Abstract
The concept that progression of cancer is regulated by interactions of cancer cells with their microenvironment was postulated by Stephen Paget over a century ago. Contemporary tumour microenvironment (TME) research focuses on the identification of tumour-interacting microenvironmental constituents, such as resident or infiltrating non-tumour cells, soluble factors and extracellular matrix components, and the large variety of mechanisms by which these constituents regulate and shape the malignant phenotype of tumour cells. In this Timeline article, we review the developmental phases of the TME paradigm since its initial description. While illuminating controversies, we discuss the importance of interactions between various microenvironmental components and tumour cells and provide an overview and assessment of therapeutic opportunities and modalities by which the TME can be targeted.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Schmidt, A. & Weber, O. F. In memoriam of Rudolf Virchow: a historical retrospective including aspects of inflammation, infection and neoplasia. Contrib. Microbiol. 13, 1–15 (2006).
Paget, S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 8, 98–101 (1989).
Witz, I. P. & Levy-Nissenbaum, O. The tumor microenvironment in the post-PAGET era. Cancer Lett. 242, 1–10 (2006).
Mueller, M. M. & Fusenig, N. E. Friends or foes – bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 4, 839–849 (2004).
Jodele, S., Blavier, L., Yoon, J. M. & DeClerck, Y. A. Modifying the soil to affect the seed: role of stromal-derived matrix metalloproteinases in cancer progression. Cancer Metastasis Rev. 25, 35–43 (2006).
Talmadge, J. E. & Fidler, I. J. AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res. 70, 5649–5669 (2010).
Vogelstein, B. & Kinzler, K. W. The multistep nature of cancer. Trends Genet. 9, 138–141 (1993).
Vogelstein, B. & Kinzler, K. W. Cancer genes and the pathways they control. Nat. Med. 10, 789–799 (2004).
Richmond, A. & Thomas, H. G. Melanoma growth stimulatory activity: isolation from human melanoma tumors and characterization of tissue distribution. J. Cell. Biochem. 36, 185–198 (1988).
Aguirre Ghiso, J. A., Alonso, D. F., Farias, E. F., Gomez, D. E. & de Kier Joffe, E. B. Deregulation of the signaling pathways controlling urokinase production. Its relationship with the invasive phenotype. Eur. J. Biochem. 263, 295–304 (1999).
Weaver, V. M., Fischer, A. H., Peterson, O. W. & Bissell, M. J. The importance of the microenvironment in breast cancer progression: recapitulation of mammary tumorigenesis using a unique human mammary epithelial cell model and a three-dimensional culture assay. Biochem. Cell Biol. 74, 833–851 (1996).
Pohl, J., Radler-Pohl, A. & Schirrmacher, V. A model to account for the effects of oncogenes, TPA, and retinoic acid on the regulation of genes involved in metastasis. Cancer Metastasis Rev. 7, 347–356 (1988).
Levi-Montalcini, R. & Hamburger, V. Selective growth stimulating effects of mouse sarcoma on the sensory and sympathetic nervous system of the chick embryo. J. Exp. Zool. 116, 321–361 (1951).
Cohen, S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J. Biol. Chem. 237, 1555–1562 (1962).
Sutherland, E. W. & Rall, T. W. Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles. J. Biol. Chem. 232, 1077–1091 (1958).
Gilman, A. G. G proteins and dual control of adenylate cyclase. Cell 36, 577–579 (1984).
Sager, R. Expression genetics in cancer: shifting the focus from DNA to RNA. Proc. Natl Acad. Sci. USA 94, 952–955 (1997).
Szatrowski, T. P. & Nathan, C. F. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 51, 794–798 (1991).
Witz, I. P. Tumor-microenvironment interactions: dangerous liaisons. Adv. Cancer Res. 100, 203–222 (2008).
Vaupel, P., Kallinowski, F. & Okunieff, P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 49, 6449–6465 (1989).
Radinsky, R. Paracrine growth regulation of human colon carcinoma organ-specific metastasis. Cancer Metastasis Rev. 12, 345–361 (1993).
Stracke, M. L., Murata, J., Aznavoorian, S. & Liotta, L. A. The role of the extracellular matrix in tumor cell metastasis. In Vivo 8, 49–58 (1994).
Nicolson, G. L. Tumor microenvironment: paracrine and autocrine growth mechanisms and metastasis to specific sites. Front. Radiat. Ther. Oncol. 28, 11–24 (1994).
Shih, I. M. & Herlyn, M. Autocrine and paracrine roles for growth factors in melanoma. In Vivo 8, 113–123 (1994).
Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).
Orimo, A. & Weinberg, R. A. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle 5, 1597–1601 (2006).
Witz, I. P. Yin-yang activities and vicious cycles in the tumor microenvironment. Cancer Res. 68, 9–13 (2008).
Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nature reviews. Cancer 9, 239–252 (2009).
Pickup, M., Novitskiy, S. & Moses, H. L. The roles of TGFbeta in the tumour microenvironment. Nat. Rev. Cancer 13, 788–799 (2013).
Klein-Goldberg, A., Maman, S. & Witz, I. P. The role played by the microenvironment in site-specific metastasis. Cancer Lett. 352, 54–58 (2014).
Noback, C. R. Placentation and angiogenesis in the amnion of a baboon (Papio papio). Anat. Rec. 94, 553–567 (1946).
Folkman, J., Merler, E., Abernathy, C. & Williams, G. Isolation of a tumor factor responsible for angiogenesis. J. Exp. Med. 133, 275–288 (1971).
O’Reilly, M. S. et al. Angiostatin: a circulating endothelial cell inhibitor that suppresses angiogenesis and tumor growth. Cold Spring Harb. Symp. Quant. Biol. 59, 471–482 (1994).
Auerbach, R., Arensman, R., Kubai, L. & Folkman, J. Tumor-induced angiogenesis: lack of inhibition by irradiation. Int. J. Cancer 15, 241–245 (1975).
Langer, R., Conn, H., Vacanti, J., Haudenschild, C. & Folkman, J. Control of tumor growth in animals by infusion of an angiogenesis inhibitor. Proc. Natl Acad. Sci. USA 77, 4331–4335 (1980).
Gimbrone, M. A. Jr., Leapman, S. B., Cotran, R. S. & Folkman, J. Tumor dormancy in vivo by prevention of neovascularization. J. Exp. Med. 136, 261–276 (1972).
Folkman, J. The role of angiogenesis in tumor growth. Semin. Cancer Biol. 3, 65–71 (1992).
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).
Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306–1309 (1989).
Leek, R. D. et al. Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J. Pathol. 190, 430–436 (2000).
Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592–603 (2008).
Ebos, J. M., Lee, C. R. & Kerbel, R. S. Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin. Cancer Res. 15, 5020–5025 (2009).
Li, J. L. et al. DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res. 71, 6073–6083 (2011).
Partanen, J. et al. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol. Cell. Biol. 12, 1698–1707 (1992).
Maisonpierre, P. C. et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55–60 (1997).
Biel, N. M. & Siemann, D. W. Targeting the Angiopoietin-2/Tie-2 axis in conjunction with VEGF signal interference. Cancer Lett. 380, 525–533 (2016).
De Palma, M., Murdoch, C., Venneri, M. A., Naldini, L. & Lewis, C. E. Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends Immunol. 28, 519–524 (2007).
Mazzieri, R. et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19, 512–526 (2011).
Frentzas, S. et al. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nature Med. 22, 1294–1302 (2016).
Jayson, G. C., Kerbel, R., Ellis, L. M. & Harris, A. L. Antiangiogenic therapy in oncology: current status and future directions. Lancet 388, 518–529 (2016).
Annabi, B., Naud, E., Lee, Y. T., Eliopoulos, N. & Galipeau, J. Vascular progenitors derived from murine bone marrow stromal cells are regulated by fibroblast growth factor and are avidly recruited by vascularizing tumors. J. Cell. Biochem. 91, 1146–1158 (2004).
Garcia-Barros, M. et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300, 1155–1159 (2003).
De Palma, M., Venneri, M. A., Roca, C. & Naldini, L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat. Med. 9, 789–795 (2003).
Iwasaki, A. & Medzhitov, R. Control of adaptive immunity by the innate immune system. Nat. Immunol. 16, 343–353 (2015).
Wang, K. & Karin, M. Tumor-elicited inflammation and colorectal cancer. Adv. Cancer Res. 128, 173–196 (2015).
