO) method was introduced. With the hot spots, pharmacophores for the inhibitor design were constructed, then virtual screening was performed to an in-house library. Next, we performed molecular docking simulations and FMO calculations for screening results to study the binding modes and affinities between PPI inhibitors and TEAD1. As a result of the virtual screening, three compounds were selected as virtual hit compounds. In order to confirm their biological activities, cellular (luciferase activity, proximity ligation assay and wound healing assay in A375 cells, qRT-PCR in HEK 293T cells) and biophysical assays (surface plasmon resonance assays) were performed. Based on the findings of the study, we propose a novel PPI inhibitor BY03 and demonstrate a profitable strategy to analyze YAP–TEAD PPI and discover novel PPI inhibitors. Full article

(This article belongs to the Special Issue Hippo Signaling Pathway in Cancers)

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21 pages, 1797 KiB

Open AccessFeature PaperReview

Identification and Targeting of Mutant Peptide Neoantigens in Cancer Immunotherapy

by Daniel J. Verdon and Misty R. Jenkins

Cancers 2021, 13(16), 4245; https://doi.org/10.3390/cancers13164245 - 23 Aug 2021

Cited by 18 | Viewed by 7230

Abstract

In recent decades, adoptive cell transfer and checkpoint blockade therapies have revolutionized immunotherapeutic approaches to cancer treatment. Advances in whole exome/genome sequencing and bioinformatic detection of tumour-specific genetic variations and the amino acid sequence alterations they induce have revealed that T cell mediated [...] Read more.

In recent decades, adoptive cell transfer and checkpoint blockade therapies have revolutionized immunotherapeutic approaches to cancer treatment. Advances in whole exome/genome sequencing and bioinformatic detection of tumour-specific genetic variations and the amino acid sequence alterations they induce have revealed that T cell mediated anti-tumour immunity is substantially directed at mutated peptide sequences, and the identification and therapeutic targeting of patient-specific mutated peptide antigens now represents an exciting and rapidly progressing frontier of personalized medicine in the treatment of cancer. This review outlines the historical identification and validation of mutated peptide neoantigens as a target of the immune system, and the technical development of bioinformatic and experimental strategies for detecting, confirming and prioritizing both patient-specific or “private” and frequently occurring, shared “public” neoantigenic targets. Further, we examine the range of therapeutic modalities that have demonstrated preclinical and clinical anti-tumour efficacy through specifically targeting neoantigens, including adoptive T cell transfer, checkpoint blockade and neoantigen vaccination. Full article

(This article belongs to the Special Issue Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens Expressed by Solid Tumors)

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10 pages, 1819 KiB

Open AccessArticle

Comparison of FLASH Proton Entrance and the Spread-Out Bragg Peak Dose Regions in the Sparing of Mouse Intestinal Crypts and in a Pancreatic Tumor Model

by Michele M. Kim, Ioannis I. Verginadis, Denisa Goia, Allison Haertter, Khayrullo Shoniyozov, Wei Zou, Amit Maity, Theresa M. Busch, James M. Metz, Keith A. Cengel, Lei Dong, Costas Koumenis and Eric S. Diffenderfer

Cancers 2021, 13(16), 4244; https://doi.org/10.3390/cancers13164244 - 23 Aug 2021

Cited by 75 | Viewed by 5099

Abstract

Ultra-high dose rate FLASH proton radiotherapy (F-PRT) has been shown to reduce normal tissue toxicity compared to standard dose rate proton radiotherapy (S-PRT) in experiments using the entrance portion of the proton depth dose profile, while proton therapy uses a spread-out Bragg peak [...] Read more.

Ultra-high dose rate FLASH proton radiotherapy (F-PRT) has been shown to reduce normal tissue toxicity compared to standard dose rate proton radiotherapy (S-PRT) in experiments using the entrance portion of the proton depth dose profile, while proton therapy uses a spread-out Bragg peak (SOBP) with unknown effects on FLASH toxicity sparing. To investigate, the biological effects of F-PRT using an SOBP and the entrance region were compared to S-PRT in mouse intestine. In this study, 8–10-week-old C57BL/6J mice underwent 15 Gy (absorbed dose) whole abdomen irradiation in four groups: (1) SOBP F-PRT, (2) SOBP S-PRT, (3) entrance F-PRT, and (4) entrance S-PRT. Mice were injected with EdU 3.5 days after irradiation, and jejunum segments were harvested and preserved. EdU-positive proliferating cells and regenerated intestinal crypts were quantified. The SOBP had a modulation (width) of 2.5 cm from the proximal to distal 90%. Dose rates with a SOBP for F-PRT or S-PRT were 108.2 ± 8.3 Gy/s or 0.82 ± 0.14 Gy/s, respectively. In the entrance region, dose rates were 107.1 ± 15.2 Gy/s and 0.83 ± 0.19 Gy/s, respectively. Both entrance and SOBP F-PRT preserved a significantly higher number of EdU + /crypt cells and percentage of regenerated crypts compared to S-PRT. Moreover, tumor growth studies showed no difference between SOBP and entrance for either of the treatment modalities. Full article

(This article belongs to the Section Cancer Therapy)

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(a) Schematic and (b) photo of the beam line design with ridge filter and range shifters to deliver a spread-out Bragg peak (SOBP) in the mouse. (c) Model of ridge filter and (d) photo of the printed ridge filter with protective casing. Full article ">Figure 2
(a) EBT3 Gafchromic film irradiated at the mid-SOBP with a 2 × 2 cm2 field size. x and y lateral profiles are shown on the right. (b) Relative depth dose of SOBP used to irradiate mice measured by the multi-layer ionization chamber (MLIC). Mice were placed in a holder in order to be within the shaded blue region. Film (circles) and multi-layer ion chamber measurements (solid line) agreed. The red x indicates the point at which absolute dose measurements were performed for the SOBP studies. (c) Surface plot of relative depth dose measured by a stack of 20 films with 2 to10 mm pieces of solid water plastic between films. Full article ">Figure 3
Relative depth dose measurement with a ridge filter in the beam line at various angles. The inset plot shows a zoom of the SOBP region. All studies were performed with the ridge filter at 2.5° for a flat SOBP. Full article ">Figure 4
(a) Representative images of EdU (green) staining in frozen jejunum sections at 3.5 days post 15 Gy of whole abdominal irradiation (10× magnification; scale bar 100 mm) with FLASH proton radiotherapy (F-PRT) or standard proton radiotherapy (S-PRT) dose rate protons in the entrance and SOBP region of the depth dose profile. (b) Quantification of EdU+ cells per crypt. (c) Quantification of the % regenerated crypts. Data presented as mean ± SEM; n.s. = not significant. Full article ">Figure 5
(a) Tumor growth curves of mice following 18 Gy focal irradiation with protons at standard (S-PRT Entrance, solid red; S-PRT SOBP, dotted red) versus FLASH (F-PRT Entrance, solid green; F-PRT SOBP, dotted green) dose rates. Unirradiated mice served as a control group (NR, blue). Black arrow indicates the time of irradiation. Data expressed as mean ± SEM. (b) Kaplan–Meier survival analysis of the mice from (a). Full article ">

15 pages, 5864 KiB

Open AccessArticle

Adhesion of Platelets to Colon Cancer Cells Is Necessary to Promote Tumor Development in Xenograft, Genetic and Inflammation Models

by Marica Cariello, Elena Piccinin, Roberta Zerlotin, Marilidia Piglionica, Claudia Peres, Chiara Divella, Anna Signorile, Gaetano Villani, Giuseppe Ingravallo, Carlo Sabbà and Antonio Moschetta

Cancers 2021, 13(16), 4243; https://doi.org/10.3390/cancers13164243 - 23 Aug 2021

Cited by 7 | Viewed by 2745

Abstract

Platelets represent the linkage between tissue damage and inflammatory response with a putative role in tumorigenesis. Given the importance of the microenvironment in colon cancer development, we elucidated the eventual role of platelets-cancer cells crosstalk in in vivo colon cancer models. To evaluate [...] Read more.

Platelets represent the linkage between tissue damage and inflammatory response with a putative role in tumorigenesis. Given the importance of the microenvironment in colon cancer development, we elucidated the eventual role of platelets-cancer cells crosstalk in in vivo colon cancer models. To evaluate the involvement of platelets in intestinal tumorigenesis, we first analyzed if the ablation of β-integrin P-selectin that drives platelets-cell adhesion, would contribute to platelets-colon cancer cell interaction and drive cancer progression. In a xenograft tumor model, we observed that when tumors are inoculated with platelets, the ablation of P-selectin significantly reduced tumor growth compared to control platelets. Furthermore, in genetic models, as well as in chronic colitis-associated colorectal carcinogenesis, P-selectin ablated mice displayed a significant reduction in tumor number and size compared to control mice. Taken together, our data highlights the importance of platelets in the tumor microenvironment for intestinal tumorigenesis. These results support the hypothesis that a strategy aimed to inhibit platelets adhesion to tumor cells are able to block tumor growth and could represent a novel therapeutic approach to colon cancer treatment. Full article

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32 pages, 4143 KiB

Open AccessReview

Emerging Principles in the Transcriptional Control by YAP and TAZ

by Alejandro Lopez-Hernandez, Silvia Sberna and Stefano Campaner

Cancers 2021, 13(16), 4242; https://doi.org/10.3390/cancers13164242 - 23 Aug 2021

Cited by 28 | Viewed by 5481

Abstract

Yes-associated protein (YAP) and TAZ are transcriptional cofactors that sit at the crossroad of several signaling pathways involved in cell growth and differentiation. As such, they play essential functions during embryonic development, regeneration, and, once deregulated, in cancer progression. In this review, we [...] Read more.

Yes-associated protein (YAP) and TAZ are transcriptional cofactors that sit at the crossroad of several signaling pathways involved in cell growth and differentiation. As such, they play essential functions during embryonic development, regeneration, and, once deregulated, in cancer progression. In this review, we will revise the current literature and provide an overview of how YAP/TAZ control transcription. We will focus on data concerning the modulation of the basal transcriptional machinery, their ability to epigenetically remodel the enhancer–promoter landscape, and the mechanisms used to integrate transcriptional cues from multiple pathways. This reveals how YAP/TAZ activation in cancer cells leads to extensive transcriptional control that spans several hallmarks of cancer. The definition of the molecular mechanism of transcriptional control and the identification of the pathways regulated by YAP/TAZ may provide therapeutic opportunities for the effective treatment of YAP/TAZ-driven tumors. Full article

(This article belongs to the Special Issue YAP (Yes-Associated Protein) in Cancer)

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YAP/TAZ orchestrate transcriptional control by interacting with other transcription factors (TFs). A schematic overview of the general mechanisms by which YAP/TAZ can integrate with other transcription factors in order to modulate complex transcriptional responses. (a) Regulation of YAP/TAZ targets by cis interactions with other TFs; (b) regulation of other TFs targets by YAP/TAZ; (c) regulation of YAZ/TAZ activity on their targets mediated only by protein–protein chromatin-associated complexes; (d) modulation of other TFs activity, on their respective targets, mediated only by protein–protein chromatin-associated complexes; (e) modulation based on non-nuclear protein–protein interaction. Please note that although DNA regulatory elements have been placed near the transcribed genes, it is implied that these modes of regulation apply to both promoters and enhancers. Created with BioRender.com. (<a href="https://help.biorender.com/en/articles/3619405-how-do-i-cite-biorender" target="_blank">https://help.biorender.com/en/articles/3619405-how-do-i-cite-biorender</a>, accessed on 23 July 2021). Full article ">Figure 2
Cancer cell programs controlled by YAP and TAZ. This figure summarizes the biological processes controlled by YAP and TAZ in cancer cells. For each program, key downstream genes/pathways are reported according to their documented role as effectors of the indicated biological program. For the sake of simplicity, genes are all represented as regulated by YAP/YAZ, but it is implied that in many cases, the expression of these genes depends on the integration with other transcription factors, as detailed in the text. Created with BioRender.com. (<a href="https://help.biorender.com/en/articles/3619405-how-do-i-cite-biorender" target="_blank">https://help.biorender.com/en/articles/3619405-how-do-i-cite-biorender</a>, accessed on 23 July 2021). Full article ">

18 pages, 5238 KiB

Open AccessArticle

Helicobacter pylori CagA Induces Cortactin Y-470 Phosphorylation-Dependent Gastric Epithelial Cell Scattering via Abl, Vav2 and Rac1 Activation

by Nicole Tegtmeyer, Aileen Harrer, Klemens Rottner and Steffen Backert

Cancers 2021, 13(16), 4241; https://doi.org/10.3390/cancers13164241 - 23 Aug 2021

Cited by 12 | Viewed by 2834

Abstract

The pathogen Helicobacter pylori is the first reported bacterial type-1 carcinogen playing a role in the development of human malignancies, including gastric adenocarcinoma. Cancer cell motility is an important process in this scenario, however, the molecular mechanisms are still not fully understood. Here, [...] Read more.

