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Cells
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Oral Diseases: Biological and Molecular Pathogenesis
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Oral Diseases: Biological and Molecular Pathogenesis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 August 2024) | Viewed by 4200

Special Issue Editor

Prof. Dr. Hiromasa Hasegawa

E-Mail Website
Guest Editor
1. Department of Laboratory Medicine, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan 2. Hard Tissue Pathology Unit, Graduate School of Oral Medicine, Matsumoto Dental University, 1780 Hirookagohara, Shiojiri, Nagano 399-0781, Japan
Interests: bnormal cornification of oral mucosa and diseases; molecular changes of odontogenic lesions; molecular pathology of soft tissue neoplasms of the oral cavity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The era of advanced molecular technology in the 2000s has provided us with a wealth of knowledge in all areas of disease, including the oral region. These developments may clarify the pathogenesis of oral neoplasia, oral mucous diseases and other oral diseases, and improve strategies for diagnosing or treating them. Currently, we are on the way to achieving a breakthrough for many oral diseases. There is no striking impact of single pathogenesis in most oral diseases, unlike clear cell odontogenic carcinoma harboring an EWSR1 rearrangement, and the pathogenesis of most oral diseases is multifactorial and complex. Cellular character, cell kinetics, abnormal protein distribution or genetic changes are closely related to the development of oral disease. In this Special Issue, we encourage the submission of papers highlighting new advances in the biological or molecular pathogenesis of oral diseases, with a particular focus on aspects of unique cellular alterations. Original research articles and reviews are welcome. Research areas may include, but are not limited to the following: oral squamous cell carcinoma, oral dysplasia, oral lichen planus, odontogenic neoplasms, odontogenic cysts and other inflammatory disorders of the oral cavity.

Prof. Dr. Hiromasa Hasegawa
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • pathogenesis
  • immunohistochemical and molecular alteration
  • oral diseases

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Published Papers (2 papers)

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Research

25 pages, 3128 KiB  
Article
Genomic Engineering of Oral Keratinocytes to Establish In Vitro Oral Potentially Malignant Disease Models as a Platform for Treatment Investigation
by Leon J. Wils, Marijke Buijze, Marijke Stigter-van Walsum, Arjen Brink, Britt E. van Kempen, Laura Peferoen, Elisabeth R. Brouns, Jan G. A. M. de Visscher, Erik H. van der Meij, Elisabeth Bloemena, Jos B. Poell and Ruud H. Brakenhoff
Cells 2024, 13(8), 710; https://doi.org/10.3390/cells13080710 - 19 Apr 2024
Viewed by 1542
Abstract
Precancerous cells in the oral cavity may appear as oral potentially malignant disorders, but they may also present as dysplasia without visual manifestation in tumor-adjacent tissue. As it is currently not possible to prevent the malignant transformation of these oral precancers, new treatments [...] Read more.
Precancerous cells in the oral cavity may appear as oral potentially malignant disorders, but they may also present as dysplasia without visual manifestation in tumor-adjacent tissue. As it is currently not possible to prevent the malignant transformation of these oral precancers, new treatments are urgently awaited. Here, we generated precancer culture models using a previously established method for the generation of oral keratinocyte cultures and incorporated CRISPR/Cas9 editing. The generated cell lines were used to investigate the efficacy of a set of small molecule inhibitors. Tumor-adjacent mucosa and oral leukoplakia biopsies were cultured and genetically characterized. Mutations were introduced in CDKN2A and TP53 using CRISPR/Cas9 and combined with the ectopic activation of telomerase to generate cell lines with prolonged proliferation. The method was tested in normal oral keratinocytes and tumor-adjacent biopsies and subsequently applied to a large set of oral leukoplakia biopsies. Finally, a subset of the immortalized cell lines was used to assess the efficacy of a set of small molecule inhibitors. Culturing and genomic engineering was highly efficient for normal and tumor-adjacent oral keratinocytes, but success rates in oral leukoplakia were remarkably low. Knock-out of CDKN2A in combination with either the activation of telomerase or knock-out of TP53 seemed a prerequisite for immortalization. Prolonged culturing was accompanied by additional genetic aberrations in these cultures. The generated cell lines were more sensitive than normal keratinocytes to small molecule inhibitors of previously identified targets. In conclusion, while very effective for normal keratinocytes and tumor-adjacent biopsies, the success rate of oral leukoplakia cell culturing methods was very low. Genomic engineering enabled the prolonged culturing of OL-derived keratinocytes but was associated with acquired genetic changes. Further studies are required to assess to what extent the immortalized cultures faithfully represent characteristics of the cells in vivo. Full article
(This article belongs to the Special Issue Oral Diseases: Biological and Molecular Pathogenesis)
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Figure 1