Oberyszyn, T. M. Inflammation and wound healing. Front. Biosci. 12, 2993–2999 (2007).
Martin, P. & Leibovich, S. J. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol. 15, 599–607 (2005).
Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).
Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759–771 (2013).
Devroede, G. J., Taylor, W. F., Sauer, W. G., Jackman, R. J. & Stickler, G. B. Cancer risk and life expectancy of children with ulcerative colitis. N. Engl. J. Med. 285, 17–21 (1971).
Viaje, A., Slaga, T. J., Wigler, M. & Weinstein, I. B. Effects of antiinflammatory agents on mouse skin tumor promotion, epidermal DNA synthesis, phorbol ester-induced cellular proliferation, and production of plasminogen activator. Cancer Res. 37, 1530–1536 (1977).
Lynch, N. R., Castes, M., Astoin, M. & Salomon, J. C. Mechanism of inhibition of tumour growth by aspirin and indomethacin. Br. J. Cancer 38, 503–512 (1978).
Gorog, P. & Kovacs, I. B. Experimental inflammation and tumor growth: chemical carcinogenesis in adjuvant arthritic rats. Inflammation 3, 359–364 (1979).
Zajicek, G. Inflammation initiates cancer by depleting stem cells. Med. Hypotheses 18, 207–219 (1985).
Borrello, M. G. et al. Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1oncogene. Proc. Natl Acad. Sci. USA 102, 14825–14830 (2005).
Ancrile, B., & Lim, K. H. & Counter, C. M. Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev. 21, 1714–1719 (2007).
Donnelly, B. A. Primary “inflammatory” carcinoma of the breast: a report of five cases and a review of the literature. Ann. Surg. 128, 918–930 (1948).
Costa, R. et al. Developmental therapeutics for inflammatory breast cancer: biology and translational directions. Oncotarget 8, 12417–12432 (2016).
Haupt, H. M., Hood, A. F. & Cohen, M. H. Inflammatory melanoma. J. Am. Acad. Dermatol. 10, 52–55 (1984).
Klein, E., Becker, S., Svedmyr, E., Jondal, M. & Vanky, F. Tumor infiltrating lymphocytes. Ann. NY Acad. Sci. 276, 207–216 (1976).
Richters, A. & Kaspersky, C. L. Surface immunoglobulin positive lymphocytes in human breast cancer tissue and homolateral axillary lymph nodes. Cancer 35, 129–133 (1975).
Brubaker, D. B. & Whiteside, T. L. Localization of human T lymphocytes in tissue sections by a rosetting technique. Am. J. Pathol. 88, 323–332 (1977).
Yron, I., Wood, T. A. Jr., Spiess, P. J. & Rosenberg, S. A. In vitro growth of murine T cells. V. The isolation and growth of lymphoid cells infiltrating syngeneic solid tumors. J. Immunol. 125, 238–245 (1980).
Vose, B. M., Vanky, F., Argov, S. & Klein, E. Natural cytotoxicity in man: activity of lymph node and tumor-infiltrating lymphocytes. Eur. J. Immunol. 7, 353–357 (1977).
Brunner, K. T., MacDonald, H. R. & Cerottini, J. C. Quantitation and clonal isolation of cytolytic T lymphocyte precursors selectively infiltrating murine sarcoma virus-induced tumors. J. Exp. Med. 154, 362–373 (1981).
Vose, B. M. & Moore, M. Human tumor-infiltrating lymphocytes: a marker of host response. Semin. Hematol. 22, 27–40 (1985).
Chiou, S. H., Sheu, B. C., Chang, W. C., Huang, S. C. & Hong-Nerng, H. Current concepts of tumor-infiltrating lymphocytes in human malignancies. J. Reprod. Immunol. 67, 35–50 (2005).
Zolla, S. The effect of plasmacytomas on the immune response of mice. J. Immunol. 108, 1039–1048 (1972).
Fischer, B., Muller, B., Fischer, K. G., Baur, N. & Kreutz, W. Acidic pH inhibits non-MHC-restricted killer cell functions. Clin. Immunol. 96, 252–263 (2000).
Drake, C. G., Jaffee, E. & Pardoll, D. M. Mechanisms of immune evasion by tumors. Adv. Immunol. 90, 51–81 (2006).
Gajewski, T. F., Meng, Y. & Harlin, H. Immune suppression in the tumor microenvironment. J. Immunother. 29, 233–240 (2006).
Rosenberg, S. A., Spiess, P. & Lafreniere, R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233, 1318–1321 (1986).
Kodumudi, K. N. et al. Immune checkpoint blockade to improve tumor infiltrating lymphocytes for adoptive cell therapy. PLoS ONE 11, e0153053 (2016).
Fernandez-Poma, S. M. et al. Expansion of tumor-infiltrating CD8+ T cells expressing PD-1 improves the efficacy of adoptive T cell therapy. Cancer Res. 77, 3672–3684 (2017).
Parkhurst, M. et al. Isolation of T-cell receptors specifically reactive with mutated tumor-associated antigens from tumor-infiltrating lymphocytes based on CD137 expression. Clin. Cancer Res. 23, 2491–2505 (2017).
Gross, G., Waks, T. & Eshhar, Z. Expression of immunoglobulin-T cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc. Natl Acad. Sci. USA 86, 10024–10028 (1989).
Goverman, J. et al. Chimeric immunoglobulin-T cell receptor proteins form functional receptors: implications for T cell receptor complex formation and activation. Cell 60, 929–939 (1990).
Almasbak, H., Aarvak, T. & Vemuri, M. C. CAR T cell therapy: a game changer in cancer treatment. J. Immunol. Res. 2016, 5474602 (2016).
Pegram, H. J., Smith, E. L., Rafiq, S. & Brentjens, R. J. CAR therapy for hematological cancers: can success seen in the treatment of B cell acute lymphoblastic leukemia be applied to other hematological malignancies? Immunotherapy 7, 545–561 (2015).
Gauthier, J. & Yakoub-Agha, I. Chimeric antigen-receptor T cell therapy for hematological malignancies and solid tumors: clinical data to date, current limitations and perspectives. Curr. Res. Transl Med. 65, 93–102 (2017).
Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49 (2011).
Brodbeck, T., Nehmann, N., Bethge, A., Wedemann, G. & Schumacher, U. Perforin-dependent direct cytotoxicity in natural killer cells induces considerable knockdown of spontaneous lung metastases and computer modelling-proven tumor cell dormancy in a HT29 human colon cancer xenograft mouse model. Mol. Cancer 13, 244 (2014).
Langers, I., Renoux, V. M., Thiry, M., Delvenne, P. & Jacobs, N. Natural killer cells: role in local tumor growth and metastasis. Biologics 6, 73–82 (2012).
Sceneay, J. et al. Primary tumor hypoxia recruits CD11b+ /Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res. 72, 3906–3911 (2012).
Witz, I. P. Tumor-bound immunoglobulins: in situ expressions of humoral immunity. Adv. Cancer Res. 25, 95–148 (1977).
Ran, M. & Witz, I. P. Tumor-associated immunoglobulins. Enhancement of syngeneic tumors by IgG2-containing tumor eluates. Int. J. Cancer 9, 242–247 (1972).
Tan, T. T. & Coussens, L. M. Humoral immunity, inflammation and cancer. Curr. Opin. Immunol. 19, 209–216 (2007).
de Visser, K. E., Korets, L. V. & Coussens, L. M. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7, 411–423 (2005).
Pylayeva-Gupta, Y. et al. IL35-producing B cells promote the development of pancreatic neoplasia. Cancer Discov. 6, 247–255 (2016).
Affara, N. I. et al. B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell 25, 809–821 (2014).
Andreu, P. et al. FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17, 121–134 (2010).
Hersh, E. M., Mavligit, G. M., Gutterman, J. U. & Barsales, P. B. Mononuclear cell content of human solid tumors. Med. Pediatr. Oncol. 2, 1–9 (1976).
Russel, S. W., Doe, W. F. & Cochrane, C. G. Number of macrophages and distribution of mitotic activity in regressing and progressing Moloney sarcomas. J. Immunol. 116, 164–166 (1976).
Totterman, T. H., Parthenais, E., Hayry, P., Timonen, T. & Saksela, E. Cytological and functional analysis of inflammatory infiltrates in human malignant tumors. III. Further functional investigations using cultured autochthonous tumor cell lines and freeze-thawed infiltrating inflammatory cells. Cell. Immunol. 55, 219–226 (1980).
