Abstract
Cancers can be described as “rogue organs” (Balkwill FR, Capasso M, Hagemann T, J Cell Sci 125:5591–5596, 2012) because they are composed of multiple cell types and tissues. The transformed cells can recruit and alter healthy cells from surrounding tissues for their own benefit. It is these interactions that create the tumor microenvironment (TME). The TME describes the cells, factors, and extracellular matrix proteins that make up the tumor and the area around it; the biology of the TME influences tumor progression. Changes in the TME can lead to the growth and development of the tumor, the death of the tumor, or tumor metastasis. Metastasis is the process by which cancer spreads from its initial site to a different part of the body. Metastasis occurs when cancer cells enter the circulatory system or lymphatic system after they break away from a tumor. Once the cells leave, they can travel to a different part of the body and form new tumors. Therefore, understanding the TME is critical to fully understand cancer and find a way to successfully combat it. Knowledge of the TME can better inform researchers of the ability of potential therapies to reach tumor cells. It can also give researchers potential targets to kill the tumor. Instead of directly killing the cancer cells, therapies can target an aspect of the TME which could then halt tumor development or lead to tumor death. In other cases, targeting another aspect of the TME could make it easier for another therapy to kill the cancer cells, for example, using nanoparticles with collagenases to target the collagen in the surrounding environment to expose the cancer cells to drugs (Zinger A, et al, ACS Nano 13(10):11008–11021, 2019).
The TME can be split simply into cells and the structural matrix. Within these groups are fibroblasts, structural proteins, immune cells, lymphocytes, bone marrow-derived inflammatory cells, blood vessels, and signaling molecules (Spill F, et al, Curr Opin Biotechnol 40:41–48, 2016; Del Prete A, et al, Curr Opin Pharmacol 35:40–47, 2017; Arneth B, Medicina (Kaunas) 56(1), 2019). From structure to providing nutrients for growth, each of these components plays a critical role in tumor maintenance. Together these components impact cancer growth, development, and resistance to therapies (Hanahan D, Coussens LM, Cancer Cell 21:309–322, 2012). In this chapter, we will describe the TME and express the importance of the cellular and structural elements of the TME.
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References
Balkwill, F. R., Capasso, M., & Hagemann, T. (2012). The tumor microenvironment at a glance. Journal of Cell Science, 125(Pt 23), 5591–5596.
Zinger, A., et al. (2019). Collagenase nanoparticles enhance the penetration of drugs into pancreatic tumors. ACS Nano, 13(10), 11008–11021.
Spill, F., et al. (2016). Impact of the physical microenvironment on tumor progression and metastasis. Current Opinion in Biotechnology, 40, 41–48.
Del Prete, A., et al. (2017). Leukocyte trafficking in tumor microenvironment. Current Opinion in Pharmacology, 35, 40–47.
Arneth, B. (2019). Tumor microenvironment. Medicina (Kaunas, Lithuania), 56(1).
Hanahan, D., & Coussens, L. M. (2012). Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell, 21(3), 309–322.
Pattabiraman, D. R., & Weinberg, R. A. (2014). Tackling the cancer stem cells – What challenges do they pose? Nature Reviews Drug Discovery, 13(7), 497–512.
Korneev, K. V., et al. (2017). TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis. Cytokine, 89, 127–135.
LeBleu, V. (2015). Imaging the tumor microenvironment. Cancer Journal, 21, 174–178.
Sugimoto, H., et al. (2006). Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biology & Therapy, 5, 1640–1646.
Li, B., & Wang, J. H. (2011). Fibroblasts and myofibroblasts in wound healing: Force generation and measurement. Journal of Tissue Viability, 20, 108–120.
Desmoulière, A., Guyot, C., & Gabbiani, G. (2004). The stroma reaction myofibroblast: A key player in the control of tumor cell behavior. The International Journal of Developmental Biology, 48, 509–517.