The pathogen Helicobacter pylori is the first reported bacterial type-1 carcinogen playing a role in the development of human malignancies, including gastric adenocarcinoma. Cancer cell motility is an important process in this scenario, however, the molecular mechanisms are still not fully understood. Here, we demonstrate that H. pylori subverts the actin-binding protein cortactin through its type-IV secretion system and injected oncoprotein CagA, e.g., by inducing tyrosine phosphorylation of cortactin at Y-470, which triggers gastric epithelial cell scattering and motility. During infection of AGS cells, cortactin was discovered to undergo tyrosine dephosphorylation at residues Y-421 and Y-486, which is mediated through inactivation of Src kinase. However, H. pylori also profoundly activates tyrosine kinase Abl, which simultaneously phosphorylates cortactin at Y-470. Phosphorylated cortactin interacts with the SH2-domain of Vav2, a guanine nucleotide exchange factor for the Rho-family of GTPases. The cortactin/Vav2 complex then stimulates a previously unrecognized activation cascade including the small GTPase Rac1, to effect actin rearrangements and cell scattering. We hypothesize that injected CagA targets cortactin to locally open the gastric epithelium in order to get access to certain nutrients. This may disturb the cellular barrier functions, likely contributing to the induction of cell motility, which is important in gastric cancer development. Full article

(This article belongs to the Special Issue Unravelling Gastric Cancer Pathobiology: From Correa Cascade to Patchwork Vision)

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Cortactin undergoes dephosphorylation at tyrosine residues Y-421 and Y-486, and phosphorylation at Y-470 during H. pylori infection. (A) Schematic representation of the cortactin domain structure. Three tyrosine phosphorylation sites in human cortactin are shown on top, their mouse counterparts on the bottom. (B) AGS cells were co-incubated with wt H. pylori or ΔcagA mutant for 6 h. Mock control and infected cells were harvested and separated into cytoplasmic and membrane fractions. The loading control blots for cortactin and integrin-β1 are shown. (C) Phosphorylation of cortactin at tyrosine residues 421, 470 and 486 was investigated with the indicated phosphotyrosine-specific antibodies. (D) Densitometric quantification of cortactin tyrosine phosphorylation bands of Western blots in panel C. Error bars represent +/− standard deviation (SD). The results are from three independent experiments. p-values of ≤0.001 (***) were considered as statistically significant. Full article ">Figure 2
Cortactin Y-470 is phosphorylated by activated Abl kinase and forms a physical complex with Vav2 and Rac1, associated with cell motility. (A) AGS cells were infected for 6 h with H. pylori in the presence or absence of the Abl-specific inhibitors imatinib and SKI-DV2-43. Cell lysates were probed with indicated antibodies, demonstrating the activated Abl phosphorylated cortactin at Y-470 (arrows). (B) Densitometric quantification of phospho-band intensities for Abl (Y-412) and cortactin (Y-470). (C) Phase contrast microscopy revealed that H. pylori induces cell scattering, which is abolished by the Abl inhibitor imatinib. 400× magnification, scale bars represent 10 µm (D) AGS cells were co-incubated with wt H. pylori or ΔcagA mutant for 6 h, followed by immunoprecipitation (IP) using cortactin antibodies. Resulting blots were probed with antibodies as indicated. The results show that cortactin phosphorylated at Y-470 interacts with Vav2 and Rac1 in a CagA-dependent manner. (E) Band intensities of Rac1 and Vav2 bound to phosphorylated cortactin were quantified using the Image Lab software version 6.1. Error bars represent +/− SD. The results are from three independent experiments. p-values of ≤0.001 (***) were considered as statistically significant. Full article ">Figure 3
Vav2 forms a physical complex with Rac1 and cortactin phosphorylated at Y-470. (A) AGS cells were infected for 6 h with wt H. pylori or ΔcagA mutant, followed by immunoprecipitation (IP) using Vav2 antibodies. The corresponding Western blots were probed with antibodies as indicated. The results suggest that Vav2 interacts with Rac1 and cortactin phosphorylated at Y-470 in a CagA-dependent fashion. (B) Band intensities of Rac1 and phosphorylated cortactin bound to precipitated Vav2 were quantified using the Image Lab Software (Bio-Rad). Error bars represent +/− SD. p-value of ≤0.001 (***) was considered as statistically significant. Full article ">Figure 4
Cortactin phosphorylation at Y-470 temporally correlating with Rac1 activation during H. pylori infection. (A) AGS cells were infected with H. pylori wt or ΔcagA mutant for different times, i.e., 60, 120 and 240 min, followed by probing with α-cortactin-PY-470 (top) or Rac1-GTP pulldown and α-Rac1 Western blot (middle). The α-Rac1 blot of total cell lysates served as loading control (bottom). (B) Quantification of band intensities on Western blots showing cortactin levels phosphorylated at Y-470 and relative Rac1-GTP activity. The results are from three independent experiments. p-values of ≤0.01 (**) and ≤0.001 (***) were considered as statistically significant. The results confirm that the induction of cortactin phosphorylation at Y-470 and activation of Rac1 display a temporal correlation. Full article ">Figure 5
Vav2 binds via its SH2 domain to cortactin phosphorylated at Y-470. (A) Schematic representation of the Vav2 domain structure.. (B) AGS cells were transfected with GFP-Vav2 wt and various GFP-Vav2 mutant constructs, as indicated, for 48 h, followed by infection with H. pylori for 6 h. Cell lysates were harvested and subjected to IP using α-GFP antibodies to precipitate GFP-Vav2. Similarly, presence of each construct in the IPs was confirmed by α-GFP antibody Western blot (top). This blot was then re-probed with α-cortactin antibody. (C) Densitometric quantification of cortactin band intensities bound to precipitated GFP-Vav2. (D) AGS cells were transfected with GFP-cortactin wt and various GFP-cortactin phospho-mutant constructs, as indicated, for 48 h in the presence or absence of HA-tagged Vav2 plasmid. Total cell lysates were probed with α-GFP antibodies showing similar amounts of GFP-cortactin proteins present in each lane (top). Parallel samples were subjected to IP using α-HA antibodies to precipitate HA-tagged Vav2 (middle). This blot was then re-probed with α-GFP antibodies to detect bound cortactin (bottom). (E) Densitometric quantification of cortactin band intensities bound to precipitated HA-Vav2. The results show that cortactin and Vav2 can bind to each other by a typical phosphotyrosine-SH2 domain interaction. Error bars represent +/− standard deviation (SD). The results are from three independent experiments. p-values of ≤0.05 (*), and ≤0.001 (***) were considered as statistically significant. n.s.: not significant. Full article ">Figure 6
Control blots for the knockdown of cortactin and Vav2 by siRNAs and quantification of Rac1-GTP levels in AGS cells infected with H. pylori. (A) AGS cells were grown, treated with siRNAs and then infected with H. pylori wt, as described in <a href="#cancers-13-04241-f007" class="html-fig">Figure 7</a>. The resulting cell lysates were probed with the indicated antibodies to demonstrate successful downregulation of cortactin and Vav2 expression, respectively, and equal protein loading in each lane. (B) A second set of samples, as shown in panel A, were subjected to Rac1-GTP pulldowns. The resulting α-Rac1 blot (bottom) was quantified by densitometric evaluation of the bands employing the luminescence imager. The sample showing the strongest Rac1 signal corresponds to 100% Rac1 activity in the respective blot. Inhibition of Rac1-GTP levels by knockdown of cortactin or Vav2 were quantified in three independent experiments. p-values of ≤0.001 (***) were considered to report on statistically significant differences. Full article ">Figure 7
Importance of cortactin, Vav2 and Rac1 expression as well as cortactin tyrosine phosphorylation for AGS cell migration during infection with H. pylori. (A) Confluent cell monolayers of AGS cells were transfected with siRNAs against cortactin, Vav2 and Rac1, scrambled siRNAs or Cortactin-Y466D, Cortactin-Y466F and vector control constructs. Then, cells were wounded using a pipette tip, followed by infection with H. pylori for 48 h (middle and bottom) or treatment with PBS buffer as control (top). All images at 100× magnification, scale bar represents 100 µm. (B) The areas following wound closure were measured after 48 h of infection. Error bars represent +/− standard deviation (SD). The results are from three independent experiments. p-values of ≤0.001 (***) were considered as statistically highly significant. (C) Proposed signal transduction cascade of injected CagA leading successively to activation of Abl kinase, phosphorylation of cortactin at Y-470, Vav2 binding, Rac1 GTPase activation and cell motility. Full article ">

17 pages, 921 KiB

Open AccessReview

The Role of Circular RNAs in Keratinocyte Carcinomas

by Thomas Meyer, Michael Sand, Lutz Schmitz and Eggert Stockfleth

Cancers 2021, 13(16), 4240; https://doi.org/10.3390/cancers13164240 - 23 Aug 2021

Cited by 3 | Viewed by 2842

Abstract

Keratinocyte carcinomas (KC) include basal cell carcinomas (BCC) and cutaneous squamous cell carcinomas (cSCC) and represents the most common cancer in Europe and North America. Both entities are characterized by a very high mutational burden, mainly UV signature mutations. Predominately mutated genes in [...] Read more.

Keratinocyte carcinomas (KC) include basal cell carcinomas (BCC) and cutaneous squamous cell carcinomas (cSCC) and represents the most common cancer in Europe and North America. Both entities are characterized by a very high mutational burden, mainly UV signature mutations. Predominately mutated genes in BCC belong to the sonic hedgehog pathway, whereas, in cSCC, TP53, CDKN2A, NOTCH1/2 and others are most frequently mutated. In addition, the dysregulation of factors associated with epithelial to mesenchymal transition (EMT) was shown in invasive cSCC. The expression of factors associated with tumorigenesis can be controlled in several ways and include non-coding RNA molecules, such as micro RNAs (miRNA) long noncoding RNAs (lncRNA) and circular RNAs (circRNA). To update findings on circRNA in KC, we reviewed 13 papers published since 2016, identified in a PubMed search. In both BCC and cSCC, numerous circRNAs were identified that were differently expressed compared to healthy skin. Some of them were shown to target miRNAs that are also dysregulated in KC. Moreover, some studies confirmed the biological functions of individual circRNAs involved in cancer development. Thus, circRNAs may be used as biomarkers of disease and disease progression and represent potential targets of new therapeutic approaches for KC. Full article

(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)

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10 pages, 821 KiB

Open AccessArticle

CD200 Baseline Serum Levels Predict Prognosis of Chronic Lymphocytic Leukemia

by Giovanni D’Arena, Candida Vitale, Marta Coscia, Daniela Lamorte, Giuseppe Pietrantuono, Francesca Perutelli, Fiorella D’Auria, Teodora Statuto, Luciana Valvano, Annamaria Tomasso, Valentina Griggio, Rebecca Jones, Giovanna Mansueto, Oreste Villani, Simona D’Agostino, Vito Viglioglia, Vincenzo De Feo, Fabrizio Calapai, Carmen Mannucci, Alessandro Sgambato, Dimitar G. Efremov and Luca Laurenti Show full author list Hide full author list

Cancers 2021, 13(16), 4239; https://doi.org/10.3390/cancers13164239 - 23 Aug 2021

Cited by 4 | Viewed by 2894

Abstract

Membrane-bound CD200 is overexpressed in chronic lymphocytic leukemia (CLL), and there is some evidence that its soluble ectodomain (sCD200) could also be involved in the pathophysiology and the disease. However, very little is known about sCD200’s prognostic significance. sCD200 was tested at diagnosis [...] Read more.