Haskill, S., Becker, S., Fowler, W. & Walton, L. Mononuclear-cell infiltration in ovarian cancer. I. Inflammatory-cell infiltrates from tumour and ascites material. Br. J. Cancer 45, 728–736 (1982).
Kumar, V. & Gabrilovich, D. I. Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunology 143, 512–519 (2014).
Evans, R. Macrophages and neoplasms: new insights and their implication in tumor immunobiology. Cancer Metastasis Rev. 1, 227–239 (1982).
Cianciolo, G. J. Antiinflammatory proteins associated with human and murine neoplasms. Biochim. Biophys. Acta 865, 69–82 (1986).
Woods, A. E. & Papadimitriou, J. M. The effect of inflammatory stimuli on the stroma of neoplasms: the involvement of mononuclear phagocytes. J. Pathol. 123, 165–174 (1977).
Kadhim, S. A. & Rees, R. C. Enhancement of tumor growth in mice: evidence for the involvement of host macrophages. Cell. Immunol. 87, 259–269 (1984).
Ronnov-Jessen, L., Petersen, O. W. & Bissell, M. J. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol. Rev. 76, 69–125 (1996).
Goede, V., Brogelli, L., Ziche, M. & Augustin, H. G. Induction of inflammatory angiogenesis by monocyte chemoattractant protein-1. Int. J. Cancer 82, 765–770 (1999).
Haskill, S., Koren, H., Becker, S., Fowler, W. & Walton, L. Mononuclear-cell infiltration in ovarian cancer. III. Suppressor-cell and ADCC activity of macrophages from ascitic and solid ovarian tumours. Br. J. Cancer 45, 747–753 (1982).
Kreider, J. W., Bartlett, G. L. & Butkiewicz, B. L. Relationship of tumor leucocytic infiltration to host defense mechanisms and prognosis. Cancer Metastasis Rev. 3, 53–74 (1984).
Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).
Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).
Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).
Harney, A. S. et al. Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov. 5, 932–943 CD-15-0012 (2015).
Penny, H. L. et al. Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma. Oncoimmunology 5, e1191731 (2016).
Segaliny, A. I. et al. Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment. Int. J. Cancer 137, 73–85 (2015).
Kitamura, T. et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med. 212, 1043–1059 (2015).
Engstrom, A., Erlandsson, A., Delbro, D. & Wijkander, J. Conditioned media from macrophages of M1, but not M2 phenotype, inhibit the proliferation of the colon cancer cell lines HT-29 and CACO-2. Int. J. Oncol. 44, 385–392 (2014).
Laoui, D. et al. Tumor-associated macrophages in breast cancer: distinct subsets, distinct functions. Int. J. Dev. Biol. 55, 861–867 (2011).
Snodgrass, M. J., Morahan, P. S. & Kaplan, A. M. Histopathology of the host response to Lewis lung carcinoma: modulation by pyran. J. Natl Cancer Inst. 55, 455–462 (1975).
Gregory, A. D. & Houghton, A. M. Tumor-associated neutrophils: new targets for cancer therapy. Cancer Res. 71, 2411–2416 (2011).
Brandau, S., Dumitru, C. A. & Lang, S. Protumor and antitumor functions of neutrophil granulocytes. Semin. Immunopathol. 35, 163–176 (2013).
Sagiv, J. Y. et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 10, 562–573 (2015).
Droeser, R. A. et al. High myeloperoxidase positive cell infiltration in colorectal cancer is an independent favorable prognostic factor. PLOS ONE 8, e64814 (2013).
Rao, H. L. et al. Increased intratumoral neutrophil in colorectal carcinomas correlates closely with malignant phenotype and predicts patients’ adverse prognosis. PLoS ONE 7, e30806 (2012).
Wikberg, M. L. et al. Neutrophil infiltration is a favorable prognostic factor in early stages of colon cancer. Hum. Pathol. 68, 193–202 (2017).
Thurnher, M. et al. Human renal-cell carcinoma tissue contains dendritic cells. Int. J. Cancer 68, 1–7 (1996).
Chaux, P., Hammann, A., Martin, F. & Martin, M. Surface phenotype and functions of tumor-infiltrating dendritic cells: CD8 expression by a cell subpopulation. Eur. J. Immunol. 23, 2517–2525 (1993).
Troy, A. J., Summers, K. L., Davidson, P. J., Atkinson, C. H. & Hart, D. N. Minimal recruitment and activation of dendritic cells within renal cell carcinoma. Clin. Cancer Res. 4, 585–593 (1998).
Zong, J., Keskinov, A. A., Shurin, G. V. & Shurin, M. R. Tumor-derived factors modulating dendritic cell function. Cancer Immunol. Immunother. 65, 821–833 (2016).
Ma, Y., Shurin, G. V., Gutkin, D. W. & Shurin, M. R. Tumor associated regulatory dendritic cells. Seminars Cancer Biol. 22, 298–306 (2012).
Veglia, F. & Gabrilovich, D. I. Dendritic cells in cancer: the role revisited. Curr. Opin. Immunol. 45, 43–51 (2017).
Strober, S. Natural suppressor (NS) cells, neonatal tolerance, and total lymphoid irradiation: exploring obscure relationships. Annu. Rev. Immunol. 2, 219–237 (1984).
Young, M. R., Kolesiak, K., Wright, M. A. & Gabrilovich, D. I. Chemoattraction of femoral CD34+ progenitor cells by tumor-derived vascular endothelial cell growth factor. Clin. Exp. Metastasis 17, 881–888 (1999).
Ostrand-Rosenberg, S. & Sinha, P. Myeloid-derived suppressor cells: linking inflammation and cancer. J. Immunol. 182, 4499–4506 (2009).
Marx, J. Cancer immunology. Cancer’s bulwark against immune attack: MDS cells. Science 319, 154–156 (2008).
Coussens, L. M. et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999).
Cimpean, A. M. et al. Mast cells in breast cancer angiogenesis. Crit. Rev. Oncol. Hematol. 115, 23–26 (2017).
Gasic, G. J., Gasic, T. B., Galanti, N., Johnson, T. & Murphy, S. Platelet-tumor-cell interactions in mice. The role of platelets in the spread of malignant disease. Int. J. Cancer 11, 704–718 (1973).
Nieswandt, B., Hafner, M., Echtenacher, B. & Mannel, D. N. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res. 59, 1295–1300 (1999).
Borsig, L. et al. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc. Natl Acad. Sci. USA 98, 3352–3357 (2001).
Labelle, M., Begum, S. & Hynes, R. O. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 20, 576–590 (2011).
Tang, M. et al. Platelet microparticle-mediated transfer of miR-939 to epithelial ovarian cancer cells promotes epithelial to mesenchymal transition. Oncotarget 8, 97464–97475 (2017).
Yan, M. & Jurasz, P. The role of platelets in the tumor microenvironment: From solid tumors to leukemia. Biochim. Biophys. Acta 1863, 392–400 (2016).
Unanue, E. R. & Dixon, F. J. Experimental glomerulonephritis. V. studies interaction nephrotoxic antibodies with tissue of the rat. J. Exp. Med. 121, 697–714 (1965).
Lerner, R. A., Glassock, R. J. & Dixon, F. J. The role of anti-glomerular basement membrane antibody in the pathogenesis of human glomerulonephritis. J. Exp. Med. 126, 989–1004 (1967).
Witz, I., Yagi, Y. & Pressman, D. IgG associated with microsomes from autochthonous hepatomas and normal liver of rats. Cancer Res. 27, 2295–2299 (1967).
Cahalon, L. et al. Autoantibody-mediated regulation of tumor growth. Ann. N Y Acad. Sci. 651, 393–408 (1992).
Ran, M., Klein, G. & Witz, I. P. Tumor-bound immunoglobulins. Evidence for the in vivo coating of tumor cells by potentially cytotoxic anti-tumour antibodies. Int. J. Cancer 17, 90–97 (1976).
Braslawsky, G. R., Yaackubowicz, M., Frensdorff, A. & Witz, I. P. Receptors for immune complexes on cells within a non-lymphoid murine tumor. J. Immunol. 116, 1571–1578 (1976).
Gergely, J. & Sarmay, G. Fc gamma receptors in malignancies: friends or enemies? Adv. Cancer Res. 64, 211–245 (1994).