Radisky, D. C., Kenny, P. A., & Bissell, M. J. (2007). Fibrosis and cancer: Do myofibroblasts come also from epithelial cells via EMT? Journal of Cellular Biochemistry, 101, 830–839.
Kalluri, R., & Zeisberg, M. (2006). Fibroblasts in cancer. Nature Reviews. Cancer, 6(5), 392–401.
Willis, B. C., duBois, R. M., & Borok, Z. (2006). Epithelial origin of myofibroblasts during fibrosis in the lung. Proceedings of the American Thoracic Society, 3, 377–382.
Tomasek, J. J., et al. (2002). Myofibroblasts and mechano-regulation of connective tissue remodelling. Nature Reviews Molecular Cell Biology, 3, 349–363.
Spaeth, E. L., et al. (2009). Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One, 4, e4992.
Brittan, M., et al. (2002). Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon. Gut, 50, 752–757.
Bhome, R., et al. (2015). A top-down view of the tumor microenvironment: structure, cells and signaling. Frontiers in Cell and Developmental Biology, 3(33).
Bonnans, C., Chou, J., & Werb, Z. (2014). Remodelling the extracellular matrix in development and disease. Nature Reviews. Molecular Cell Biology, 15(12), 786–801.
Erez, N., et al. (2010). Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell, 17, 135–147.
Erler, J. T., et al. (2006). Lysyl oxidase is essential for hypoxia-induced metastasis. Nature, 440(7088), 1222–1226.
Levental, K. R., et al. (2009). Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell, 139(5), 891–906.
Pietras, K., et al. (2008). Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Medicine, 5(1), e19.
Orimo, A., et al. (2005). Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 12(3), 335–348.
Nieman, K. M., et al. (2011). Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature Medicine, 17(11), 1498–1503.
Carmeliet, P., & Jain, R. K. (2011). Molecular mechanisms and clinical applications of angiogenesis. Nature, 473, 298–307.
Armulik, A., Genové, G., & Betsholtz, C. (2011). Pericytes: Developmental, physiological, and pathological perspectives, problems, and promises. Developmental Cell, 21, 193–215.
O’Keeffe, M. B., et al. (2008). Investigation of pericytes, hypoxia, and vascularity in bladder tumors: Association with clinical outcomes. Oncology Research, 17, 93–101.
Yonenaga, Y., et al. (2005). Absence of smooth muscle actin-positive pericyte coverage of tumor vessels correlates with hematogenous metastasis and prognosis of colorectal cancer patients. Oncology, 69, 159–166.
Cooke, V. G., et al. (2012). Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell, 21(1), 66–81.
Alitalo, K. (2011). The lymphatic vasculature in disease. Nature Medicine, 17, 1371–1380.
Swartz, M. A., & Lund, A. W. (2012). Lymphatic and interstitial flow in the tumour microenvironment: Linking mechanobiology with immunity. Nature Reviews Cancer, 12, 210–219.
Tlsty, T. D., & Coussens, L. M. (2006). Tumor stroma and regulation of cancer development. Annual Review of Pathology, 1, 119–150.
Mantovani, A., et al. (2008). Cancer-related inflammation. Nature, 454(7203), 436–444.
Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144(5), 646–674.
Qian, B. Z., & Pollard, J. W. (2010). Macrophage diversity enhances tumor progression and metastasis. Cell, 141, 39–51.
Condeelis, J., & Pollard, J. W. (2006). Macrophages: Obligate partners for tumor cell migration, invasion, and metastasis. Cell, 124, 263–266.
Bingle, L., Brown, N. J., & Lewis, C. E. (2002). The role of tumour-associated macrophages in tumour progression: Implications for new anticancer therapies. Journal of Pathology, 196, 254–265.
Seyfried, T. N., & Huysentruyt, L. C. (2013). On the origin of cancer metastasis. Critical Reviews in Oncogenesis, 18(1–2), 43–73.
Chaffer, C., & Weinberg, R. (2011). A perspective on cancer cell metastasis. Science, 331(6024), 1559–1564.