Figure 1
<p>Changes in telomere length and telomerase activity over time between VU-preSCC-M3 and VU-preSCC-M3-TERT<sup>+</sup>. The top graph shows the population doublings for both cell lines over time. The middle graph shows the changes in average telomere length over time per chromosome end. The bottom graph shows the changes in telomerase activity over time. In addition, three control samples were included with known telomere lengths and telomerase activities: MCF-7, VU-SCC-040, and the reference sample from the used kits. The bottom row shows the control samples and the cell passages for the M3 cell cultures.</p> Full article ">Figure 2
<p>Overview of population doublings and genetic aberrations in a tumor-adjacent and normal oral keratinocyte cell culture. The top graph shows the number of population doublings for each included culture. The color of each bar indicates the proliferation status for each culture. In addition, a “/” indicates extended lifespan while “∞” indicates that the cell line was immortal. In the middle graph, the CNAs for each culture are presented, with the chromosomes on the y-axis. The bottom graph contains the mutations present in each culture. The colors indicate the types of mutations. Below the graphs, the modifications for each culture are indicated and the proliferation status is provided, where “X” indicates limited proliferation, “/” indicates extended lifespan, and “∞” indicates immortalization. In addition, the study ID for each set of cultures is provided. PDs = population doublings. CNA = copy number aberration.</p> Full article ">Figure 3
<p>Overview of population doublings and genetic aberrations in five tumor-adjacent oral keratinocyte cell cultures. The top graph shows the number of population doublings for each included culture. The color of each bar indicates the proliferation status for each culture. In addition, a “/” indicates extended lifespan while “∞” indicates that the cell line was immortal. In the middle graph, the CNAs for each culture are presented, with the chromosomes on the y-axis. The bottom graph contains the mutations present in each culture. The colors indicate the types of mutations. Below the graphs, the modifications for each culture are indicated and the proliferation status is provided, where “X” indicates limited proliferation, “/” indicates extended lifespan, and “∞” indicates immortalization. In addition, the study ID for each set of cultures is provided. PDs = population doublings. CNA = copy number aberration. del = deletion. ins = insertion.</p> Full article ">Figure 4
<p>Overview of population doublings and genetic aberrations in a panel of oral leukoplakia cultures, including three that were genetically modified. The top graph shows the number of population doublings for each included culture. The color of each bar indicates the proliferation status for each culture. In addition, a “/” indicates extended lifespan while “∞” indicates that the cell line was immortal. In the middle graph, the CNAs for each culture are presented, with the chromosomes on the y-axis. The bottom graph contains the mutations present in each culture. The colors indicate the types of mutations. Below the graphs, the modifications for each culture are indicated and the proliferation status is provided, where “0” indicates no proliferation, “X” indicates limited proliferation, “/” indicates extended lifespan, and “∞” indicates immortalization. In addition, the study ID for each set of cultures is provided. PDs = population doublings. CNA = copy number aberration. del = deletion.</p> Full article ">Figure 5
<p>Effectivity of MCL1 inhibitor S63845 for OL treatment. (<b>Top</b>): Dose–response curves showing the relative cell viability of modified cell lines (black) with sensitive tumor line UM-SCC-22A (red) and epithelial line UPPP60 (green) as a reference indicating the therapeutic window of MCL1 inhibitor S63845. Experiments were performed 3 times in triplicate and the averaged value of the 3 experiments is presented. (<b>Bottom</b>): Plot showing the IC50 for MCL1 inhibitor S63845 in all included cell lines. Samples are sorted based on cell type as indicated by color. The dotted red line indicates the IC50 for UM-SCC-22A, defined as the sensitive cell line. The dotted green line indicates the IC50 for UPPP60, defined as the insensitive cell line.</p> Full article ">
18 pages, 10326 KiB  
Article
Neoadjuvant Radiochemotherapy Alters the Immune and Metabolic Microenvironment in Oral Cancer—Analyses of CD68, CD163, TGF-β1, GLUT-1 and HIF-1α Expressions
by Manuel Weber, Jutta Ries, Kristina Braun, Falk Wehrhan, Luitpold Distel, Carol Geppert, Rainer Lutz, Marco Kesting and Leah Trumet
Cells 2024, 13(5), 397; https://doi.org/10.3390/cells13050397 - 25 Feb 2024
Cited by 1 | Viewed by 2207
Abstract
Background: The first-line treatment of oral squamous cell carcinoma (OSCC) involves surgical tumor resection, followed by adjuvant radio(chemo)therapy (R(C)T) in advanced cases. Neoadjuvant radio- and/or chemotherapy has failed to show improved survival in OSCC. Recently, neoadjuvant immunotherapy has shown promising therapeutic efficacy in [...] Read more.
Background: The first-line treatment of oral squamous cell carcinoma (OSCC) involves surgical tumor resection, followed by adjuvant radio(chemo)therapy (R(C)T) in advanced cases. Neoadjuvant radio- and/or chemotherapy has failed to show improved survival in OSCC. Recently, neoadjuvant immunotherapy has shown promising therapeutic efficacy in phase 2 trials. In this context, the addition of radio- and chemotherapy is being reconsidered. Therefore, a better understanding of the tumor-biologic effects of neoadjuvant RCT would be beneficial. The current study was conducted on a retrospective cohort of patients who received neoadjuvant RCT for the treatment of oral cancer. The aim of the study was to evaluate the influence of neoadjuvant RCT on the immunological tumor microenvironment (TME) and hypoxic and glucose metabolisms. Methods: A cohort of 45 OSSC tissue samples from patients were analyzed before and after RCT (total 50.4 Gy; 1.8 Gy 5× weekly; Cisplatin + 5-Fluorouracil). Immunohistochemistry for CD68, CD163, TGF-β, GLUT-1 and HIF-1α was performed using tissue microarrays and automated cell counting. Differences in expression before and after RCT and associations with histomorphological parameters (T-status, N-status) were assessed using the Mann–Whitney U test. Results: Tumor resection specimens after neoadjuvant RCT showed a significant decrease in CD68 infiltration and a significant increase in CD163 cell density. The CD68/CD163 ratio was significantly lower after RCT, indicating a shift toward M2 polarization. The GLUT-1 and HIF-1α expressions were significantly lower after RCT. Larger tumors (T3/T4) showed a lower GLUT-1 expression. Other biomarkers were not associated with the T- and N-status. Conclusions: Neoadjuvant RCT with 50.4 Gy induced a shift toward the M2 polarization of macrophages in the TME. This change in immune composition is not favorable and may be prognostically negative and counteract immunotherapeutic approaches. In addition, the decreased expressions in GLUT-1 and HIF-1α indicate reductions in the glucose metabolism and hypoxic energy metabolism in response to “high dose” neoadjuvant RCT, which may be therapeutically desirable. Full article
(This article belongs to the Special Issue Oral Diseases: Biological and Molecular Pathogenesis)
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Figure 1