Cohen-Solal, J. F. et al. Metastatic melanomas express inhibitory low affinity fc gamma receptor and escape humoral immunity. Dermatol. Res. Pract. 2010, 657406 (2010).
Zusman, T. et al. The murine Fc-gamma (Fc gamma) receptor type II B1 is a tumorigenicity-enhancing factor in polyoma-virus-transformed 3T3 cells. Int. J. Cancer 65, 221–229 (1996).
Zusman, T. et al. Contribution of the intracellular domain of murine Fc-gamma receptor type IIB1 to its tumor-enhancing potential. Int. J. Cancer 68, 219–227 (1996).
DiLillo, D. J. & Ravetch, J. V. Fc-receptor interactions regulate both cytotoxic and immunomodulatory therapeutic antibody effector functions. Cancer Immunol. Res. 3, 704–713 (2015).
Mantovani, A. Tumor-associated macrophages in neoplastic progression: a paradigm for the in vivo function of chemokines. Lab Invest. 71, 5–16 (1994).
Zou, L. et al. Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res. 64, 8451–8455 (2004).
Gobert, M. et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res. 69, 2000–2009 (2009).
Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).
Ben-Baruch, A. Organ selectivity in metastasis: regulation by chemokines and their receptors. Clin. Exp. Metastasis 25, 345–356 (2008).
Springer, T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76, 301–314 (1994).
Reymond, N., d’Agua, B. B. & Ridley, A. J. Crossing the endothelial barrier during metastasis. Nat. Rev. Cancer 13, 858–870 (2013).
Gospodarowicz, D., Greenburg, G. & Birdwell, C. R. Determination of cellular shape by the extracellular matrix and its correlation with the control of cellular growth. Cancer Res. 38, 4155–4171 (1978).
Vlodavsky, I., Lui, G. M. & Gospodarowicz, D. Morphological appearance, growth behavior and migratory activity of human tumor cells maintained on extracellular matrix versus plastic. Cell 19, 607–616 (1980).
Vlodavsky, I. & Gospodarowicz, D. Respective roles of laminin and fibronectin in adhesion of human carcinoma and sarcoma cells. Nature 289, 304–306 (1981).
Terranova, V. P., Liotta, L. A., Russo, R. G. & Martin, G. R. Role of laminin in the attachment and metastasis of murine tumor cells. Cancer Res. 42, 2265–2269 (1982).
Katz, B. Z. & Witz, I. P. In vitro exposure of polyoma-virus-transformed cells to laminin augments their in vivo malignancy phenotype. Invasion Metastasis 13, 185–194 (1993).
Jun, S. et al. Laminin adhesion-selected primary human colon-cancer cells are more tumorigenic than the parenteral and nonadherent cells. Int. J. Oncol. 4, 55–60 (1994).
Yamamura, K., Kibbey, M. C. & Kleinman, H. K. Melanoma cells selected for adhesion to laminin peptides have different malignant properties. Cancer Res. 53, 423–428 (1993).
Wai, P. Y. et al. Osteopontin silencing by small interfering RNA suppresses in vitro and in vivo CT26 murine colon adenocarcinoma metastasis. Carcinogenesis 26, 741–751 (2005).
Erler, J. T. & Weaver, V. M. Three-dimensional context regulation of metastasis. Clin. Exp. Metastasis 26, 35–49 (2009).
Bissell, M. J., Hall, H. G. & Parry, G. How does the extracellular matrix direct gene expression? J. Theor. Biol. 99, 31–68 (1982).
Dolberg, D. S. & Bissell, M. J. Inability of Rous sarcoma virus to cause sarcomas in the avian embryo. Nature 309, 552–556 (1984).
Dolberg, D. S., Hollingsworth, R., Hertle, M. & Bissell, M. J. Wounding and its role in RSV-mediated tumor formation. Science 230, 676–678 (1985).
Malik, R., Lelkes, P. I. & Cukierman, E. Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer. Trends Biotechnol. 33, 230–236 (2015).
Liu, H. et al. Therapeutic potential of perineural invasion, hypoxia and desmoplasia in pancreatic cancer. Curr. Pharm. Des. 18, 2395–2403 (2012).
Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 6, 392–401 (2006).
Dvorak, H. F., Dickersin, G. R., Dvorak, A. M., Manseau, E. J. & Pyne, K. Human breast carcinoma: fibrin deposits and desmoplasia. Inflammatory cell type and distribution. Microvasculature and infarction. J. Natl Cancer Inst. 67, 335–345 (1981).
Lubkin, S. R. & Jackson, T. Multiphase mechanics of capsule formation in tumors. J. Biomech. Eng. 124, 237–243 (2002).
Cardone, A., Tolino, A., Zarcone, R., Borruto Caracciolo, G. & Tartaglia, E. Prognostic value of desmoplastic reaction and lymphocytic infiltration in the management of breast cancer. Panminerva Med. 39, 174–177 (1997).
Ray, J. M. & Stetler-Stevenson, W. G. The role of matrix metalloproteases and their inhibitors in tumour invasion, metastasis and angiogenesis. Eur. Respir. J. 7, 2062–2072 (1994).
Liotta, L. A. & Stetler-Stevenson, W. G. Metalloproteinases and cancer invasion. Semin. Cancer Biol. 1, 99–106 (1990).
Matrisian, L. M. et al. The role of the matrix metalloproteinase stromelysin in the progression of squamous cell carcinomas. Am. J. Med. Sci. 302, 157–162 (1991).
Sternlicht, M. D., Bissell, M. J. & Werb, Z. The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter. Oncogene 19, 1102–1113 (2000).
Coussens, L. M. & Werb, Z. Matrix metalloproteinases and the development of cancer. Chem. Biol. 3, 895–904 (1996).
Coussens, L. M., Tinkle, C. L., Hanahan, D. & Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103, 481–490 (2000).
Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2, 737–744 (2000).
Brown, P. D. Matrix metalloproteinase inhibitors in the treatment of cancer. Med. Oncol. 14, 1–10 (1997).
Whittaker, M. & Brown, P. Recent advances in matrix metalloproteinase inhibitor research and development. Curr. Opin. Drug Discov. Devel. 1, 157–164 (1998).
Brown, P. D. Clinical studies with matrix metalloproteinase inhibitors. Acta Pathol. Microbiol. Immunol. Scand. C. 107, 174–180 (1999).
Wagenaar-Miller, R. A., Gorden, L. & Matrisian, L. M. Matrix metalloproteinases in colorectal cancer: is it worth talking about? Cancer Metastasis Rev. 23, 119–135 (2004).
Mannello, F., Tonti, G. & Papa, S. Matrix metalloproteinase inhibitors as anticancer therapeutics. Curr. Cancer Drug Targets 5, 285–298 (2005).
Decock, J., Thirkettle, S., Wagstaff, L. & Edwards, D. R. Matrix metalloproteinases: protective roles in cancer. J. Cell. Mol. Med. 15, 1254–1265 (2011).
Levin, M., Udi, Y., Solomonov, I. & Sagi, I. Next generation matrix metalloproteinase inhibitors – novel strategies bring new prospects. Biochim. Biophys. Acta 1864, 1927–1939 (2017).
Pupa, S. M., Menard, S., Forti, S. & Tagliabue, E. New insights into the role of extracellular matrix during tumor onset and progression. J. Cell. Physiol. 192, 259–267 (2002).
Butler, T. P., Grantham, F. H. & Gullino, P. M. Bulk transfer of fluid in the interstitial compartment of mammary tumors. Cancer Res. 35, 3084–3088 (1975).
Boucher, Y. & Jain, R. K. Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Cancer Res. 52, 5110–5114 (1992).
Skobe, M. et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat. Med. 7, 192–198 (2001).
Helmlinger, G., Netti, P. A., Lichtenbeld, H. C., Melder, R. J. & Jain, R. K. Solid stress inhibits the growth of multicellular tumor spheroids. Nat. Biotechnol. 15, 778–783 (1997).
Samani, A., Zubovits, J. & Plewes, D. Elastic moduli of normal and pathological human breast tissues: an inversion-technique-based investigation of 169 samples. Phys. Med. Biol. 52, 1565–1576 (2007).
Sarntinoranont, M., Rooney, F. & Ferrari, M. Interstitial stress and fluid pressure within a growing tumor. Ann. Biomed. Eng. 31, 327–335 (2003).