Grivennikov, S. I., Greten, F. R., & Karin, M. (2010). Immunity, inflammation, and cancer. Cell, 140(6), 883–899.
Lu, P., et al. (2011). Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harbor Perspectives in Biology, 3(12).
Balkwill, F., Charles, K. A., & Mantovani, A. (2005). Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell, 7(3), 211–217.
Fridman, W. H., et al. (2012). The immune contexture in human tumours: Impact on clinical outcome. Nature Reviews Cancer, 12, 298–306.
Campbell, D. J., & Koch, M. A. (2011). Treg cells: Patrolling a dangerous neighborhood. Nature Medicine, 17(8), 929–930.
Tzankov, A., et al. (2008). Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma. Haematologica, 93, 193–200.
Koreishi, A. F., et al. (2010). The role of cytotoxic and regulatory T cells in relapsed/refractory Hodgkin lymphoma. Applied Immunohistochemistry & Molecular Morphology, 18, 206–211.
Fozza, C., & Longinotti, M. (2011). T-cell traffic jam in Hodgkin’s lymphoma: Pathogenetic and therapeutic implications. Advanced Hematology.
Lin, E. Y., et al. (2006). Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Research, 66, 11238–11246.
Zumsteg, A., & Christofori, G. (2009). Corrupt policemen: Inflammatory cells promote tumor angiogenesis. Current Opinion in Oncology, 21, 60–70.
Ojalvo, L. S., et al. (2010). Gene expression analysis of macrophages that facilitate tumor invasion supports a role for Wnt-signaling in mediating their activity in primary mammary tumors. Journal of Immunology, 184, 702–712.
Murdoch, C., Giannoudis, A., & Lewis, C. E. (2004). Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood, 104, 2224–2234.
Burke, B., et al. (2002). Expression of HIF-1alpha by human macrophages: Implications for the use of macrophages in hypoxia-regulated cancer gene therapy. Journal of Pathology, 196, 204–212.
White, J. R., et al. (2004). Genetic amplification of the transcriptional response to hypoxia as a novel means of identifying regulators of angiogenesis. Genomics, 83, 1–8.
Pekarek, L. A., et al. (1995). Inhibition of tumor growth by elimination of granulocytes. Journal of Experimental Medicine, 181, 435–440.
Shojaei, F., et al. (2008). Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proceedings of the National Academy of Sciences of the United States of America, 105, 2640–2645.
Nozawa, H., Chiu, C., & Hanahan, D. (2006). Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America, 103, 12493–12498.
De Larco, J. E., Wuertz, B. R., & Furcht, L. T. (2004). The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8. Clinical Cancer Research, 10, 4895–4900.
Youn, J. I., & Gabrilovich, D. I. (2010). The biology of myeloid-derived suppressor cells: The blessing and the curse of morphological and functional heterogeneity. European Journal of Immunology, 40, 2969–2975.
Colombo, M. P., et al. (1992). Local cytokine availability elicits tumor rejection and systemic immunity through granulocyte-T-lymphocyte cross-talk. Cancer Research, 52, 4853–4857.
Fridlender, Z. G., et al. (2009). Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell, 16, 183–194.
Granot, Z., et al. (2011). Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell, 20, 300–311.
Hicks, A. M., et al. (2006). Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. Proceedings of the National Academy of Sciences of the United States of America, 103(20), 7753–7758.
Jain, R. K. (2005). Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science, 307, 58–62.
Armulik, A., Abramsson, A., & Betsholtz, C. (2005). Endothelial/pericyte interactions. Circulation Research, 97(6), 512–523.
Azzi, S., Hebda, J. K., & Gavard, J. (2013). Vascular permeability and drug delivery in cancers. Frontiers in Oncology, 3, 211.
Bergers, G., & Song, S. (2005). The role of pericytes in blood-vessel formation and maintenance. Neuro-Oncology, 7(4), 452–464.