Figure 1
<p>Example of automated cell counting in a tumor resection specimen. The image shows an example of the automated cell counting used to determine the labeling index (LI) in a tumor resection specimen stained for CD68. The left micrograph shows the stained TMA sample. The right micrograph displays a visualization of the cell counting performed in the QuPath software (<a href="https://qupath.github.io/" target="_blank">https://qupath.github.io/</a>). All detected cells allocated to the stroma compartment are marked in green, and cells allocated to the epithelial tumor compartment are indicated in red.</p> Full article ">Figure 2
<p>Antibody-stained tissue samples of biopsy and resection. (<b>a</b>) Example of CD68 staining in biopsy. (<b>b</b>) Example of CD68 staining in resection. (<b>c</b>) Example of CD163 staining in biopsy. (<b>d</b>) Example of CD163 expression in resection. (<b>e</b>) Example of GLUT-1 expression in biopsy. (<b>f</b>) Example of GLUT-1 expression in resection. (<b>g</b>) Example of HIF-1α expression in biopsy. (<b>h</b>) Example of HIF-1α expression in resection. (<b>i</b>) Example of TGF-β expression in biopsy. (<b>j</b>) Example of TGF-β expression in resection. The figure shows examples of a tissue specimen with the staining of Glut1, HIF-1α, TGF-β, CD68 and CD163. Biopsies are shown on the left, and the resections of the same patient on the right. On each sample, the biomarker and the size scale are labeled. Each slide was scanned with the Pannoramic 250 Flash II scanner (3D Histech, Budapest, Hungary).</p> Full article ">Figure 3
<p>Comparison of tissue’s overall LIs in biopsy (pre RCT) and resection (post RCT). (<b>a</b>) CD68 expression in biopsy versus resection. (<b>b</b>) CD163 expression in biopsy versus resection. (<b>c</b>) CD68/CD163 ratio of expression in biopsy versus resection. (<b>d</b>) GLUT-1 expression in biopsy versus resection. (<b>e</b>) HIF-1α expression in biopsy versus resection. (<b>f</b>) TGF-β expression in biopsy versus resection. The boxplots show the labelling indices (LIs) of CD68 (<b>a</b>), CD163 (<b>b</b>), the CD68/CD163 ratio (<b>c</b>), GLUT-1 (<b>d</b>), HIF-1α (<b>e</b>) and TGF-β (<b>f</b>) in OSCC biopsy (orange) and OSCC resection (red). The analyzed tissue compartment was both the epithelial tumor compartment and the tumor stroma, the overall specimen. The Man–Whitney U test was used for the statistical analysis. The significant <span class="html-italic">p</span>-values are marked bold.</p> Full article ">Figure 4
<p>Comparison of tissue stromal LIs in biopsy (pre RCT) and resection (post RCT). (<b>a</b>) CD68 expression in biopsy versus resection. (<b>b</b>) CD163 expression in biopsy versus resection. (<b>c</b>) CD68/CD163 ratio of expression in biopsy versus resection. (<b>d</b>) GLUT-1 expression in biopsy versus resection. (<b>e</b>) HIF-1α expression in biopsy versus resection. (<b>f</b>) TGF-β expression in biopsy versus resection. The boxplots show the labelling indices (LIs) of CD68 (<b>a</b>), CD163 (<b>b</b>), the CD86/CD163 ratio (<b>c</b>), GLUT-1 (<b>d</b>), HIF-1α (<b>e</b>) and TGF-β (<b>f</b>) in OSCC biopsy (orange) and OSCC resection (red). The analyzed tissue compartment was the stroma only. The Man–Whitney U test was used for the statistical analysis. The significant p-values are marked bold.</p> Full article ">
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