Tomasek, J. J., Gabbiani, G., Hinz, B., Chaponnier, C. & Brown, R. A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 3, 349–363 (2002).
Discher, D. E., Janmey, P. & Wang, Y. L. Tissue cells feel and respond to the stiffness of their substrate. Science 310, 1139–1143 (2005).
Paszek, M. J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).
Butcher, D. T., Alliston, T. & Weaver, V. M. A tense situation: forcing tumour progression. Nat. Rev. Cancer 9, 108–122 (2009).
De Wever, O. & Mareel, M. Role of myofibroblasts at the invasion front. Biol. Chem. 383, 55–67 (2002).
Micke, P. & Ostman, A. Tumour-stroma interaction: cancer-associated fibroblasts as novel targets in anti-cancer therapy? Lung Cancer 45 (Suppl. 2), S163–175 (2004).
Delinassios, J. G., Kottaridis, S. D. & Garas, J. Uncontrolled growth of tumour stromal fibroblasts in vitro. Exp. Cell Biol. 51, 201–209 (1983).
Delinassios, J. G. Cytocidal effects of human fibroblasts on HeLa cells in vitro. Biol. Cell 59, 69–77 (1987).
Yan, G., Fukabori, Y., McBride, G., Nikolaropolous, S. & McKeehan, W. L. Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy. Mol. Cell. Biol. 13, 4513–4522 (1993).
Ellis, M. J., Singer, C., Hornby, A., Rasmussen, A. & Cullen, K. J. Insulin-like growth factor mediated stromal-epithelial interactions in human breast cancer. Breast Cancer Res. Treat. 31, 249–261 (1994).
Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).
Bucala, R., Ritchlin, C., Winchester, R. & Cerami, A. Constitutive production of inflammatory and mitogenic cytokines by rheumatoid synovial fibroblasts. J. Exp. Med. 173, 569–574 (1991).
Powell, D. W. et al. Myofibroblasts. I. Paracrine cells important in health and disease. Am. J. Physiol. 277, C1–C9 (1999).
Gaggioli, C. et al. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 9, 1392–1400 (2007).
Schofield, R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4, 7–25 (1978).
Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 3, 730–737 (1997).
Fuchs, E., Tumbar, T. & Guasch, G. Socializing with the neighbors: stem cells and their niche. Cell 116, 769–778 (2004).
Lu, P., Weaver, V. M. & Werb, Z. The extracellular matrix: a dynamic niche in cancer progression. J. Cell Biol. 196, 395–406 (2012).
Calabrese, C. et al. A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69–82 (2007).
Pistollato, F. et al. Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma. Stem Cells 28, 851–862 (2010).
Hjelmeland, A. B. et al. Acidic stress promotes a glioma stem cell phenotype. Cell Death Differ. 18, 829–840 (2011).
Charles, N. et al. Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell 6, 141–152 (2010).
Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 12, 468–476 (2010).
Lu, H. et al. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat. Cell Biol. 16, 1105–1117 (2014).
Zhou, W. et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat. Cell Biol. 17, 170–182 (2015).
Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).
Gullino, P. M., Clark, S. H. & Grantham, F. H. The interstitial fluid of solid tumors. Cancer Res. 24, 780–794 (1964).
Pavlides, S. et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8, 3984–4001 (2009).
Parks, S. K., Chiche, J. & Pouyssegur, J. Disrupting proton dynamics and energy metabolism for cancer therapy. Nat. Rev. Cancer 13, 611–623 (2013).
Thomlinson, R. H. & Gray, L. H. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Cancer 9, 539–549 (1955).
Overgaard, J. Effect of hyperthermia on malignant cells in vivo. A review and a hypothesis. Cancer 39, 2637–2646 (1977).
Teicher, B. A., Lazo, J. S. & Sartorelli, A. C. Classification of antineoplastic agents by their selective toxicities toward oxygenated and hypoxic tumor cells. Cancer Res. 41, 73–81 (1981).
Wilson, W. R. & Hay, M. P. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer 11, 393–410 (2011).
Vaupel, P., Fortmeyer, H. P., Runkel, S. & Kallinowski, F. Blood flow, oxygen consumption, and tissue oxygenation of human breast cancer xenografts in nude rats. Cancer Res. 47, 3496–3503 (1987).
Goldberg, M. A., Dunning, S. P. & Bunn, H. F. Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. Science 242, 1412–1415 (1988).
Alabaster, O., Woods, T., Ortiz-Sanchez, V. & Jahangeer, S. Influence of microenvironmental pH on adriamycin resistance. Cancer Res. 49, 5638–5643 (1989).
Tannock, I. F. & Rotin, D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res. 49, 4373–4384 (1989).
Kourembanas, S., Marsden, P. A., McQuillan, L. P. & Faller, D. V. Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. J. Clin. Invest. 88, 1054–1057 (1991).
Semenza, G. L., Roth, P. H., Fang, H. M. & Wang, G. L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J. Biol. Chem. 269, 23757–23763 (1994).
Wang, G. L. & Semenza, G. L. Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem. 270, 1230–1237 (1995).
Semenza, G. L. The hypoxic tumor microenvironment: a driving force for breast cancer progression. Biochim. Biophys. Acta 1863, 382–391 (2016).
Denko, N. C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat. Rev. Cancer 8, 705–713 (2008).
Giaccia, A., Siim, B. G. & Johnson, R. S. HIF-1 as a target for drug development. Nat. Rev. Drug Discov. 2, 803–811 (2003).
Reddy, B. S., Mastromarino, A. & Wynder, E. L. Further leads on metabolic epidemiology of large bowel cancer. Cancer Res. 35, 3403–3406 (1975).
McBurney, M. I., Van Soest, P. J. & Jeraci, J. L. Colonic carcinogenesis: the microbial feast or famine mechanism. Nutr. Cancer 10, 23–28 (1987).
Dalmasso, G., Cougnoux, A., Delmas, J., Darfeuille-Michaud, A. & Bonnet, R. The bacterial genotoxin colibactin promotes colon tumor growth by modifying the tumor microenvironment. Gut Microbes 5, 675–680 (2014).
Kipanyula, M. J. et al. Signaling pathways bridging microbial-triggered inflammation and cancer. Cell Signal 25, 403–416 (2013).
Grivennikov, S. I. et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491, 254–258 (2012).
Pidgeon, G. P. et al. The role of endotoxin/lipopolysaccharide in surgically induced tumour growth in a murine model of metastatic disease. Br. J. Cancer 81, 1311–1317 (1999).
Dzutsev, A., Goldszmid, R. S., Viaud, S., Zitvogel, L. & Trinchieri, G. The role of the microbiota in inflammation, carcinogenesis, and cancer therapy. Eur. J. Immunol. 45, 17–31 (2015).
Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967–970 (2013).
Viaud, S. et al. Harnessing the intestinal microbiome for optimal therapeutic immunomodulation. Cancer Res. 74, 4217–4221 (2014).
Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).
Cantwell, A. R. Jr. Bacteriologic investigation and histologic observations of variably acid-fast bacteria in three cases of cutaneous Kaposi’s sarcoma. Growth 45, 79–89 (1981).
Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).
Kaplan, R. N., Psaila, B. & Lyden, D. Niche-to-niche migration of bone-marrow-derived cells. Trends Mol. Med. 13, 72–81 (2007).
van Deventer, H. W., Palmieri, D. A., Wu, Q. P., McCook, E. C. & Serody, J. S. Circulating fibrocytes prepare the lung for cancer metastasis by recruiting Ly-6 C+ monocytes via CCL2. J. Immunol. 190, 4861–4867 (2013).
Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).
Peinado, H. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18, 883–891 (2012).
Costa-Silva, B. et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17, 816–826 (2015).
Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015).
Zhang, L. et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527, 100–104 (2015).
Gabriel, K. et al. Regulation of the tumor suppressor PTEN through exosomes: a diagnostic potential for prostate cancer. PLoS ONE 8, e70047 (2013).
Putz, U. et al. The tumor suppressor PTEN is exported in exosomes and has phosphatase activity in recipient cells. Sci. Signal 5, ra70. (2012).
Duda, D. G. & Jain, R. K. Premetastatic lung “niche”: is vascular endothelial growth factor receptor 1 activation required? Cancer Res. 70, 5670–5673 (2010).
Dawson, M. R., Duda, D. G., Fukumura, D. & Jain, R. K. VEGFR1-activity-independent metastasis formation. Nature 461, E4 discussion E5. (2009).