Membrane-bound CD200 is overexpressed in chronic lymphocytic leukemia (CLL), and there is some evidence that its soluble ectodomain (sCD200) could also be involved in the pathophysiology and the disease. However, very little is known about sCD200’s prognostic significance. sCD200 was tested at diagnosis in 272 patients with CLL and in 78 age- and sex-matched healthy subjects using a specific human CD200 (OX-2 membrane glycoprotein) ELISA kit. A significantly higher concentration of sCD200 was found in CLL patients compared to controls. In our cohort, sCD200 was significantly higher in patients who were older than 66 years, with Binet stage C, unmutated IgVH and unfavorable (del11q or del17p) FISH. Time-to-first treatment and overall survival were significantly shorter in patients with higher sCD200 concentration, using as a cut-off 1281 pg/mL, the median value for sCD200 concentration in the whole CLL cohort. However, the prognostic impact of sCD200 was not confirmed in multivariate analysis. Baseline sCD200 values appeared to have an impact on the response to chemotherapy or chemo-immunotherapy, but not to targeted agents. Collectively, our data show that sCD200 serum levels correlate with more aggressive clinical and biological features and are able to predict a worse prognosis. This work supports the relevant role of CD200 not only as a diagnostic tool but also as a prognostic indicator and a potential therapeutic target in CLL. Full article

(This article belongs to the Special Issue Therapeutic Targets in Chronic Lymphocytic Leukemia)

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14 pages, 3375 KiB

Open AccessArticle

Adipsin-Dependent Secretion of Hepatocyte Growth Factor Regulates the Adipocyte-Cancer Stem Cell Interaction

by Masahiro Mizuno, Behnoush Khaledian, Masao Maeda, Takanori Hayashi, Seiya Mizuno, Eiji Munetsuna, Takashi Watanabe, Seishi Kono, Seiji Okada, Motoshi Suzuki, Shintaro Takao, Hironobu Minami, Naoya Asai, Fumihiro Sugiyama, Satoru Takahashi and Yohei Shimono

Cancers 2021, 13(16), 4238; https://doi.org/10.3390/cancers13164238 - 23 Aug 2021

Cited by 11 | Viewed by 4271

Abstract

Adipose tissue is a component of the tumor microenvironment and is involved in tumor progression. We have previously shown that adipokine adipsin (CFD) functions as an enhancer of tumor proliferation and cancer stem cell (CSC) properties in breast cancers. We established the Cfd-knockout [...] Read more.

Adipose tissue is a component of the tumor microenvironment and is involved in tumor progression. We have previously shown that adipokine adipsin (CFD) functions as an enhancer of tumor proliferation and cancer stem cell (CSC) properties in breast cancers. We established the Cfd-knockout (KO) mice and the mammary adipose tissue-derived stem cells (mADSCs) from them. Cfd-KO in mADSCs significantly reduced their ability to enhance tumorsphere formation of breast cancer patient-derived xenograft (PDX) cells, which was restored by the addition of Cfd in the culture medium. Hepatocyte growth factor (HGF) was expressed and secreted from mADSCs in a Cfd-dependent manner. HGF rescued the reduced ability of Cfd-KO mADSCs to promote tumorsphere formation in vitro and tumor formation in vivo by breast cancer PDX cells. These results suggest that HGF is a downstream effector of Cfd in mADSCs that enhances the CSC properties in breast cancers. Full article

(This article belongs to the Special Issue From Progression to Metastasis of Solid Cancer)

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16 pages, 775 KiB

Open AccessReview

Epigenetic Changes Affecting the Development of Hepatocellular Carcinoma

by Ewa Wolinska and Maciej Skrzypczak

Cancers 2021, 13(16), 4237; https://doi.org/10.3390/cancers13164237 - 23 Aug 2021

Cited by 15 | Viewed by 3987

Abstract

Hepatocellular carcinoma (HCC) remains a serious oncologic issue with still a dismal prognosis. So far, no key molecular mechanism that underlies its pathogenesis has been identified. Recently, by specific molecular approaches, many genetic and epigenetic changes arising during HCC pathogenesis were detected. Epigenetic [...] Read more.

Hepatocellular carcinoma (HCC) remains a serious oncologic issue with still a dismal prognosis. So far, no key molecular mechanism that underlies its pathogenesis has been identified. Recently, by specific molecular approaches, many genetic and epigenetic changes arising during HCC pathogenesis were detected. Epigenetic studies revealed modified methylation patterns in HCC tumors, dysfunction of enzymes engaged in the DNA methylation process, and a set of histone modifications that influence gene expression. HCC cells are also influenced by the disrupted function of non-coding RNAs, such as micro RNAs and long non-coding RNAs. Moreover, a role of liver cancer stem cells in HCC development is becoming evident. The reversibility of epigenetic changes offers the possibility of influencing them and regulating their undesirable effects. All these data can be used not only to identify new therapeutic targets but also to predict treatment response. This review focuses on epigenetic changes in hepatocellular carcinoma and their possible implications in HCC therapy. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Hepatocarcinogenesis)

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16 pages, 483 KiB

Open AccessStudy Protocol

Prospective Evaluation of Radiotherapy-Induced Immunologic and Genetic Effects in Colorectal Cancer Oligo-Metastatic Patients with Lung-Limited Disease: The PRELUDE-1 Study

by Alessandro Ottaiano, Angela Petito, Mariachiara Santorsola, Valerio Gigantino, Maurizio Capuozzo, Daniela Fontanella, Rossella Di Franco, Valentina Borzillo, Sergio Buonopane, Vincenzo Ravo, Esmeralda Scipilliti, Giuseppe Totaro, Marcello Serra, Gianluca Ametrano, Roberta Penta, Fabiana Tatangelo, Giosuè Scognamiglio, Annabella Di Mauro, Maurizio Di Bonito, Maria Napolitano, Stefania Scala, Giuseppina Rea, Sara Santagata, Angela Lombardi, Anna Grimaldi, Carlo Caputo, Anna Crispo, Egidio Celentano, Gianfranco De Feo, Luisa Circelli, Giovanni Savarese, Raffaella Ruggiero, Francesco Perri, Vincenza Granata, Gerardo Botti, Michele Caraglia, Guglielmo Nasti and Paolo Muto Show full author list Hide full author list

Cancers 2021, 13(16), 4236; https://doi.org/10.3390/cancers13164236 - 23 Aug 2021

Cited by 8 | Viewed by 2961

Abstract

Background: in recent years, the management of advanced colorectal cancer (CRC) has been greatly improved with integrated strategies including stereotactic radiation therapy (SRT). The administration of SRT has been demonstrated, particularly in oligo-metastatic (om) CRC, to be a safe and effective option. Interestingly, [...] Read more.

Background: in recent years, the management of advanced colorectal cancer (CRC) has been greatly improved with integrated strategies including stereotactic radiation therapy (SRT). The administration of SRT has been demonstrated, particularly in oligo-metastatic (om) CRC, to be a safe and effective option. Interestingly, it has been demonstrated that SRT can induce regression of tumors in non-irradiated regions (“abscopal effect”) through stimulation of anti-tumor immune effects (“radiation-induced immunity”). We have recently shown that lung-limited omCRC is characterized by regression of tumor clones bearing specific key driver gene mutations. Aims: to assess the genetic evolution on tumor cancer cells induced by SRT in lung-limited omCRC. Secondary objectives included descriptions of the abscopal effect, responses’ duration, toxicity, and progression-free survival. A translational research will be performed to evaluate tumor genetic evolution (through liquid biopsies and Next Generation Sequencing), HLA class I repertoire, peripheral immune cells, and cytokine dynamics. Methods: PRELUDE-1 is a prospective translational study. SRT will be administered only to the largest nodule (with a maximum diameter ≤ 25 mm) in omCRC with two or three radiologically evident lesions. The sample size is based on the innovative hypothesis that radiation-induced immunity could induce regression of tumor clones bearing KRAS oncogene mutations. According to the binomial test, considering the frequency of KRAS mutations and assuming a probability of mutant KRAS→wild type KRAS of p₀ = 0.0077, with α = 0.05 and 1-β = 0.60, the final sample size is 25 patients. Full article

(This article belongs to the Special Issue Clinical Perspective and Translational Oncology of Liquid Biopsy)

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18 pages, 6362 KiB

Open AccessReview

Challenges and Future Perspectives of Immunotherapy in Pancreatic Cancer

by Anna Maxi Wandmacher, Anne Letsch and Susanne Sebens

Cancers 2021, 13(16), 4235; https://doi.org/10.3390/cancers13164235 - 23 Aug 2021

Cited by 19 | Viewed by 4368

Abstract

To date, extensive efforts to harness immunotherapeutic strategies for the treatment of pancreatic ductal adenocarcinoma (PDAC) have yielded disappointing results in clinical trials. These strategies mainly focused on cancer vaccines and immune checkpoint inhibitors alone or in combination with chemotherapeutic or targeted agents. [...] Read more.

To date, extensive efforts to harness immunotherapeutic strategies for the treatment of pancreatic ductal adenocarcinoma (PDAC) have yielded disappointing results in clinical trials. These strategies mainly focused on cancer vaccines and immune checkpoint inhibitors alone or in combination with chemotherapeutic or targeted agents. However, the growing preclinical and clinical data sets from these efforts have established valuable insights into the immunological characteristics of PDAC biology. Most notable are the immunosuppressive role of the tumour microenvironment (TME) and PDAC’s characteristically poor immunogenicity resulting from tumour intrinsic features. Moreover, PDAC tumour heterogeneity has been increasingly well characterized and may additionally limit a “one-fits-all” immunotherapeutic strategy. In this review, we first outline mechanisms of immunosuppression and immune evasion in PDAC. Secondly, we summarize recently published data on preclinical and clinical efforts to establish immunotherapeutic strategies for the treatment of PDAC including diverse combinatorial treatment approaches aiming at overcoming this resistance towards immunotherapeutic strategies. Particularly, these combinatorial treatment approaches seek to concomitantly increase PDAC antigenicity, boost PDAC directed T-cell responses, and impair the immunosuppressive character of the TME in order to allow immunotherapeutic agents to unleash their full potential. Eventually, the thorough understanding of the currently available data on immunotherapeutic treatment strategies of PDAC will enable researchers and clinicians to develop improved treatment regimens and to design innovative clinical trials to overcome the pronounced immunosuppression of PDAC. Full article

(This article belongs to the Special Issue Inflammation and the Immunosuppressive Pancreatic Cancer Microenvironment)

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18 pages, 27519 KiB

Open AccessArticle

Quantitative Tyrosine Phosphoproteome Profiling of AXL Receptor Tyrosine Kinase Signaling Network

by Xinyan Wu, Li Wang, Nicole A. Pearson, Santosh Renuse, Ran Cheng, Ye Liang, Dong-Gi Mun, Anil K. Madugundu, Yaoyu Xu, Parkash S. Gill and Akhilesh Pandey

Cancers 2021, 13(16), 4234; https://doi.org/10.3390/cancers13164234 - 23 Aug 2021

Cited by 5 | Viewed by 4405

Abstract

Overexpression and amplification of AXL receptor tyrosine kinase (RTK) has been found in several hematologic and solid malignancies. Activation of AXL can enhance tumor-promoting processes such as cancer cell proliferation, migration, invasion and survival. Despite the important role of AXL in cancer development, [...] Read more.

Overexpression and amplification of AXL receptor tyrosine kinase (RTK) has been found in several hematologic and solid malignancies. Activation of AXL can enhance tumor-promoting processes such as cancer cell proliferation, migration, invasion and survival. Despite the important role of AXL in cancer development, a deep and quantitative mapping of its temporal dynamic signaling transduction has not yet been reported. Here, we used a TMT labeling-based quantitative proteomics approach to characterize the temporal dynamics of the phosphotyrosine proteome induced by AXL activation. We identified >1100 phosphotyrosine sites and observed a widespread upregulation of tyrosine phosphorylation induced by GAS6 stimulation. We also detected several tyrosine sites whose phosphorylation levels were reduced upon AXL activation. Gene set enrichment-based pathway analysis indicated the activation of several cancer-promoting and cell migration/invasion-related signaling pathways, including RAS, EGFR, focal adhesion, VEGFR and cytoskeletal rearrangement pathways. We also observed a rapid induction of phosphorylation of protein tyrosine phosphatases, including PTPN11 and PTPRA, upon GAS6 stimulation. The novel molecules downstream of AXL identified in this study along with the detailed global quantitative map elucidating the temporal dynamics of AXL activation should not only help understand the oncogenic role of AXL, but also aid in developing therapeutic options to effectively target AXL. Full article

(This article belongs to the Special Issue Proteomics in Cancer)