Parangi, S., et al. (1996). Antiangiogenic therapy of transgenic mice impairs de novo tumor growth. Proceedings of the National Academy of Sciences of the United States of America, 93(5), 2002–2007.
Brem, H., et al. (1993). The combination of antiangiogenic agents to inhibit primary tumor growth and metastasis. Journal of Pediatric Surgery, 28(10), 1253–1125.
Hanahan, D., & Folkman, J. (1996). Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 86(3), 353–364.
Bergers, G., et al. (1999). Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science, 284(5415), 808–812.
Buchanan, C. F., et al. (2012). Cross-talk between endothelial and breast cancer cells regulates reciprocal expression of angiogenic factors in vitro. Journal of Cellular Biochemistry, 113(4), 1142–1151.
Szot, C. S., et al. (2013). In vitro angiogenesis induced by tumor-endothelial cell co-culture in bilayered, collagen I hydrogel bioengineered tumors. Tissue Engineering. Part C, Methods, 19(11), 864–874.
Lu, P., Weaver, V. M., & Werb, Z. (2012). The extracellular matrix: A dynamic niche in cancer progression. Journal of Cell Biology, 196(4), 395–406.
Hynes, R. O. (2009). The extracellular matrix: Not just pretty fibrils. Science, 326(5957), 1216–1219.
Feig, C., et al. (2013). Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America, 110, 20212–20217.
Anderson, B. O., et al. (2011). Optimisation of breast cancer management in low-resource and middle-resource countries: Executive summary of the Breast Health Global Initiative consensus, 2010. Lancet Oncology, 12(4), 387–398.
Frantz, C., Stewart, K. M., & Weaver, V. M. (2010). The extracellular matrix at a glance. Journal of Cell Science, 123, 4195–4200.
Hynes, R. O. (1992). Integrins – Versatility, modulation, and signaling in cell-adhesion. Cell, 69(1), 11–25.
Desgrosellier, J. S., & Cheresh, D. A. (2010). Integrins in cancer: Biological implications and therapeutic opportunities. Nature Reviews Cancer, 10(1), 9–22.
Huang, C. Y., & Ogawa, R. (2010). Mechanotransduction in bone repair and regeneration. FASEB Journal, 24(10), 3625–3632.
Takayama, S., et al. (2005). The relationship between bone metastasis from human breast cancer and integrin αvβ3 expression. Anticancer Research, 25(1A), 79–83.
Bates, R. C., et al. (2005). Transcriptional activation of integrin β6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. The Journal of Clinical Investigation, 115(2), 339–347.
Elayadi, A. N., et al. (2007). A peptide selected by biopanning identifies the integrin αvβ6 as a prognostic biomarker for nonsmall cell lung cancer. Cancer Research, 67(12), 5889–5895.
Taylor, S. T., Hickman, J. A., & Dive, C. (2000). Epigenetic determinants of resistance to etoposide regulation of Bcl-xL and Bax by tumor microenvironmental factors. JNCI: Journal of the National Cancer Institute, 92(1), 18–23.
Slack-Davis, J. K., et al. (2009). Vascular cell adhesion Molecule-1 is a regulator of ovarian cancer peritoneal metastasis. Cancer Research, 69(4), 1469–1476.
Nista, A., et al. (1997). Functional role of α4β1 and α5β1 integrin fibronectin receptors expressed on adriamycin-resistant MCF-7 human mammary carcinoma cells. International Journal of Cancer, 72(1), 133–141.
Stewart, R. L., & O’Connor, K. L. (2015). Clinical significance of the integrin α6β4 in human malignancies. Laboratory Investigation, 95(9), 976–986.
Chao, C., et al. (1996). A function for the integrin α6β4 in the invasive properties of colorectal carcinoma cells. Cancer Research, 56(20), 4811–4819.
Bello, L., et al. (2001). αvβ3 and αvβ5 integrin expression in glioma periphery. Neurosurgery, 49(2), 380–390.