Cox, T. R., Gartland, A. & Erler, J. T. The pre-metastatic niche: is metastasis random? Bonekey Rep. 1, 80 (2012).
Tarin, D. & Price, J. E. Metastatic colonization potential of primary tumour cells in mice. Br. J. Cancer 39, 740–754 (1979).
Tarin, D. & Price, J. E. Influence of microenvironment and vascular anatomy on “metastatic” colonization potential of mammary tumors. Cancer Res. 41, 3604–3609 (1981).
Horak, E., Darling, D. L. & Tarin, D. Analysis of organ-specific effects on metastatic tumor formation by studies in vitro. J. Natl Cancer Inst. 76, 913–922 (1986).
Nicolson, G. L. Organ specificity of tumor metastasis: role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites. Cancer Metastasis Rev. 7, 143–188 (1988).
Price, J. E., Naito, S. & Fidler, I. J. Growth in an organ microenvironment as a selective process in metastasis. Clin. Exp. Metastasis 6, 91–102 (1988).
Pauli, B. U., Augustin-Voss, H. G., el-Sabban, M. E., Johnson, R. C. & Hammer, D. A. Organ-preference of metastasis. The role of endothelial cell adhesion molecules. Cancer Metastasis Rev. 9, 175–189 (1990).
Pienta, K. J., Robertson, B. A., Coffey, D. S. & Taichman, R. S. The cancer diaspora: metastasis beyond the seed and soil hypothesis. Clin. Cancer Res. 19, 5849–5855 (2013).
Coman, D. R. Mechanisms responsible for the origin and distribution of blood-borne tumor metastases: a review. Cancer Res. 13, 397–404 (1953).
Fidler, I. J. & Nicolson, G. L. Organ selectivity for implantation survival and growth of B16 melanoma variant tumor lines. J. Natl Cancer Inst. 57, 1199–1202 (1976).
Sato, Y., Goto, Y., Narita, N. & Hoon, D. S. Cancer cells expressing toll-like receptors and the tumor microenvironment. Cancer Microenviron. 2 (Suppl. 1), 205–214 (2009).
Maman, S. & Witz, I.P. The metastatic microenvironment. In: The tumor immunoenvironment. Shurin, M.R., Umansky, V., Malyguine, A., editors. New York, NY: Springer, 745 (2013).
Lowery, F. J. & Yu, D. Growth factor signaling in metastasis: current understanding and future opportunities. Cancer Metastasis Rev. 31, 479–491 (2012).
Nguyen, D. X., Bos, P. D. & Massague, J. Metastasis: from dissemination to organ-specific colonization. Nat. Rev. Cancer 9, 274–284 (2009).
Wculek, S. K. & Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413–417 (2015).
Hoon, D. S. et al. Molecular mechanisms of metastasis. J. Surg. Oncol. 103, 508–517 (2011).
Zlotnik, A., Burkhardt, A. M. & Homey, B. Homeostatic chemokine receptors and organ-specific metastasis. Nat. Rev. Immunol. 11, 597–606 (2011).
Ye, X. & Weinberg, R. A. Epithelial-mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol. 25, 675–686 (2015).
Fischer, K. R. et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527, 472–476 (2015).
Zheng, X. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015).
Montesano, R., Matsumoto, K., Nakamura, T. & Orci, L. Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor. Cell 67, 901–908 (1991).
Miettinen, P. J., Ebner, R., Lopez, A. R. & Derynck, R. TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J. Cell Biol. 127, 2021–2036 (1994).
Bates, R. C. & Mercurio, A. M. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol. Biol. Cell 14, 1790–1800 (2003).
Sullivan, D. E., Ferris, M., Nguyen, H., Abboud, E. & Brody, A. R. TNF-alpha induces TGF-beta1 expression in lung fibroblasts at the transcriptional level via AP-1 activation. J. Cell. Mol. Med. 13, 1866–1876 (2009).
Sullivan, N. J. et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 28, 2940–2947 (2009).
Yang, M. H. et al. Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat. Cell Biol. 10, 295–305 (2008).
Leight, J. L., Wozniak, M. A., Chen, S., Lynch, M. L. & Chen, C. S. Matrix rigidity regulates a switch between TGF-beta1-induced apoptosis and epithelial-mesenchymal transition. Mol. Biol. Cell 23, 781–791 (2012).
Ye, X. et al. Upholding a role for EMT in breast cancer metastasis. Nature 547, E1–E3 (2017).
Nieto, M. A. Context-specific roles of EMT programmes in cancer cell dissemination. Nat. Cell Biol. 19, 416–418 (2017).
Dearnaley, D. P. et al. Increased detection of mammary carcinoma cells in marrow smears using antisera to epithelial membrane antigen. Br. J. Cancer 44, 85–90 (1981).
Schlimok, G. et al. In vivo and in vitro labelling of epithelial tumor cells with anti 17-1A monoclonal antibodies in bone marrow of cancer patients. Hybridoma 5 (Suppl. 1), S163–S170 (1986).
Riethmuller, G. & Johnson, J. P. Monoclonal antibodies in the detection and therapy of micrometastatic epithelial cancers. Curr. Opin. Immunol. 4, 647–655 (1992).
Wikman, H., Vessella, R. & Pantel, K. Cancer micrometastasis and tumour dormancy. Acta Pathol. Microbiol. Immunol. Scand. C. 116, 754–770 (2008).
Townson, J. L. & Chambers, A. F. Dormancy of solitary metastatic cells. Cell Cycle 5, 1744–1750 (2006).
Izraely, S. et al. The metastatic microenvironment: brain-residing melanoma metastasis and dormant micrometastasis. Int. J. Cancer 131, 1071–1082 (2012).
Edry Botzer, L. et al. Lung-residing metastatic and dormant neuroblastoma cells. Am. J. Pathol. 179, 524–536 (2011).
Sosa, M. S., Bragado, P. & Aguirre-Ghiso, J. A. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat. Rev. Cancer 14, 611–622 (2014).
Aguirre-Ghiso, J. A., Liu, D., Mignatti, A., Kovalski, K. & Ossowski, L. Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol. Biol. Cell 12, 863–879 (2001).
Gray, B. N. & Watkins, E. Jr. Immunologic approach to cancer therapy. Med. Clin. North Am. 59, 327–337 (1975).
Yefenof, E. et al. Induction of B cell tumor dormancy by anti-idiotypic antibodies. Curr. Opin. Immunol. 5, 740–744 (1993).
Racila, E. et al. Tumor dormancy and cell signaling. II. Antibody as an agonist in inducing dormancy of a B cell lymphoma in SCID mice. J. Exp. Med. 181, 1539–1550 (1995).
Uhr, J. W. et al. Role of antibody signaling in inducing tumor dormancy. Adv. Exp. Med. Biol. 406, 69–74 (1996).
Farrar, J. D. et al. Cancer dormancy. VII. A regulatory role for CD8+ T cells and IFN-gamma in establishing and maintaining the tumor-dormant state. J. Immunol. 162, 2842–2849 (1999).
Gohongi, T. et al. Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor beta1. Nat. Med. 5, 1203–1208 (1999).
Tse, J. C. & Kalluri, R. Waking up dormant tumors. Breast Cancer Res. 13, 310 (2011).
Bragado, P., Sosa, M. S., Keely, P., Condeelis, J. & Aguirre-Ghiso, J. A. Microenvironments dictating tumor cell dormancy. Recent Results Cancer Res. 195, 25–39 (2012).
Maman, S. et al. The beta subunit of hemoglobin (HBB2/HBB) suppresses neuroblastoma growth and metastasis. Cancer Res. 77, 14–26 (2017).
Leung, C. T. & Brugge, J. S. Outgrowth of single oncogene-expressing cells from suppressive epithelial environments. Nature 482, 410–413 (2012).
Elkabets, M. et al. Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice. J. Clin. Invest. 121, 784–799 (2011).
Bailey-Downs, L. C. et al. Development and characterization of a preclinical model of breast cancer lung micrometastatic to macrometastatic progression. PLoS ONE 9, e98624 (2014).
Willis, L. et al. What can be learnt about disease progression in breast cancer dormancy from relapse data? PLoS ONE 8, e62320 (2013).
Sleeman, J. P. The lymph node as a bridgehead in the metastatic dissemination of tumors. Recent Results Cancer Res. 157, 55–81 (2000).