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Figure 1
AXL expression and GAS6 stimulation in breast cancer cell lines. (A). Scatter plot showing AXL expression levels based on RNA-Seq data and its protein expression based on proteomics data (both from CCLA) as indicated. The color of the dots represents the subtype of breast cancer cell lines: TNBC (red), luminal A (green), luminal B (blue) and HER2+ (yellow). (B). Western blot results showing AXL expression level in a panel of nine TNBC cell lines. Beta-actin serves as a loading control. (C). MDA-MB-231 cells were treated with the indicated concentration (ng/mL) of GAS6 for 10 min. Phosphorylation levels of AXL and AKT and their total protein expression levels were examined by Western blot analysis. (D). MDA-MB-231 cells were treated with 400 ng/mL GAS6 for different time points as indicated. Phosphorylation levels of AXL and AKT and their total protein expression levels were examined by Western blot analysis as shown. (The original western blot images were included in <a href="#app1-cancers-13-04234" class="html-app">Figure S1</a>). Full article ">Figure 2
A schematic depicting the strategy used for temporal quantitative phosphotyrosine proteomic profiling of GAS6-treated MDA-MB-231 cells. All experiments were performed in triplicate. Cells were serum starved for 18 h and treated with 400 ng/mL GAS6 for 5 min, 10 min, 1 h or 5 h. After the GAS6 treatment, cells were harvested and lysed in 8 M urea buffer, followed by trypsin digestion and desalting. Tyrosine phosphorylated peptides were enriched with anti-pTyr antibody (pY1000). Enriched peptides were labeled with the TMTpro kit and analyzed by Orbitrap Eclipse. Full article ">Figure 3
Dynamic regulation of tyrosine phosphorylation induced by the activation of GAS6/AXL signaling cascades. (A). Plot showing the number of upregulated and downregulated tyrosine phosphorylation sites at the indicated time points. (B). Venn diagram showing the overlap of regulated tyrosine phosphorylation sites at different times. (C). Fuzzy C-means clustering showing clusters of phosphotyrosine sites with dynamic regulation patterns. (D). A heatmap visualizing the hierarchical clustering of phosphotyrosine sites regulated by AXL. Each column represents the intensity at the indicated time points after GAS6 treatment. Full article ">Figure 4
Signaling pathways activated by AXL. (A,B). Enriched signaling pathways for proteins with upregulated (A) or downregulated (B) tyrosine phosphorylation. Pathway analysis was performed using DAVID [<a href="#B29-cancers-13-04234" class="html-bibr">29</a>] based on the KEGG [<a href="#B42-cancers-13-04234" class="html-bibr">42</a>] pathway database and replotted using an R package. The size of the circle represents the number of proteins identified in each pathway. The color scheme represents −log10(p-value) as indicated. (C). Bubble plot displaying the alterations in tyrosine phosphorylation of protein tyrosine phosphatases (PTP), serine/threonine kinases, non-receptor tyrosine kinases (NRTK) and receptor tyrosine kinases (RTK). The color scheme represents the fold-changes upon GAS6 treatment of individual tyrosine phosphosites at the indicated time points. The size of the circle represents −log10(p-value) compared to untreated MDA-MB-231 cells. Full article ">Figure 5
Site-specific regulation of tyrosine kinases and protein tyrosine phosphatases by AXL activation. (A). Schematic representation of receptor tyrosine kinases (top left panel), non-receptor tyrosine kinases (top right panel) and protein tyrosine phosphatases (middle panel) along with phosphorylation sites regulated by AXL activation and the time course. Black bars with red filled circles at the end denote phosphorylation modification. The embedded column plots depict the regulation pattern of individual phosphotyrosine sites. The domain structures of the molecules are shown with the key in the panel at the bottom. (B). Multiple sequences alignment of the amino acid sequences of the tyrosine kinase domain of the RTKs and NTRKs regulated by Axl. The box indicates the activation loop of the kinase domain. Regulated phosphotyrosine residues identified in this study were highlighted in pink. Full article ">Figure 6
Western blot-based validation of selected molecules in the Axl signaling pathway. (A). MDA-MB-231 cells were treated with 400 ng/mL GAS6 for the indicated duration. Cell lysates were analyzed with Western blot analysis using phospho-specific antibodies against EPHA2 (pY772), AXL (pY703/pY702), PZR (pY263), SHP2/PTPN11 (pY580), PTPRA (pY798) and CDK1 (pY15) and antibodies against the corresponding protein as indicated. β-actin served as a loading control. The arrows indicate the three isoforms of PZR protein. (B). Western blot analysis to confirm the dynamic regulation of phosphorylation of the indicated proteins in HCC1395 cells treated with 400 ng/mL GAS6 for different time courses (as indicated). (C). MDA-MB-231 cells were pretreated with 2 µM R428 prior to GAS6 stimulation for 5 or 10 min, respectively. Protein phosphorylation levels were detected by indicated phospho-specific antibodies. (The original western blot images were included in <a href="#app1-cancers-13-04234" class="html-app">Figure S1</a>). Full article ">

27 pages, 6608 KiB

Open AccessFeature PaperReview

Tumor Microenvironment in Breast Cancer—Updates on Therapeutic Implications and Pathologic Assessment

by Joshua J. Li, Julia Y. Tsang and Gary M. Tse

Cancers 2021, 13(16), 4233; https://doi.org/10.3390/cancers13164233 - 23 Aug 2021

Cited by 96 | Viewed by 7464

Abstract

The tumor microenvironment (TME) in breast cancer comprises local factors, cancer cells, immune cells and stromal cells of the local and distant tissues. The interaction between cancer cells and their microenvironment plays important roles in tumor proliferation, propagation and response to therapies. There [...] Read more.

The tumor microenvironment (TME) in breast cancer comprises local factors, cancer cells, immune cells and stromal cells of the local and distant tissues. The interaction between cancer cells and their microenvironment plays important roles in tumor proliferation, propagation and response to therapies. There is increasing research in exploring and manipulating the non-cancerous components of the TME for breast cancer treatment. As the TME is now increasingly recognized as a treatment target, its pathologic assessment has become a critical component of breast cancer management. The latest WHO classification of tumors of the breast listed stromal response pattern/fibrotic focus as a prognostic factor and includes recommendations on the assessment of tumor infiltrating lymphocytes and PD-1/PD-L1 expression, with therapeutic implications. This review dissects the TME of breast cancer, describes pathologic assessment relevant for prognostication and treatment decision, and details therapeutic options that interacts with and/or exploits the TME in breast cancer. Full article

(This article belongs to the Special Issue Radiotherapy and Chemotherapy for Cancers)

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Effects of (a) Radiotherapy and (b) Chemotherapy on the Breast Cancer Tumor Microenvironment. Full article ">Figure 1 Cont.
Effects of (a) Radiotherapy and (b) Chemotherapy on the Breast Cancer Tumor Microenvironment. Full article ">Figure 2
Tumor infiltrating lymphocytes on H&E sections. (a) Breast cancer with dense stromal infiltrating lymphocytes, H&E, 200× magnification; (b) Breast cancer with sparse lymphocytic infiltrates, H&E, 200×. Full article ">Figure 3
Fibrotic Foci on H&E Sections. (a) H&E, 20×; (b) H&E, 100×. Full article ">Figure 4
Immunohistochemistry for immune cells in the tumor microenvironment. (a) CD8 stain highlights cytotoxic T-cells among lymphocytes, CD8, 200×; (b) CD68 highlights tumor associated macrophages which are difficult to identify by H&E, CD68, 200×. Full article ">Figure 5
PD-L1 Immunohistochemistry. (a) Example of negative PD-L1 expression in tumor and immune cells, Ventana SP142, 200×; (b) Positive PD-L1 staining in tumor and immune cells, Ventana SP142, 200×; (c) Positive staining in immune cells only, Ventana SP142, 400×. Full article ">Figure 6
CD31 stain for assessment of microvessel density, CD31, 200×. Full article ">

12 pages, 1095 KiB

Open AccessArticle

Exploration of Novel Prognostic Markers in Grade 3 Neuroendocrine Neoplasia

by Rebecca Abdelmalak, Mark P. Lythgoe, Joanne Evans, Michael Flynn, Justin Waters, Andy Webb, David J. Pinato and Rohini Sharma

Cancers 2021, 13(16), 4232; https://doi.org/10.3390/cancers13164232 - 23 Aug 2021

Cited by 8 | Viewed by 2029

Abstract

Background: High-grade neuroendocrine tumours and carcinomas (NET/NECs) behave aggressively, typically presenting at an advanced stage. Prognosis is poor, with median survival between 5 and 34 months. The mainstay of treatment is palliative systemic therapy. However, therapy carries a risk of toxicity, which can [...] Read more.

Background: High-grade neuroendocrine tumours and carcinomas (NET/NECs) behave aggressively, typically presenting at an advanced stage. Prognosis is poor, with median survival between 5 and 34 months. The mainstay of treatment is palliative systemic therapy. However, therapy carries a risk of toxicity, which can reduce quality of life. Therefore, accurate prognostic scores for risk stratification of patients with high-grade NET/NECs are needed to help guide patient management to decide whether active treatment is likely to improve overall survival (OS). We aimed to compare the prognostic ability of published prognostic scores to predict OS in a cohort of patients with high-grade NET/NECs of any primary site. Methods: Treatment, biochemical and clinicopathological data were collected retrospectively from 77 patients with high-grade NET/NECs across three hospitals between 2016 and 2020. Variables including performance status (PS), Ki-67, age at diagnosis, previous treatment and presence of liver metastases were recorded. Pre-treatment neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, modified Glasgow prognostic score (mGPS), and gastrointestinal neuroendocrine carcinoma (GI-NEC) score were derived. Univariable and multivariable survival analyses were used to assess prognostic ability. Results: The median age of the cohort was 63 years (range: 31–85); 53% of subjects were female. Grade 3 NETs (G3-NETs) were identified in 32 patients and NECs in 45 patients. The median OS was 13.45 months (range: 0.87–65.37) with no difference observed between G3-NETs and NECs. Univariable analysis revealed that NLR (n = 72, p = 0.049), mGPS (n = 56, p = 0.003), GI-NEC score (n = 27, p = 0.0007) and Ki-67 (n = 66, p = 0.007) were significantly associated with OS. Multivariable analysis confirmed that elevated mGPS (p = 0.046), GI-NEC score (p = 0.036), and Ki-67 (p = 0.02) were independently prognostic for reduced OS across the entire cohort. mGPS was identified as an independent prognostic factor in G3-NETs. Independent predictors of OS in NECs were PS and Ki-67. Conclusions: mGPS, PS and Ki-67 are independent prognostic markers in high-grade NET/NEC patients. Our study supports the use of these prognostic scores for risk stratification of patients with high grade cancers and as useful tools to guide treatment decisions. Full article

(This article belongs to the Special Issue Advanced Neuroendocrine Tumors)

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16 pages, 3924 KiB

Open AccessArticle

MET Mutation Is a Potential Therapeutic Target for Advanced Endometrial Cancer

by Yu-Min Yeh, Pei-Ying Wu, Peng-Chan Lin, Pei-Fang Su, Ya-Ting Hsu, Keng-Fu Hsu and Meng-Ru Shen

Cancers 2021, 13(16), 4231; https://doi.org/10.3390/cancers13164231 - 23 Aug 2021

Cited by 4 | Viewed by 3022

Abstract

An optimal therapeutic regimen for endometrial cancer with extra-uterine metastasis is unavailable. This study aims to improve our understanding of the genomic landscape of advanced endometrial cancer and identify potential therapeutic targets. The clinical and genomic profiles of 81 patients with stage III [...] Read more.

An optimal therapeutic regimen for endometrial cancer with extra-uterine metastasis is unavailable. This study aims to improve our understanding of the genomic landscape of advanced endometrial cancer and identify potential therapeutic targets. The clinical and genomic profiles of 81 patients with stage III or IV endometrial cancer were integrated. To identify genomic aberrations associated with clinical outcomes, Cox proportional hazard regression was used. The impacts of the genomic aberrations were validated in vitro and in vivo. The mutation status of MET, U2AF1, BCL9, PPP2R1A, IDH2, CBL, BTK, and CHEK2 were positively correlated with poor clinical outcomes. MET mutations occurred in 30% of the patients who presented with poor overall survival (hazard ratio, 2.606; 95% confidence interval, 1.167~5.819; adjusted p-value, 0.067). Concurrent MET and KRAS mutations presented with the worst outcomes. MET mutations in hepatocyte growth factor (HGF)-binding (58.1%) or kinase (16.2%) domains resulted in differential HGF-induced c-MET phosphorylation. Different types of MET mutations differentially affected tumor growth and displayed different sensitivities to cisplatin and tyrosine kinase inhibitors. MET N375S mutation is a germline variant that causes chemoresistance to cisplatin, with a high incidence in Eastern Asia. This study highlights the ethnic differences in the biology of the disease, which can influence treatment recommendations and the genome-guided clinical trials of advanced endometrial cancer. Full article