Sung, V., et al. (1998). Bone sialoprotein supports breast cancer cell adhesion proliferation and migration through differential usage of the αvβ3 and αvβ5 integrins. Journal of Cellular Physiology, 176(3), 482–494.
Montgomery, A. M., Reisfeld, R. A., & Cheresh, D. A. (1994). Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen. Proceedings of the National Academy of Sciences, 91(19), 8856.
Max, R., et al. (1997). Immunohistochemical analysis of integrin αvβ3 expression on tumor-associated vessels of human carcinomas. International Journal of Cancer, 71(3), 320–324.
Zutter, M. M., et al. (1995). Re-expression of the alpha 2 beta 1 integrin abrogates the malignant phenotype of breast carcinoma cells. Proceedings of the National Academy of Sciences, 92(16), 7411.
Balasubramanian, P., et al. (2013). Collagen in human tissues: Structure, function, and biomedical implications from a tissue engineering perspective. In A. Abe et al. (Eds.), Polymer composites – Polyolefin fractionation – Polymeric peptidomimetics – Collagens (pp. 173–206). Springer.
Weigelt, B., & Bissell, M. J. (2008). Unraveling the microenvironmental influences on the normal mammary gland and breast cancer. Seminars in Cancer Biology, 18, 311–321.
Arneth, B. (2020). Tumor microenvironment. Medicina (Kaunas), 56(1), 15.
Walker, C., Mojares, E., & Del Río Hernández, A. (2018). Role of extracellular matrix in development and cancer progression. International Journal of Molecular Sciences, 19, 3028.
Lerner, I., et al. (2011). Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice. The Journal of Clinical Investigation, 121(5), 1709–1721.
Edovitsky, E., et al. (2004). Heparanase gene silencing, tumor invasiveness, angiogenesis, and metastasis. Journal of the National Cancer Institute, 96, 1219–1230.
Petz, M., et al. (2012). La enhances IRES-mediated translation of laminin B1 during malignant epithelial to mesenchymal transition. Nucleic Acids Research, 40(1), 290–302.
Boyle, S. T., et al. (2020). Acute compressive stress activates RHO/ROCK-mediated cellular processes. Small GTPases, 11(5), 354–370.
El-Haibi, C. P., et al. (2012). Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy. Proceedings of the National Academy of Sciences of the United States of America, 109(43), 17460–17465.
Heldin, P., et al. (2013). Deregulation of hyaluronan synthesis, degradation and binding promotes breast cancer. Journal of Biochemistry, 154(5), 395–408.
Venning, F. A., Wullkopf, L., & Erler, J. T. (2015). Targeting ECM disrupts cancer progression. Frontiers in Oncology, 5.
Nagaharu, K., et al. (2011). Tenascin C induces epithelial-mesenchymal transition-like change accompanied by SRC activation and focal adhesion kinase phosphorylation in human breast cancer cells. American Journal of Pathology, 178(2), 754–763.
Yoshida, T., et al. (1997). Co-expression of tenascin and fibronectin in epithelial and stromal cells of benign lesions and ductal carcinomas in the human breast. Journal of Pathology, 182(4), 421–428.
Mennerich, D., et al. (2004). Shift of syndecan-1 expression from epithelial to stromal cells during progression of solid tumours. European Journal of Cancer, 40(9), 1373–1382.
Shen, M., et al. (2019). Tinagl1 suppresses triple-negative breast cancer progression and metastasis by simultaneously inhibiting integrin/FAK and EGFR signaling. Cancer Cell, 35(1), 64.
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Freeman, J.W. (2021). Structural Biology of the Tumor Microenvironment. In: Banerjee, D., Tiwari, R.K. (eds) Tumor Microenvironment: Cellular, Metabolic and Immunologic Interactions . Advances in Experimental Medicine and Biology, vol 1350. Springer, Cham. https://doi.org/10.1007/978-3-030-83282-7_4
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