Gould, E. A., Winship, T., Philbin, P. H. & Kerr, H. H. Observations on a “sentinel node” in cancer of the parotid. Cancer 13, 77–78 (1960).
Cochran, A. J. et al. Sentinel lymph nodes show profound downregulation of antigen-presenting cells of the paracortex: implications for tumor biology and treatment. Mod. Pathol. 14, 604–608 (2001).
Qian, C. N. et al. Preparing the “soil”: the primary tumor induces vasculature reorganization in the sentinel lymph node before the arrival of metastatic cancer cells. Cancer Res. 66, 10365–10376 (2006).
Hood, J. L., San, R. S. & Wickline, S. A. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 71, 3792–3801 (2011).
Essner, R. Sentinel lymph node biopsy and melanoma biology. Clin Cancer Res. 12, 2320s–2325s. (2006).
Riedel, A., Shorthouse, D., Haas, L., Hall, B. A. & Shields, J. Tumor-induced stromal reprogramming drives lymph node transformation. Nat. Immunol. 17, 1118–1127 (2016).
Wong, S. Y. & Hynes, R. O. Tumor-lymphatic interactions in an activated stromal microenvironment. J. Cell. Biochem. 101, 840–850 (2007).
Nathanson, S. D., Shah, R. & Rosso, K. Sentinel lymph node metastases in cancer: causes, detection and their role in disease progression. Semin. Cell Dev. Biol. 38, 106–116 (2015).
Naxerova, K. et al. Origins of lymphatic and distant metastases in human colorectal cancer. Science 357, 55–60 (2017).
Kwok, T. T. & Twentyman, P. R. The relationship between tumour geometry and the response of tumour cells to cytotoxic drugs—an in vitro study using EMT6 multicellular spheroids. Int. J. Cancer 35, 675–682 (1985).
Kroemer, G. Galluzzi, L. Kepp, O & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).
Siemann, D. W., Chapman, M. & Beikirch, A. Effects of oxygenation and pH on tumor cell response to alkylating chemotherapy. Int. J. Radiat. Oncol. Biol. Phys. 20, 287–289 (1991).
Durand, R. E. The influence of microenvironmental factors during cancer therapy. In Vivo 8, 691–702 (1994).
Fidler, I. J. et al. Modulation of tumor cell response to chemotherapy by the organ environment. Cancer Metastasis Rev. 13, 209–222 (1994).
van der Zee, J. Heating the patient: a promising approach? Ann. Oncol. 13, 1173–1184 (2002).
Bicher, H. I. et al. Effects of hyperthermia on normal and tumor microenvironment. Radiology 137, 523–530 (1980).
Gerweck, L. E. Modification of cell lethality at elevated temperatures. The pH effect. Radiat. Res. 70, 224–235 (1977).
Song, C. W. Effect of local hyperthermia on blood flow and microenvironment: a review. Cancer Res 44, 4721s–4730s (1984).
Rofstad, E. K. Step-down heating of human melanoma xenografts: effects of the tumour microenvironment. Br. J. Cancer 70, 453–458 (1994).
Novitzky, N. & Mohamed, R. Alterations in both the hematopoietic microenvironment and the progenitor cell population follow the recovery from myeloablative therapy and bone marrow transplantation. Exp. Hematol. 23, 1661–1666 (1995).
Galotto, M. et al. Stromal damage as consequence of high-dose chemo/radiotherapy in bone marrow transplant recipients. Exp. Hematol. 27, 1460–1466 (1999).
Imaizumi, N., Monnier, Y., Hegi, M., Mirimanoff, R. O. & Ruegg, C. Radiotherapy suppresses angiogenesis in mice through TGF-betaRI/ALK5-dependent inhibition of endothelial cell sprouting. PLoS ONE 5, e11084 (2010).
von Essen, C. F. Radiation enhancement of metastasis: a review. Clin. Exp. Metastasis 9, 77–104 (1991).
Katz, O. B. & Shaked, Y. Host effects contributing to cancer therapy resistance. Drug Resist. Updat. 19, 33–42 (2015).
Shiao, S. L. & Coussens, L. M. The tumor-immune microenvironment and response to radiation therapy. Drug Resist. Updat. 15, 411–421 (2010).
De Palma, M. & Lewis, C. E. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23, 277–286 (2013).
Welt, S. et al. Antibody targeting in metastatic colon cancer: a phase I study of monoclonal antibody F19 against a cell-surface protein of reactive tumor stromal fibroblasts. J. Clin. Oncol. 12, 1193–1203 (1994).
Zardi, L. & Neri, D. Affinity reagents against tumour-associated extracellular molecules and newforming vessels. Adv. Drug Deliv. Rev. 31, 43–52 (1998).
Sung, S. Y. & Chung, L. W. Prostate tumor-stroma interaction: molecular mechanisms and opportunities for therapeutic targeting. Differentiation 70, 506–521 (2002).
Muul, L. M., Spiess, P. J., Director, E. P. & Rosenberg, S. A. Identification of specific cytolytic immune responses against autologous tumor in humans bearing malignant melanoma. J. Immunol. 138, 989–995 (1987).
Chen, L. et al. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 71, 1093–1102 (1992).
Chambers, C. A., Kuhns, M. S., Egen, J. G. & Allison, J. P. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu. Rev. Immunol. 19, 565–594 (2001).
Nagai, H. et al. In vivo elimination of CD25+ regulatory T cells leads to tumor rejection of B16F10 melanoma, when combined with interleukin-12 gene transfer. Exp. Dermatol. 13, 613–620 (2004).
Medina-Echeverz, J. et al. Successful colon cancer eradication after chemoimmunotherapy is associated with profound phenotypic change of intratumoral myeloid cells. J. Immunol. 186, 807–815 (2011).
Byrne, W. L., Mills, K. H., Lederer, J. A. & O’Sullivan, G. C. Targeting regulatory T cells in cancer. Cancer Res. 71, 6915–6920 (2011).
Albeituni, S. H., Ding, C. & Yan, J. Hampering immune suppressors: therapeutic targeting of myeloid-derived suppressor cells in cancer. Cancer J. 19, 490–501 (2013).
Mole, R. H. Whole body irradiation; radiobiology or medicine? Br. J. Radiol 26, 234–241 (1953).
Demaria, S. et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int. J. Radiat. Oncol. Biol. Phys. 58, 862–870 (2004).
Golden, E. B. et al. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol. 16, 795–803 (2015).
Wahl, M. I. & Carpenter, G. Role of growth factors and their receptors in the control of normal cell proliferation and cancer. Clin. Physiol. Biochem. 5, 130–139 (1987).
Verstraete, K. & Savvides, S. N. Extracellular assembly and activation principles of oncogenic class III receptor tyrosine kinases. Nat. Rev. Cancer 12, 753–766 (2012).
Schwartz, G. K. et al. Inhibition of invasion of invasive human bladder carcinoma cells by protein kinase C inhibitor staurosporine. J. Natl Cancer Inst. 82, 1753–1756 (1990).
Yoneda, T. et al. The antiproliferative effects of tyrosine kinase inhibitors tyrphostins on a human squamous cell carcinoma in vitro and in nude mice. Cancer Res. 51, 4430–4435 (1991).
Minana, M. D., Felipo, V., Cortes, F. & Grisolia, S. Inhibition of protein kinase C arrests proliferation of human tumors. FEBS Lett. 284, 60–62 (1991).
Pegram, M. D. et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J. Clin. Oncol. 16, 2659–2671 (1998).
Pegram, M. & Slamon, D. Biological rationale for HER2/neu (c-erbB2) as a target for monoclonal antibody therapy. Semin. Oncol. 27, 13–19 (2000).
Jain, R. K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7, 987–989 (2001).
Jain, R. K. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J. Clin. Oncol. 31, 2205–2218 (2013).
Nguyen, A. N. et al. Normalizing the bone marrow microenvironment with p38 inhibitor reduces multiple myeloma cell proliferation and adhesion and suppresses osteoclast formation. Exp. Cell Res. 312, 1909–1923 (2006).
Chiche, J., Ricci, J. E. & Pouyssegur, J. Tumor hypoxia and metabolism — towards novel anticancer approaches. Ann. Endocrinol. 74, 111–114 (2013).
Bingle, L., Brown, N. J. & Lewis, C. E. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J. Pathol. 196, 254–265 (2002).