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Impact of MET mutation and concurrent genetic mutations on the clinical outcome of advanced endometrial cancer. (A) Kaplan–Meier curves for overall survival (OS) in patients with and without MET mutation compared using the log-rank test. (B–D) Kaplan–Meier curves for OS were analyzed between the MET wild-type and MET mutant patients with or without concurrent PIK3R1 (B), PIK3CA mutation (C), and KRAS (D). Full article ">Figure 2
Differential effects of various MET mutations on c-MET phosphorylation and cellular functions. (A) The structure of c-MET (left) and distribution of MET mutations (right). Sema, semaphoring domain; PSI, plexin–semaphorin–integrin domain; IPT, immunoglobulin–plexin–transcription domain. (B) Representative images and grading of c-MET expression in endometrial cancer. The expression of c-MET was scored as grade 1–3, according to the percentage of the positively-stained tumor cells and the intensity of the staining. (C) Time course of c-MET phosphorylation in response to HGF (50 ng/mL) stimulation. Cell lysates from various clones of the endometrial cancer RL95-2 cells were immunoblotted with anti-c-MET, anti-phospho-c-MET, and anti-α-tubulin antibodies (upper). The expression levels were quantified, and the ratios of phosphor-c-MET to total c-MET are shown (bottom). (D) Cell proliferation, invasion, and migration. (E) Assays using various clones of the RL95-2 cells. Each value represents the mean ± standard error of mean (SEM) from at least three experiments. *, p < 0.05; **, p < 0.01. Full article ">Figure 3
Antitumor effects of cisplatin and tyrosine kinase inhibitors in endometrial cancer xenografts harboring different MET mutations. 1 × 106 RL95-2 cells carrying wild-type or mutant MET, including N375S, G1085R, and G1087E, were injected into the posterior flank of SCID mice subcutaneously. The tumors were allowed to grow and were treated by observation only (A,B), cisplatin (1 mg/kg) twice a week (C,D), crizotinib (25 mg/kg) by oral gavage twice a week (E,F), or SU11274 (6 mg/kg) twice a week (G,H) (n = 5 in each treatment group). Tumor size and body weight were measured twice a week. Data are presented as the mean tumor size ± SEM. *, p < 0.05; **, p < 0.01; NS, non-significance. Full article ">Figure 4
The clinical impact, distribution, and frequency of the germline MET N375S variant. (A) OS of advanced endometrial cancer patients with and without the MET N375S variant. (B) The distribution and frequency of MET variants in 35 paired normal and tumor tissues. Whole-genome sequencing was used to analyze DNA extracted from blood samples or adjacent non-tumor specimens to determine germline MET variants. (C) The distribution and frequency of germline MET variants in cancer patients and the normal Taiwan population. The database from the Taiwan Biobank, which contained germline whole-genome sequencing data of 499 normal Taiwanese individuals, was used to compare the distribution and frequency of germline MET variants in the NCKUH cohort and the normal Taiwan population. (D) The alternative allele frequency of MET c.1124 (N375S) in the different ethnic groups. The frequency of the variant allele in MET c.1124 was compared among the NCKUH cohort, the normal Taiwanese population, and different ethnic groups enrolled in the 1000 Genomes Project. Full article ">

10 pages, 420 KiB

Open AccessArticle

Concordance of Child Self-Reported and Parent Proxy-Reported Posttraumatic Growth in Childhood Cancer Survivors

by Veronika Koutná, Marek Blatný and Martin Jelínek

Cancers 2021, 13(16), 4230; https://doi.org/10.3390/cancers13164230 - 23 Aug 2021

Cited by 5 | Viewed by 2864

Abstract

This article aimed to analyze concordance of parent- and child-reported child posttraumatic growth (PTG) following pediatric cancer, the influence of the parents’ own level of PTG on the level of concordance and the influence of the parents’ and the child’s own level of [...] Read more.

This article aimed to analyze concordance of parent- and child-reported child posttraumatic growth (PTG) following pediatric cancer, the influence of the parents’ own level of PTG on the level of concordance and the influence of the parents’ and the child’s own level of PTG on the parents’ proxy reports of PTG in the child. The sample included 127 parent–child dyads. The children provided self-reports of PTG and the parents provided reports of their own as well as the child’s PTG. Overall, the results showed poor parent–child agreement on the child PTG, with the parents proxy-reporting higher levels of PTG than the children. The parents’ proxy reports of the child PTG were the most accurate at the lowest levels of the parents’ own level of PTG. The parents’ own level of PTG was a stronger predictor of the parents’ proxy reports than the child self-reported PTG. The results suggest that parents are not very accurate reporters of PTG in the child; therefore, their reports should be completed with child self-reports whenever possible. Full article

(This article belongs to the Special Issue Recent Advances in Pediatric, Adolescent and Young Adult (AYA) Psycho-Oncology)

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27 pages, 2898 KiB

Open AccessReview

Recent Advances in the Treatment of Bone Metastases and Primary Bone Tumors: An Up-to-Date Review

by Adrian Emilian Bădilă, Dragoș Mihai Rădulescu, Adelina-Gabriela Niculescu, Alexandru Mihai Grumezescu, Marius Rădulescu and Adrian Radu Rădulescu

Cancers 2021, 13(16), 4229; https://doi.org/10.3390/cancers13164229 - 23 Aug 2021

Cited by 44 | Viewed by 13577

Abstract

In the last decades, the treatment of primary and secondary bone tumors has faced a slow-down in its development, being mainly based on chemotherapy, radiotherapy, and surgical interventions. However, these conventional therapeutic strategies present a series of disadvantages (e.g., multidrug resistance, tumor recurrence, [...] Read more.

In the last decades, the treatment of primary and secondary bone tumors has faced a slow-down in its development, being mainly based on chemotherapy, radiotherapy, and surgical interventions. However, these conventional therapeutic strategies present a series of disadvantages (e.g., multidrug resistance, tumor recurrence, severe side effects, formation of large bone defects), which limit their application and efficacy. In recent years, these procedures were combined with several adjuvant therapies, with different degrees of success. To overcome the drawbacks of current therapies and improve treatment outcomes, other strategies started being investigated, like carrier-mediated drug delivery, bone substitutes for repairing bone defects, and multifunctional scaffolds with bone tissue regeneration and antitumor properties. Thus, this paper aims to present the types of bone tumors and their current treatment approaches, further focusing on the recent advances in new therapeutic alternatives. Full article

(This article belongs to the Special Issue Diagnosis and Treatment for Bone Tumor and Sarcoma)

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10 pages, 1163 KiB

Open AccessArticle

Prognostic Role of Pre-Treatment [¹⁸F]FDG PET/CT in Patients with Anaplastic Thyroid Cancer

by Hyun Jeong Kim, Hang-Seok Chang and Young Hoon Ryu

Cancers 2021, 13(16), 4228; https://doi.org/10.3390/cancers13164228 - 23 Aug 2021

Cited by 8 | Viewed by 3123

Abstract

Anaplastic thyroid carcinoma (ATC) is a rare but highly lethal disease. Therefore, its diagnosis at an early stage and a rapid and accurate establishment of a proper treatment strategy is warranted. Tumor glycolysis assessed by ¹⁸fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography [...] Read more.

Anaplastic thyroid carcinoma (ATC) is a rare but highly lethal disease. Therefore, its diagnosis at an early stage and a rapid and accurate establishment of a proper treatment strategy is warranted. Tumor glycolysis assessed by ¹⁸fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography (PET)/computed tomography (CT) is predictive of many cancers despite its limited proven applicability to ATC. We investigated the prognostic capability of [¹⁸F]FDG PET/CT in patients with ATC. Forty patients with ATC were subjected to [¹⁸F]FDG PET/CT for pre-treatment evaluation. The tumor size and stage, overall survival (OS), and PET parameters, including the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were analyzed. The 1-year OS rate was 17.5% with a mean life expectancy of 7.1 months. Distant metastasis was detected solely using PET/CT in 37.5% of cases. High SUVmax, MTV, and TLG were significantly associated with poor prognosis (p < 0.001, p = 0.002, and p < 0.001, respectively). A significant difference (p < 0.001) was observed in OS between patients with a high and low tumor SUVmax. Glucose metabolism assessed by [¹⁸F]FDG PET/CT was significantly associated with the OS of patients with ATC. PET-derived parameters such as SUVmax, MTV, and TLG are useful prognostic biomarkers for ATC. Full article

(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)

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17 pages, 1831 KiB

Open AccessArticle

Casein Kinase 1D Encodes a Novel Drug Target in Hedgehog—GLI-Driven Cancers and Tumor-Initiating Cells Resistant to SMO Inhibition

by Elisabeth Peer, Sophie Karoline Aichberger, Filip Vilotic, Wolfgang Gruber, Thomas Parigger, Sandra Grund-Gröschke, Dominik Patrick Elmer, Florian Rathje, Andrea Ramspacher, Mirko Zaja, Susanne Michel, Svetlana Hamm and Fritz Aberger

Cancers 2021, 13(16), 4227; https://doi.org/10.3390/cancers13164227 - 23 Aug 2021

Cited by 8 | Viewed by 3775

Abstract

(1) Background: Aberrant activation of the hedgehog (HH)—GLI pathway in stem-like tumor-initiating cells (TIC) is a frequent oncogenic driver signal in various human malignancies. Remarkable efficacy of anti-HH therapeutics led to the approval of HH inhibitors targeting the key pathway effector smoothened (SMO) [...] Read more.

(1) Background: Aberrant activation of the hedgehog (HH)—GLI pathway in stem-like tumor-initiating cells (TIC) is a frequent oncogenic driver signal in various human malignancies. Remarkable efficacy of anti-HH therapeutics led to the approval of HH inhibitors targeting the key pathway effector smoothened (SMO) in basal cell carcinoma and acute myeloid leukemia. However, frequent development of drug resistance and severe adverse effects of SMO inhibitors pose major challenges that require alternative treatment strategies targeting HH—GLI in TIC downstream of SMO. We therefore investigated members of the casein kinase 1 (CSNK1) family as novel drug targets in HH—GLI-driven malignancies. (2) Methods: We genetically and pharmacologically inhibited CSNK1D in HH-dependent cancer cells displaying either sensitivity or resistance to SMO inhibitors. To address the role of CSNK1D in oncogenic HH signaling and tumor growth and initiation, we quantitatively analyzed HH target gene expression, performed genetic and chemical perturbations of CSNK1D activity, and monitored the oncogenic transformation of TIC in vitro and in vivo using 3D clonogenic tumor spheroid assays and xenograft models. (3) Results: We show that CSNK1D plays a critical role in controlling oncogenic GLI activity downstream of SMO. We provide evidence that inhibition of CSNK1D interferes with oncogenic HH signaling in both SMO inhibitor-sensitive and -resistant tumor settings. Furthermore, genetic and pharmacologic perturbation of CSNK1D decreases the clonogenic growth of GLI-dependent TIC in vitro and in vivo. (4) Conclusions: Pharmacologic targeting of CSNK1D represents a novel therapeutic approach for the treatment of both SMO inhibitor-sensitive and -resistant tumors. Full article

(This article belongs to the Special Issue Stemness and Differentiation in Cancer)

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Graphical abstract

Graphical abstract
Full article ">Figure 1
RNAi-mediated inhibition of CSNK1D interferes with canonical oncogenic HH—GLI signaling. (A) Simplified schematic illustration of the canonical HH—GLI signaling pathway with pathway activators in green and inhibitors in red. PTCH and SUFU inactivate the pathway, while it is turned on by the central pathway activator SMO causing activation of the GLI transcription factor. Pharmacologically, the SMO agonist SAG activates the pathway, while it is inhibited by the SMO inhibitor vismodegib. (B) Representative Western blot analysis of GLI1 and CSNK1D in Daoy medulloblastoma cells. Cells were lentivirally transduced with shCSNK1D or control shRNA (shCtrl) and treated with or without SAG [100 nM]. Relative quantification of Western blot bands was conducted via densitometric image analysis using Image Lab 5.0 software (Bio-Rad, Vienna, Austria). Relative protein levels normalized to the loading control tERK and to the shCtrl + SAG sample are shown above each protein band. (C) qPCR analysis of GLI1 and HHIP mRNA levels of Daoy cells treated as described in (B) (n = 3). Student’s t test was used for statistical analysis (** p < 0.01). Full article ">Figure 2
RNAi-mediated inhibition of CSNK1D interferes with oncogenic HH—GLI signaling in SMOi resistant Ewing sarcoma cells. (A) Simplified schematic illustration of non-canonical, SMO-independent HH—GLI signaling in Ewing sarcoma with EWS–FLI1-driven transcription of GLI1. (B) Representative Western blot analysis of GLI1 in A673 cells treated with vismodegib [1 μM] or HPI-1 [20 μM]. (C) Representative Western blot analysis of GLI1 in A673 cells lentivirally transduced with shCSNK1D (#1, #2) or control shRNA (shCtrl). Relative quantification of Western blot bands was conducted via densitometric image analysis using Image Lab 5.0 software (Bio-Rad, Vienna, Austria). Relative protein levels normalized to the loading control tERK and to the Ctrl sample are shown above each protein band. Full article ">Figure 3
Pharmacological targeting of CSNK1D inhibits SMO-dependent GLI activation. (A) mRNA expression levels of GLI1 were analyzed by qPCR and expressed as percentage relative to the control sample (n = 3). (B) Representative Western blot analysis of GLI1 protein levels in Daoy cells treated with SAG [100 nM] and increasing concentrations of CK1D008 [0.01–10 μM] or SR-3029 [0.01–1 μM]. Relative quantification of Western blot bands was conducted via densitometric image analysis using Image Lab 5.0 software (Bio-Rad, Vienna, Austria). Relative protein levels normalized to the loading control tERK and to the SAG-treated sample are shown above each protein band. Full article ">Figure 4
Pharmacological targeting of CSNK1D inhibits oncogenic HH—GLI signaling in SMOi-resistant cells. (A) Simplified schematic illustration of SMO-independent activation of HH—GLI signaling in Daoy medulloblastoma cells caused by the loss of the negative HH—GLI pathway regulator SUFU. (B) Representative Western blot analysis of GLI1 protein levels in Daoy-shSUFU cells treated with vismo [1 μM], HPI-1 [20 μM], CK1D008 [0.1–3 μM] or SR-3029 [0.01–1 μM]. (C) Representative Western blot analysis of GLI1 in A673 cells treated with vismo [1 μM], HPI-1 [20 μM], CK1D008 [0.1–1 μM] or SR-3029 [0.03–0.3 μM]. Relative quantification of Western blot bands was conducted via densitometric image analysis using Image Lab 5.0 software (Bio-Rad, Vienna, Austria). Relative protein levels normalized to the loading control tERK and to the Ctrl sample are shown above each protein band. Full article ">Figure 5
Targeting CSNK1D reduces GLI-dependent 3D tumor spheroid formation in vitro as well as tumor engraftment in vivo. (A) A673 cells were lentivirally transduced with shCSNK1D or control shRNA (shCtrl) and cultured under anchorage-independent conditions. Representative images of formed 3D spheroid colonies (left panel). The number of 3D spheroid colonies was counted (right panel) (n = 8). (B) A673 cells were cultured under anchorage-independent conditions and treated with the GLI inhibitor HPI-1 [4 μM], CK1D008 [0.1–1 μM] or SR-3029 [0.03–0.3 μM]. The data represent the mean of six 3D culture experiments. (C) A673 cells were retrovirally transduced with GLI1, active GLI2 (GLI2act) or control overexpression constructs, cultured under anchorage-independent conditions and treated with CK1D008 at non-toxic concentration [0.3 μM]. The number of 3D spheroid colonies was counted (n = 4 experiments). (D) A673 cells were lentivirally transduced with shCSNK1D or control shRNA (shCtrl) and engrafted in the flanks of NSG mice (n = 6 mice each). Tumor volume was measured every 3–4 days. Student’s t test was used for statistical analysis (* p < 0.05; ** p < 0.01; *** p < 0.001). Full article ">

31 pages, 7838 KiB

Open AccessReview

Role of Inflammatory Mediators, Macrophages, and Neutrophils in Glioma Maintenance and Progression: Mechanistic Understanding and Potential Therapeutic Applications

by Abdul Samad Basheer, Faridah Abas, Iekhsan Othman and Rakesh Naidu

Cancers 2021, 13(16), 4226; https://doi.org/10.3390/cancers13164226 - 23 Aug 2021

Cited by 61 | Viewed by 9414

Abstract

Gliomas are the most common, highly malignant, and deadliest forms of brain tumors. These intra-cranial solid tumors are comprised of both cancerous and non-cancerous cells, which contribute to tumor development, progression, and resistance to the therapeutic regimen. A variety of soluble inflammatory mediators [...] Read more.

Gliomas are the most common, highly malignant, and deadliest forms of brain tumors. These intra-cranial solid tumors are comprised of both cancerous and non-cancerous cells, which contribute to tumor development, progression, and resistance to the therapeutic regimen. A variety of soluble inflammatory mediators (e.g., cytokines, chemokines, and chemotactic factors) are secreted by these cells, which help in creating an inflammatory microenvironment and contribute to the various stages of cancer development, maintenance, and progression. The major tumor infiltrating immune cells of the tumor microenvironment include TAMs and TANs, which are either recruited peripherally or present as brain-resident macrophages (microglia) and support stroma for cancer cell expansion and invasion. These cells are highly plastic in nature and can be polarized into different phenotypes depending upon different types of stimuli. During neuroinflammation, glioma cells interact with TAMs and TANs, facilitating tumor cell proliferation, survival, and migration. Targeting inflammatory mediators along with the reprogramming of TAMs and TANs could be of great importance in glioma treatment and may delay disease progression. In addition, an inhibition of the key signaling pathways such as NF-κB, JAK/STAT, MAPK, PI3K/Akt/mTOR, and TLRs, which are activated during neuroinflammation and have an oncogenic role in glioblastoma (GBM), can exert more pronounced anti-glioma effects. Full article

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Figure 1

Figure 1
Represents tumorigenic role of inflammatory mediators, TAMs, TANs, and signaling pathways in glioma. Green color indicates activation/release. TAMs: tumor-associated macrophages; TANs: tumor-associated neutrophils; MCP-1,3: monocyte chemoattractant proteins-1,3; CSF-1,2: colony stimulating factors-1,2; GDNF: glial cell-derived neurotrophic factor; IL-1 α, β, -4, -6, -8, -10: interleukins-1 α, β, -4, -6, -8, -10; CXCL-1, -12; chemokine (C-X-C motif) ligand-1, -12; TNF- α: tumor necrosis factor- α; COX-2: cyclooxygenase-2; PGE2: prostaglandin E2; PDGF: platelet-derived growth factor; TGF β: transforming growth factor β; VEGF: vascular endothelial growth factor; MMP-2, 9: matrix metalloproteinases-2, 9; IGFBP1: insulin-like growth factor-binding protein 1; Bmi-1: B-cell specific Moloney murine virus integration site 1; Arg-1: arginase-1; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; JAK/STAT: Janus kinase-signal transducer and activator of transcription; MAPK: Mitogen-activated protein kinase; PI3K/Akt/mTOR: Phosphatidylinositol-3-kinase-mammalian target of rapamycin; TLRs: Toll-like receptors. Full article ">Figure 2
Representation of the key signaling pathways involved in the inflammation-induced glioma genesis. (A) NF-κB pathway; (B) JAK/STAT pathway; (C) MAP Kinase pathway; (D) PI3K/Akt/mTOR pathway; (E) TLRs pathway. NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; JAK/STAT: Janus kinase-signal transducer and activator of transcription; MAPK: Mitogen-activated protein kinase; PI3K/Akt/mTOR: Phosphatidylinositol-3-kinase-mammalian target of rapamycin; TLRs: Toll-like receptors; IL-1β, -4, -6, -13, -22: interleukins-1β, -4, -6, -13, -22; CXCL-12: chemokine (C-X-C motif) ligand-12; TNF- α: tumor necrosis factor- α; COX-2: cyclooxygenase-2; PDGF: platelet-derived growth factor; TGF β: transforming growth factor β; HGF: hepatocyte growth factor; OS: oxidative stress; TROY: tumor necrosis factor receptor superfamily member 19; pSTAT3: phosphorylated signal transducer and activator of transcription 3; GDNF: glial cell-derived neurotrophic factor; Iκβα: inhibitor of kappa B alpha; EGFR: epidermal growth factor receptor; ERK: extracellular signal-regulated kinase; JNK: c-Jun N-terminal kinase; VEGF: vascular endothelial growth factor; MMPs: matrix metalloproteinases; Bax/Bcl-2: Bcl-2-associated X protein, B-cell lymphoma 2; AP-1: activator protein-1; IGFs: insulin-like growth factors; LPS: lipopolysaccharide; PI3K: phosphoinositide 3 kinase; Akt: protein kinase B; PDK: 3-phosphoinositide-dependent kinase 1; PIP2/3: phosphatidylinositol-4, 5-bisphosphate/ phosphatidylinositol-3, 4, 5-triphosphate; mTORC1/mTORC2: mechanistic target of rapamycin complex 1 and 2; TSC1/2: tuberous sclerosis complex 1/2; PTEN: phosphatase and tensin homolog: RTK: receptor tyrosine kinase; Rheb: Ras homolog enriched in brain; CD14: cluster of differentiation 14; MD2: myeloid differentiation factor 2; MyD88: myeloid differentiation factor 88; TIRAP: TIR-containing adaptor protein; TRIF: Toll/IL-1R domain-containing adapter inducing interferon-β; TRAF6, -3: TNF receptor-associated factor 6, -3; TRAM: TRIF-related adaptor molecule; RIP1: receptor-interacting protein 1; TAB-1, 2/3: TAK1-binding protein-1, 2/3; TAK1: TGF-β-activated kinase; TRADD: TNF receptor type 1-associated DEATH domain protein; IGF-1: insulin growth factor-1; CREB: cAMP response element binding protein; IRF3: interferon regulatory factor 3. Full article ">Figure 3
Represents the therapeutic benefits of targeting inflammatory mediators, TAMs, TANs, and signaling pathways in glioma. Red color indicates inhibition/blocking and green color shows activation/upregulation. NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; JAK/STAT: Janus kinase-signal transducer and activator of transcription; MAPK: Mitogen-activated protein kinase; PI3K/Akt/mTOR: Phosphatidylinositol-3-kinase-mammalian target of rapamycin; TLRs: Toll-like receptors; TAMs: tumor-associated macrophages; TANs: tumor-associated neutrophils; IL-1β, -6, -8, -10: interleukins-1β, -6, -8, -10; IL-6R: interleukin-6 receptor; TNF- α: tumor necrosis factor- α; MMP-2/9/14: matrix metalloproteinase-2/9/14; PDGFR-α: platelet-derived growth factor receptor-α; COX-2: cyclooxygenase-2; PGE2: prostaglandin E2; PAI-1: plasminogen activator inhibitor-1; VEGF: vascular endothelial growth factor; NSAIDs: non-steroidal anti-inflammatory drugs; CXCR-4: chemokine receptor type 4; STAT 3: signal transducer and activator of transcription 3; CCL2: chemokine ligand 2; MCP-1: monocyte chemoattractant protein 1; CC5R: chemokine receptor type 5; CBDDC-TANs: cell-based drug delivery carrier—tumor-associated neutrophils; PTX: paclitaxel; pSTAT3: phosphorylated signal transducer and activator of transcription 3; Arg-1: arginase-1; CSF: colony stimulating factor; Akt/PKB: protein kinase B; TMZ: temozolomide; iNOS: inducible nitric oxide synthase; NO: nitric oxide; T cell: T lymphocyte; SOCS: suppressors of cytokine signaling; CTLA-4: cytotoxic T lymphocyte associated protein-4; PD-1: programmed cell death protein-1; CD80/86: cluster of differentiation 80/86; ERK 1/2: extracellular signal-regulated kinase 1/2; JNK: c-Jun N-terminal kinase; RAI14: retinoic acid-induced 14 protein; IFN β: interferon β; B cells: B lymphocytes; DCs: dendritic cells; sil-TRADD: silencing TNF receptor type 1-associated DEATH domain protein; sil-TLR4: silencing Toll-like receptor 4. Full article ">

20 pages, 3873 KiB

Open AccessArticle

Tobacco Smoke and Electronic Cigarette Vapor Alter Enhancer RNA Expression That Can Regulate the Pathogenesis of Lung Squamous Cell Carcinoma

by Joseph C. Tsai, Omar A. Saad, Shruti Magesh, Jingyue Xu, Abby C. Lee, Wei Tse Li, Jaideep Chakladar, Mark M. Fuster, Eric Y. Chang, Jessica Wang-Rodriguez and Weg M. Ongkeko

Cancers 2021, 13(16), 4225; https://doi.org/10.3390/cancers13164225 - 23 Aug 2021

Cited by 5 | Viewed by 3553

Abstract

Tobacco is the primary etiologic agent in worsened lung squamous cell carcinoma (LUSC) outcomes. Meanwhile, it has been shown that etiologic agents alter enhancer RNAs (eRNAs) expression. Therefore, we aimed to identify the effects of tobacco and electronic cigarette (e-cigarette) use on eRNA [...] Read more.