Colombo, M. P. & Mantovani, A. Targeting myelomonocytic cells to revert inflammation-dependent cancer promotion. Cancer Res. 65, 9113–9116 (2005).
Jackson, W. D. & Woollard, K. J. Targeting monocyte and macrophage subpopulations for immunotherapy: a patent review. Expert Opin. Ther. Pat. 24, 779–790 (2014).
Kolch, W., Halasz, M., Granovskaya, M. & Kholodenko, B. N. The dynamic control of signal transduction networks in cancer cells. Nat. Rev. Cancer 15, 515–527 (2015).
Yarden, Y. & Pines, G. The ERBB network: at last, cancer therapy meets systems biology. Nat. Rev. Cancer 12, 553–563 (2012).
Gonda, T. J. & Ramsay, R. G. Directly targeting transcriptional dysregulation in cancer. Nat. Rev. Cancer 15, 686–694 (2015).
Bertolaso, M. Towards an integrated view of the neoplastic phenomena in cancer research. Hist. Philos. Life Sci. 31, 79–97 (2009).
Kienle, G. & Kiene, H. From reductionism to holism: systems-oriented approaches in cancer research. Glob. Adv. Health Med. 1, 68–77 (2012).
Chishima, T. et al. Visualization of the metastatic process by green fluorescent protein expression. Anticancer Res. 17, 2377–2384 (1997).
Yang, M. et al. Dual-color fluorescence imaging distinguishes tumor cells from induced host angiogenic vessels and stromal cells. Proc. Natl Acad. Sci. USA 100, 14259–14262 (2003).
Bouvet, M. et al. In vivo color-coded imaging of the interaction of colon cancer cells and splenocytes in the formation of liver metastases. Cancer Res. 66, 11293–11297 (2006).
Mercado, K. P., Helguera, M., Hocking, D. C. & Dalecki, D. Noninvasive quantitative imaging of collagen microstructure in three-dimensional hydrogels using high-frequency ultrasound. Tissue Eng. Part C Methods 21, 671–682 (2015).
Ring, H. C. et al. Imaging of collagen deposition disorders using optical coherence tomography. J. Eur. Acad. Dermatol. Venereol 29, 890–898 (2015).
Wang, P., Wang, P., Wang, H. W. & Cheng, J. X. Mapping lipid and collagen by multispectral photoacoustic imaging of chemical bond vibration. J. Biomed. Opt. 17, 96010–96011 (2012).
Chuang, C. H. et al. In vivo positron emission tomography imaging of protease activity by generation of a hydrophobic product from a noninhibitory protease substrate. Clin. Cancer Res. 18, 238–247 (2012).
Shiftan, L. et al. Magnetic resonance imaging visualization of hyaluronidase in ovarian carcinoma. Cancer Res. 65, 10316–10323 (2005).
Ye, F. et al. A peptide targeted contrast agent specific to fibrin-fibronectin complexes for cancer molecular imaging with MRI. Bioconjug Chem. 19, 2300–2303 (2008).
Fujita, M. et al. Brain tumor tandem targeting using a combination of monoclonal antibodies attached to biopoly(beta-L-malic acid). J. Control Release 122, 356–363 (2007).
Ottobrini, L., Martelli, C., Trabattoni, D. L., Clerici, M. & Lucignani, G. In vivo imaging of immune cell trafficking in cancer. Eur. J. Nucl. Med. Mol. Imaging 38, 949–968 (2011).
Singh, A. S., Radu, C. G. & Ribas, A. PET imaging of the immune system: immune monitoring at the whole body level. Q. J. Nucl. Med. Mol. Imaging 54, 281–290 (2010).
Freise, A. C. & Wu, A. M. In vivo imaging with antibodies and engineered fragments. Mol. Immunol. 67, 142–152 (2015).
Li, J. et al. Activatable near-infrared fluorescent probe for in vivo imaging of fibroblast activation protein-alpha. Bioconjug Chem. 23, 1704–1711 (2012).
Haberkorn, U., Altmann, A., Mier, W. & Eisenhut, M. Molecular imaging of tumor metabolism and apoptosis. Ernst Schering Found. Symp. Proc. 4, 125–152 (2007).
Serganova, I., Humm, J., Ling, C. & Blasberg, R. Tumor hypoxia imaging. Clin. Cancer Res. 12, 5260–5264 (2006).
Raghunand, N. Tissue pH measurement by magnetic resonance spectroscopy and imaging. Methods Mol. Med. 124, 347–364 (2006).
Wyckoff, J. et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 64, 7022–7029 (2004).
Nakasone, E. S. et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 21, 488–503 (2012).
McMillin, D. W., Negri, J. M. & Mitsiades, C. S. The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nat. Rev. Drug Discov. 12, 217–228 (2013).
Fang, H. & Declerck, Y. A. Targeting the tumor microenvironment: from understanding pathways to effective clinical trials. Cancer Res. 73, 4965–4977 (2013).
Chen, F. et al. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med. 13, 45 (2015).
Abdollahi, A. & Folkman, J. Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist. Updat. 13, 16–28 (2010).
Rich, A. R. On the frequency of occurrence of occult carcinoma of the prostate. J. Urol. 33, 215–223 (1935).
Nielsen, M., Thomsen, J. L., Primdahl, S., Dyreborg, U. & Andersen, J. A. Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies. Br. J. Cancer 56, 814–819 (1987).
Stoker, M. G., Shearer, M. & O’Neill, C. Growth inhibition of polyoma-transformed cells by contact with static normal fibroblasts. J. Cell Sci. 1, 297–310 (1966).
Harris, H. & Bramwell, M. E. The suppression of malignancy by terminal differentiation: evidence from hybrids between tumour cells and keratinocytes. J. Cell Sci. 87, 383–388 (1987).
Klein, G. & Klein, E. Surveillance against tumors—is it mainly immunological? Immunol. Lett. 100, 29–33 (2005).
Mintz, B. & Illmensee, K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc. Natl Acad. Sci. USA 72, 3585–3589 (1975).
Flaberg, E. et al. High-throughput live-cell imaging reveals differential inhibition of tumor cell proliferation by human fibroblasts. Int. J. Cancer 128, 2793–2802 (2011).
Bissell, M. J. & Hines, W. C. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17, 320–329 (2011).
De Wever, O., Demetter, P., Mareel, M. & Bracke, M. Stromal myofibroblasts are drivers of invasive cancer growth. Int. J. Cancer 123, 2229–2238 (2008).
Mantovani, A., Bottazzi, B., Colotta, F., Sozzani, S. & Ruco, L. The origin and function of tumor-associated macrophages. Immunol. Today 13, 265–270 (1992).
Mishra, P., Banerjee, D. & Ben-Baruch, A. Chemokines at the crossroads of tumor-fibroblast interactions that promote malignancy. J. Leukoc. Biol. 89, 31–39 (2011).
Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).
Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).
Acknowledgements
The authors thank Y. Shaked for his valuable and constructive comments on this review. The authors’ studies were supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (Needham, MA, USA), the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG)), the Sara and Natan Blutinger Foundation (West Orange, NJ, USA), the Fred August and Adele Wolpers Charitable Fund (Clifton, NJ, USA) and the James and Rita Leibman Endowment Fund for Cancer Research (New York, NY, USA).
Author information
Authors and Affiliations
Contributions
S.M. and I.P.W. contributed equally to the conceptualizing and writing of this review.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Maman, S., Witz, I.P. A history of exploring cancer in context. Nat Rev Cancer 18, 359–376 (2018). https://doi.org/10.1038/s41568-018-0006-7
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41568-018-0006-7
- Springer Nature Limited
This article is cited by
-
Modulating ferroptosis sensitivity: environmental and cellular targets within the tumor microenvironment
Journal of Experimental & Clinical Cancer Research (2024)
-
Amphiregulin promotes activated regulatory T cell-suppressive function via the AREG/EGFR pathway in laryngeal squamous cell carcinoma
Head & Face Medicine (2024)
-
Bacterial DnaK reduces the activity of anti-cancer drugs cisplatin and 5FU
Journal of Translational Medicine (2024)
-
YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8+ T cell recruitment
Molecular Cancer (2024)
-
Deciphering the heterogeneity dominated by tumor-associated macrophages for survival prognostication and prediction of immunotherapy response in lung adenocarcinoma
Scientific Reports (2024)