Tobacco is the primary etiologic agent in worsened lung squamous cell carcinoma (LUSC) outcomes. Meanwhile, it has been shown that etiologic agents alter enhancer RNAs (eRNAs) expression. Therefore, we aimed to identify the effects of tobacco and electronic cigarette (e-cigarette) use on eRNA expression in relation to LUSC outcomes. We extracted eRNA counts from RNA-sequencing data of tumor/adjacent normal tissue and before/after e-cigarette tissue from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), respectively. Tobacco-mediated LUSC eRNAs were correlated to patient survival, clinical variables, and immune-associated elements. eRNA expression was also correlated to mutation rates through the Repeated Evaluation of Variables Conditional Entropy and Redundance (REVEALER) algorithm and methylated sites through methylationArrayAnalysis. Differential expression analysis was then completed for the e-cigarette data to compare with key tobacco-mediated eRNAs. We identified 684 downregulated eRNAs and 819 upregulated eRNAs associated with tobacco-mediated LUSC, specifically, with the cancer pathological stage. We also observed a decrease in immune cell abundance in tobacco-mediated LUSC. Yet, we found an increased association of eRNA expression with immune cell abundance in tobacco-mediated LUSC. We identified 16 key eRNAs with significant correlations to 8 clinical variables, implicating these eRNAs in LUSC malignancy. Furthermore, we observed that these 16 eRNAs were highly associated with chromosomal alterations and reduced CpG site methylation. Finally, we observed large eRNA expression upregulation with e-cigarette use, which corresponded to the upregulation of the 16 key eRNAs. Our findings provide a novel mechanism by which tobacco and e-cigarette smoke influences eRNA interactions to promote LUSC pathogenesis and provide insight regarding disease progression at a molecular level. Full article

(This article belongs to the Special Issue New Insight of Non-small Cell Lung Cancer)

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Graphical abstract

Graphical abstract
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Project overview. Schematic of project workflow and analyses. Datasets were acquired from the Cancer Genome Atlas (TCGA) and the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO). Tobacco-smoke-onset LUSC, nonsmoking-onset LUSC, and electronic cigarette smoke lung samples were analyzed in separate cohorts to limit any confounding variables. Differentially expressed eRNAs were filtered by log fold change and false discovery rate (log fold change (FC) > 1 and false discovery rate (FDR) < 0.05), and significantly dysregulated eRNAs were identified and used in survival analysis, immune infiltration analysis, and clinical variable correlations. A total of 16 key eRNAs were determined to be critical to the immune landscape and tumor phenotype of LUSC, based on previous analyses. These critical eRNAs were subsequently examined further for genomic alteration and methylation patterns. Full article ">Figure 2
Correlation to Clinical Variables and Patient Survival. (A) The total amount of eRNAs identified to be correlated to patient survival and vital status in smoking-onset LUSC and nonsmoking-onset LUSC. Red correlates to smoking-onset LUSC data, and blue correlates to nonsmoking-onset LUSC data. Overall, there was a significantly greater amount of eRNAs associated with patient survival and vital status in the smoking-onset LUSC cohort. (B) Select cox proportional hazards regression plots (Kaplan–Meier) of patient survival rates (in days) in correlation to eRNA expression. (C) Bar graph representing the total significant correlations between eRNA expression and several clinical variables in both the smoking-onset LUSC cohorts and the nonsmoking-onset LUSC cohorts. Clinical variables investigated include tumor necrosis, cancer status, cancer pathological stage, cancer pathological m stage, cancer pathological n stage, cancer pathological t stage, stromal cell expression, and cancer vital status. (D) Select boxplots and scatterplots of eRNAs significantly correlated to clinical variables, including pathological stage T, pathological stage n, pathological stage m, tumor stromal cells, tumor necrosis, and tumor pathological stages 1, 2, 3, and 4. Boxplots plots were created using the Kruskal–Wallis test, while the scatterplots were created using the Spearman test, and all plots were filtered by p-value (p-value < 0.05). The various correlations in the plots suggest that the upregulation of eRNAs identified from previous analyses are associated with advanced cancer pathological stage and are negatively correlated with tumor stromal cells and tumor necrosis percent expression. Full article ">Figure 3
Correlation to immune-associated elements. (A) Bar graph comparing immune cell composition in smoking-onset LUSC and nonsmoking-onset LUSC. Red indicates smoking-onset LUSC samples, and blue refers to nonsmoking-onset LUSC samples. Overall, immune cell abundance was higher in nonsmoking LUSC samples. Error bars indicate the standard deviation. Homoscedastic t-tests were performed to compare immune cell compositions of the cohorts (** p < 0.001, * p < 0.05). (B) Bar graph comparing significant eRNA correlations to immune cell abundance in smoking-onset LUSC and nonsmoking-onset LUSC. Red indicates smoking-onset LUSC samples, and blue refers to nonsmoking-onset LUSC samples. The data suggest that there is a greater amount of significant eRNAs associated with immune cells in smoking-onset LUSC samples. (C) Bar graph summarizing immune cell correlations to the 16 critical eRNAs previously identified to be implicated in the LUSC tumor phenotype and immune environment. Blue indicates relative upregulation, while red refers to downregulation in both eRNA expression and abundance of immune cells. (D) Selected scatter plots illustrating the correlations between expression of key eRNAs and immune cell abundance. eRNAs chr19.38575229.38575296 and chr10.21430870.21431276 were downregulated with increasing CD4 and B cell expression, while chr9.27155069.27155179 was upregulated with increasing macrophage expression. The positive and negative correlations between these eRNAs and immune cell abundances suggest potential roles and interactions they might have in promoting LUSC pathogenesis and proliferation. Full article ">Figure 4
Identification and Analysis of 16 eRNAs identified to be critical to LUSC immune landscape and tumor phenotype. (A) Venn diagram summarizing the significant correlations of the selected 16 key eRNAs to patient survival, immune cell infiltration, and tumor status. Each of the 16 selected eRNAs has a high degree of association with various clinical and molecular measures of tumor severity, implicating their potential role in furthering LUSC pathogenesis and metastasis. (B) Volcano plot across all significantly dysregulated eRNAs illustrating the statistical significance versus the magnitude of change (log fold change) in survival-correlated eRNAs, tumor-presence-correlated eRNAs, and the identified 16 critical eRNAs. The 16 key eRNAs demonstrate both a high degree of statistical significance and magnitude of change in expression. (C) Associations between genomic alterations and eRNA expression in smoking-onset LUSC samples, nonsmoking-onset LUSC, and adjacent normal LUSC samples. Correlations were determined using the REVEALER algorithm (p-value < 0.05 and CIC > |0.3|). Full article ">Figure 5
Genomic alteration correlation to 16 key eRNAs via REVEALER (A) Mutation heatmaps with red on the left side indicating that an eRNA is overabundant, while red on the left side indicates that the eRNA is under abundant. The following rows below the heatmap specify copy number variant (CNV) type/genetic variants (alteration, deletion, mutation) across all samples. Each bar represents the presence or absence of a CNV in one sample. Correlations were measured using the Repeated Evaluation of Variables Conditional Entropy and Redundancy (REVEALER) algorithm (CIC > |0.3|, p < 0.05); 15/16 plots are shown here as the algorithm failed to produce a plot for chr12.51786511.51786834. (B) Boxplots correlating eRNA expression with the extent of methylation at CpG sites. In this analysis, the M-values were converted to a binary and categorical variable of “HIGH” and “LOW” in order to conduct the Kruskal–Wallis statistical test. The median abundance level for each eRNA across all samples was calculated. Values lower than the median value were assigned an abundance level of “LOW,” and values above the median value were assigned an abundance level of “HIGH.” The x-axis refers to the extent of methylation at the CpG site, and the y-axis refers to the eRNA expression level. (C) Heatmaps comparing significantly differentially expressed eRNAs in both endothelial microparticles and alveolar macrophages before/after electronic cigarette inhalation (n = 10). Full article ">

12 pages, 601 KiB

Open AccessReview

Challenges for Better Diagnosis and Management of Pancreatic and Biliary Tract Cancers Focusing on Blood Biomarkers: A Systematic Review

by Hiroto Tominaga, Juntaro Matsuzaki, Chihiro Oikawa, Kensho Toyoshima, Haruki Manabe, Eriko Ozawa, Atsushi Shimamura, Riko Yokoyama, Yusuke Serizawa, Takahiro Ochiya and Yoshimasa Saito

Cancers 2021, 13(16), 4220; https://doi.org/10.3390/cancers13164220 - 23 Aug 2021

Cited by 1 | Viewed by 2959

Abstract

Background: pancreatic cancer (PCa) and biliary tract cancer (BTC) are cancers with a poor prognosis and few effective treatments. One of the reasons for this is late detection. Many researchers are tackling to develop non-invasive biomarkers for cancer, but few are specific for [...] Read more.

Background: pancreatic cancer (PCa) and biliary tract cancer (BTC) are cancers with a poor prognosis and few effective treatments. One of the reasons for this is late detection. Many researchers are tackling to develop non-invasive biomarkers for cancer, but few are specific for PCa or BTC. In addition, genetic abnormalities occur in cancer tissues, which ultimately affect the expression of various molecules. Therefore, it is important to identify molecules that are altered in PCa and BTC. For this systematic review, a systematic review of Medline and Embase to select biomarker studies of PCa and BTC patients was conducted. Results: after reviewing 72 studies, 79 biomarker candidates were identified, including 22 nucleic acids, 43 proteins, and 14 immune cell types. Of the 72 studies, 61 examined PCa, and 11 examined BTC. Conclusion: PCa and BTC are characterized by nucleic acid, protein, and immune cell profiles that are markedly different from those of healthy subjects. These altered molecules and cell subsets may serve as cancer-specific biomarkers, particularly in blood. Further studies are needed to better understand the diagnosis and prognosis of PCa and BTC. Full article

(This article belongs to the Special Issue Novel Biomarkers of Gastrointestinal Cancer)

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9 pages, 2315 KiB

Open AccessArticle

Duration of Reduced CA19-9 Levels Is a Better Prognostic Factor Than Its Rate of Reduction for Unresectable Locally Advanced Pancreatic Cancer

by Ko Tomishima, Shigeto Ishii, Toshio Fujisawa, Muneo Ikemura, Hiroto Ota, Daishi Kabemura, Mako Ushio, Taito Fukuma, Sho Takahashi, Wataru Yamagata, Yusuke Takasaki, Akinori Suzuki, Koichi Ito, Hiroaki Saito, Akihito Nagahara and Hiroyuki Isayama

Cancers 2021, 13(16), 4224; https://doi.org/10.3390/cancers13164224 - 22 Aug 2021

Cited by 10 | Viewed by 6359

Abstract

A decrease in carbohydrate antigen (CA) 19-9 levels has been proposed as a prognostic marker for survival and recurrence in patients with pancreatic cancer. We evaluated the association between duration of reduced CA 19-9 levels during 6 months after treatment and long-term survival [...] Read more.

A decrease in carbohydrate antigen (CA) 19-9 levels has been proposed as a prognostic marker for survival and recurrence in patients with pancreatic cancer. We evaluated the association between duration of reduced CA 19-9 levels during 6 months after treatment and long-term survival for 79 patients with unresectable locally advanced pancreatic cancer (LAPC). We calculated the differences between pretreatment and monthly CA19-9 levels. We categorized 71 patients with decreases in CA19-9 levels into three groups based on the duration of these reduced levels (>2, >3, and >4 months). The cut-off level for long-term (more than 2 years) survival was identified as a 44% reduction from the baseline, using a ROC curve. A reduction duration >2 months was not associated with overall survival (p = 0.1), while >3 months was significantly associated with survival (p =.04). In multivariate analysis, a reduction duration >3 months predicted a good long-term prognosis (odds ratio = 5.75; 95% confidence interval = 1.47–22.36; p < 0.01). In patients with unresectable LAPC, the duration of reduced CA19-9 levels for more than 3 months, rather than the rate of reduction in CA19-9 levels, during 6 months after treatment was significantly associated with good prognosis. Full article

(This article belongs to the Special Issue Advances in Pancreatic Cancer Imaging)

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12 pages, 801 KiB

Open AccessArticle

Validating Methylated HOXA9 in Bronchial Lavage as a Diagnostic Tool in Patients Suspected of Lung Cancer

by Sara W. C. Wen, Rikke F. Andersen, Kristian Rasmussen, Caroline Brenner Thomsen, Torben Frøstrup Hansen, Line Nederby, Henrik Hager, Anders Jakobsen and Ole Hilberg

Cancers 2021, 13(16), 4223; https://doi.org/10.3390/cancers13164223 - 22 Aug 2021

Cited by 4 | Viewed by 1955

Abstract

Diagnosing lung cancer requires invasive procedures with high risk of complications. Methylated tumor DNA in bronchial lavage has previously shown potential as a diagnostic biomarker. We aimed to develop and validate methylated HOXA9 in bronchial lavage as a diagnostic biomarker of lung cancer. [...] Read more.

Diagnosing lung cancer requires invasive procedures with high risk of complications. Methylated tumor DNA in bronchial lavage has previously shown potential as a diagnostic biomarker. We aimed to develop and validate methylated HOXA9 in bronchial lavage as a diagnostic biomarker of lung cancer. Participants were referred on suspicion of lung cancer. Ten mL lavage fluid was collected at bronchoscopy for analysis of methylated HOXA9 based on droplet digital PCR according to our previously published method. HOXA9 status was compared with the final diagnosis. The Discovery and Validation cohorts consisted of 101 and 95 consecutively enrolled participants, respectively. In the discovery cohort, the sensitivity and specificity were 73.1% (95% CI 60.9–83.2%) and 85.3% (95% CI 68.9–95.0%), respectively. In the validation cohort, the values were 80.0% (95% CI 66.3–90.0%) and 75.6% (95% CI 60.5–87.1%), respectively. A multiple logistic regression model including age, smoking status, and methylated HOXA9 status resulted in an AUC of 84.9% (95% CI 77.3–92.4%) and 85.9% (95% CI 78.4–93.4%) for the Discovery and Validation cohorts, respectively. Methylated HOXA9 in bronchial lavage holds potential as a supplementary tool in the diagnosis of lung cancer with a clinically relevant sensitivity and specificity. It remained significant when adjusting for age and smoking status. Full article

(This article belongs to the Section Cancer Biomarkers)

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11 pages, 2289 KiB

Open AccessArticle

The “K-Sign”—A Novel CT Finding Suggestive before the Appearance of Pancreatic Cancer

by Yuko Kobashi, Masateru Uchiyama and Junichi Matsui

Cancers 2021, 13(16), 4222; https://doi.org/10.3390/cancers13164222 - 22 Aug 2021

Cited by 6 | Viewed by 2614

Abstract

Pancreatic invasive ductal adenocarcinoma (PDAC) has a poor prognosis, and the detection of PDAC during the early stage is thought to improve prognosis. In this study, we retrospectively investigated pancreatic morphological abnormalities that lead to the early diagnosis of PDAC with computed tomography [...] Read more.

Pancreatic invasive ductal adenocarcinoma (PDAC) has a poor prognosis, and the detection of PDAC during the early stage is thought to improve prognosis. In this study, we retrospectively investigated pancreatic morphological abnormalities that lead to the early diagnosis of PDAC with computed tomography (CT) imaging. In total, 41 out of 308 patients diagnosed with pancreatic cancer between 2011 and 2017 in our institution were enrolled. As a control group for the group with pancreatic cancer, 4277 patients without pancreato-biliary diseases were enrolled. We retrospectively reviewed and analyzed the clinical data including patient characteristics, the clinical course and preoperative CT imaging with pancreatic morphological features. Out of 41 patients, 24 patients (58.5%) showed local K-shaped constriction of the pancreatic parenchyma “K-sign” on preoperative CT images. Eight patients (19.5%) showed localized fatty change. Out of 4277 control patients, seven patients (0.16%) showed K-sign. “K-sign” may be used for the early diagnosis of PDAC by CT imaging. Full article

(This article belongs to the Special Issue Recent Highly Advanced Surgery for Pancreatic Cancer)

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13 pages, 793 KiB

Open AccessArticle

Survival Impact of Chronic Obstructive Pulmonary Disease or Acute Exacerbation on Patients with Rectal Adenocarcinoma Undergoing Curative Resection: A Propensity Score-Matched, Population-Based Cohort Study

by Jiaqiang Zhang, Kuo-Chin Chiu, Wei-Chun Lin and Szu-Yuan Wu

Cancers 2021, 13(16), 4221; https://doi.org/10.3390/cancers13164221 - 22 Aug 2021

Cited by 1 | Viewed by 2334

Abstract

Purpose: The survival effect of current smoking-related chronic obstructive pulmonary disease (COPD) and COPD with acute exacerbation (COPDAE) is unclear for patients with rectal adenocarcinoma undergoing curative resection. Methods: We recruited patients with clinical stage I–IIIC rectal adenocarcinoma from the Taiwan Cancer Registry [...] Read more.

Purpose: The survival effect of current smoking-related chronic obstructive pulmonary disease (COPD) and COPD with acute exacerbation (COPDAE) is unclear for patients with rectal adenocarcinoma undergoing curative resection. Methods: We recruited patients with clinical stage I–IIIC rectal adenocarcinoma from the Taiwan Cancer Registry Database who had received surgery. The Cox proportional hazards model was used to analyze all-cause mortality. We categorized the patients into two groups by using propensity score matching based on COPD status to compare overall survival outcomes: Group 1 (current smokers with COPD) and Group 2 (nonsmokers without COPD). Results: In the multivariate Cox regression analyses, the adjusted hazard ratio (aHR; 95% confidence interval (CI)) of all-cause mortality for Group 1 compared with Group 2 was 1.25 (1.04–1.51). The aHRs (95% cis) of all-cause mortality for frequency of ≥1 hospitalizations for COPDAE or ≥2 hospitalizations within 1 year before diagnosis were 1.17 (1.05–1.51) and 1.48 (1.03–2.41) compared with no COPDAE in patients with rectal adenocarcinoma undergoing curative resection. Conclusion: In patients with rectal adenocarcinoma undergoing curative resection, being a current smoker with COPD (Group 1) was associated with worse survival outcomes than being a nonsmoker without COPD (Group 2). Being hospitalized at least once for COPDAE within 1 year before the diagnosis of rectal adenocarcinoma is an independent risk factor for poor overall survival in these patients, and a higher number of hospitalizations for COPDAE within 1 year before diagnosis was associated with poorer survival. Full article

(This article belongs to the Special Issue New Insights into Colorectal Cancer)

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22 pages, 1551 KiB

Open AccessArticle

Analytical Performance of NGS-Based Molecular Genetic Tests Used in the Diagnostic Workflow of Pheochromocytoma/Paraganglioma

by Balazs Sarkadi, Istvan Liko, Gabor Nyiro, Peter Igaz, Henriett Butz and Attila Patocs

Cancers 2021, 13(16), 4219; https://doi.org/10.3390/cancers13164219 - 22 Aug 2021

Cited by 4 | Viewed by 3052

Abstract

Next Generation Sequencing (NGS)-based methods are high-throughput and cost-effective molecular genetic diagnostic tools. Targeted gene panel and whole exome sequencing (WES) are applied in clinical practice for assessing mutations of pheochromocytoma/paraganglioma (PPGL) associated genes, but the best strategy is debated. Germline mutations of [...] Read more.

Next Generation Sequencing (NGS)-based methods are high-throughput and cost-effective molecular genetic diagnostic tools. Targeted gene panel and whole exome sequencing (WES) are applied in clinical practice for assessing mutations of pheochromocytoma/paraganglioma (PPGL) associated genes, but the best strategy is debated. Germline mutations of at the least 18 PPGL genes are present in approximately 20–40% of patients, thus molecular genetic testing is recommended in all cases. We aimed to evaluate the analytical and clinical performances of NGS methods for mutation detection of PPGL-associated genes. WES (three different library preparation and bioinformatics workflows) and an in-house, hybridization based gene panel (endocrine-onco-gene-panel- ENDOGENE) was evaluated on 37 (20 WES and 17 ENDOGENE) samples with known variants. After optimization of the bioinformatic workflow, 61 additional samples were tested prospectively. All clinically relevant variants were validated with Sanger sequencing. Target capture of PPGL genes differed markedly between WES platforms and genes tested. All known variants were correctly identified by all methods, but methods of library preparations, sequencing platforms and bioinformatical settings significantly affected the diagnostic accuracy. The ENDOGENE panel identified several pathogenic mutations and unusual genotype–phenotype associations suggesting that the whole panel should be used for identification of genetic susceptibility of PPGL. Full article

(This article belongs to the Special Issue New Insights in the Genetics and Genomics of Adrenocortical Tumors and Pheochromocytomas)

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Open AccessArticle

Surgical Management of Jugular Foramen Schwannomas

by Amir Kaywan Aftahy, Maximilian Groll, Melanie Barz, Denise Bernhardt, Stephanie E. Combs, Bernhard Meyer, Chiara Negwer and Jens Gempt

Cancers 2021, 13(16), 4218; https://doi.org/10.3390/cancers13164218 - 22 Aug 2021

Cited by 14 | Viewed by 4039

Abstract

Background: Resection of jugular foramen schwannomas (JFSs) with minimal cranial nerve (CN) injury remains difficult. Reoperations in this vital region are associated with severe CN deficits. Methods: We performed a retrospective analysis at a tertiary neurosurgical center of patients who underwent surgery for [...] Read more.

Background: Resection of jugular foramen schwannomas (JFSs) with minimal cranial nerve (CN) injury remains difficult. Reoperations in this vital region are associated with severe CN deficits. Methods: We performed a retrospective analysis at a tertiary neurosurgical center of patients who underwent surgery for JFSs between June 2007 and May 2020. We included nine patients (median age 60 years, 77.8% female, 22.2% male). Preoperative symptoms included hearing loss (66.6%), headache (44.4%), hoarseness (33.3%), dysphagia (44.4%), hypoglossal nerve palsy (22.2%), facial nerve palsy (33.3%), extinguished gag reflex (22.2%), and cerebellar dysfunction (44.4%). We observed Type A, B, C, and D tumors in 3, 1, 1, and 4 patients, respectively. A total of 77.8% (7/9) underwent a retrosigmoid approach, and 33.3% (3/9) underwent an extreme lateral infrajugular transcondylar (ELITE) approach. Gross total resection (GTR) was achieved in all cases. The rate of shunt-dependent hydrocephalus was 22.2% (2/9). No further complications requiring surgical intervention occurred during follow-up. The median follow-up time was 16.5 months (range 3–84 months). Conclusions: Considering the satisfying outcome, the GTR of JFSs is feasible in performing well-known skull base approaches. Additional invasive and complicated approaches were not needed. Radiosurgery may be an effective alternative for selected patients. Full article

(This article belongs to the Special Issue Skull Base Tumours)

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A 66-year-old female patient presenting with headache, vertigo, and cerebellar dysfunction. (A) Preoperative axial and (B) coronal T1-weighted gadolinium-enhanced MRI, displaying cystic JFS (arrows), involving the CPA (Samii Type A). (C) Postoperative axial and (D) coronal MRI control, indicating complete resection (arrows) through a classic retrosigmoid approach. Postoperatively, mild facial nerve palsy (House and Brackmann II) occurred and remained during follow-up. Full article ">Figure 2
(A) For the dorsolateral approach, a lazy S or bigger C incision is used, about 1 cm posterior to the mastoid bone, extending inferiorly along the hairline. For the anterolateral ELITE procedure, a retroauricular curvilinear C-shaped, or question-mark-shaped, skin incision is begun approximately 2 to 3 cm posterior to the upper border of the ear. Inferiorly, this incision is carried down into the neck, traversing the border of the sternocleidomastoid muscle and running parallel to the body of the mandible (fingerbreadths below). For the dorsolateral approach, the sternocleidomastoid muscle is retracted anteriorly; for the anterolateral approach, it is retracted posteriorly. (B) Exposure by different techniques: (1) suprajugular, infralabyrinthine; (2) infrajugular, transcondylar; and (3) high cervical. SS, sigmoid sinus; ICA, internal carotid artery; IJV, internal jugular vein. (C) Anterolateral techniques with high cervical dissection. AICA, anterior inferior cerebellar artery; PICA, posterior inferior cerebellar artery; VA, vertebral artery; JB, jugular bulb. Full article ">Figure 3
A 56-year-old female patient presented with headache, cerebellar dysfunctions, hearing loss, hoarseness, and extinguished gag reflex. (A) Preoperative axial and (B) coronal T1-weighted gadolinium-enhanced MRI, showing an impressive JFS (arrows) with a quasi-dumbbell shape and both intra- and extracranial components through the JF (Samii Type D). (C) Postoperative axial and (D) coronal MRI control, indicating complete resection (arrows) through a dorsolateral ELITE approach. Postoperatively, no new deficits occurred, and the patient recovered from the cerebellar dysfunctions, hoarseness, and extinguished gag reflex. Full article ">Figure 4
A 26-year-old male patient presented with progressive hoarseness, dysphagia, and extinguished gag reflex. (A) Preoperative axial (arrow), (B) sagittal (circle), and (C) coronal (circle) T1-weighted gadolinium-enhanced MRI, showing the JFS with intracranial extension (Samii Type B). (D) Postoperative axial, (E) sagittal, and (F) coronal MRI control, indicating complete resection through a dorsolateral ELITE approach. Postoperatively, no new deficits occurred. He suffered from postoperative temporary vertigo; hoarseness showed slight improvement during follow-up. Full article ">Figure 5
A 46-year-old male patient presented with headache, hoarseness, dysphagia, and extinguished gag reflex. (A) Preoperative axial (arrow), (B) sagittal (circle), and (C) coronal (circle) T1-weighted gadolinium-enhanced MRI, showing a massive space-occupying extracranial jugular foramen schwannoma with extension into the JF (Samii Type C). (D) Postoperative axial, (E) sagittal, and (F) coronal MRI control, indicating complete resection through an anterolateral ELITE approach. Postoperatively, no new deficits occurred, and the patient recovered from the hoarseness and extinguished gag reflex. Dysphagia remained but improved during follow-up as well. Full article ">

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