Cancers are not composed merely of cancer cells alone; instead, they are complex ‘ecosystems’ comprising many different cell types and noncellular factors. The tumour stroma is a critical component of the tumour microenvironment, where it has crucial roles in tumour initiation, progression, and metastasis. Most anticancer therapies target cancer cells specifically, but the tumour stroma can promote the resistance of cancer cells to such therapies, eventually resulting in fatal disease. Therefore, novel treatment strategies should combine anticancer and antistromal agents. Herein, we provide an overview of the advances in understanding the complex cancer cell–tumour stroma interactions and discuss how this knowledge can result in more effective therapeutic strategies, which might ultimately improve patient outcomes.
Tumours comprise cancer cells as well as a stromal compartment with cellular and noncellular components.
The tumour stroma has critical roles in cancer development, progression, and metastasis.
Typically, anticancer therapies predominantly target cancer cells, and their effect on the tumour stroma is not taken into account.
The tumour stroma responds to anticancer therapies by inducing therapeutic resistance, which can ultimately lead to fatal disease.
Anticancer therapies should target both cancer cells and the stromal compartment to be effective and result in improved patient outcomes.
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Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2017. CA Cancer J. Clin. 67, 7–30 (2017).
Amend, S. R. & Pienta, K. J. Ecology meets cancer biology: the cancer swamp promotes the lethal cancer phenotype. Oncotarget 6, 9669–9678 (2015).
Amend, S. R., Roy, S., Brown, J. S. & Pienta, K. J. Ecological paradigms to understand the dynamics of metastasis. Cancer Lett. 380, 237–242 (2016).
Camacho, D. F. & Pienta, K. J. Disrupting the networks of cancer. Clin. Cancer Res. 18, 2801–2808 (2012).
de Groot, A. E., Roy, S., Brown, J. S., Pienta, K. J. & Amend, S. R. Revisiting seed and soil: examining the primary tumor and cancer cell foraging in metastasis. Mol. Cancer Res. 15, 361–370 (2017).
Maley, C. C. et al. Classifying the evolutionary and ecological features of neoplasms. Nat. Rev. Cancer 17, 605–619 (2017).
Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 1, 571–573 (1889).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Brown, J. M. Vasculogenesis: a crucial player in the resistance of solid tumours to radiotherapy. Br. J. Radiol. 87, 20130686 (2014).
Hida, K., Akiyama, K., Ohga, N., Maishi, N. & Hida, Y. Tumour endothelial cells acquire drug resistance in a tumour microenvironment. J. Biochem. 153, 243–249 (2013).
Kibria, G., Hatakeyama, H. & Harashima, H. Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system. Arch. Pharm. Res. 37, 4–15 (2014).
Ruffell, B. & Coussens, L. M. Macrophages and therapeutic resistance in cancer. Cancer Cell 27, 462–472 (2015).
van Beijnum, J. R., Nowak-Sliwinska, P., Huijbers, E. J., Thijssen, V. L. & Griffioen, A. W. The great escape; the hallmarks of resistance to antiangiogenic therapy. Pharmacol. Rev. 67, 441–461 (2015).
Choi, J., Cha, Y. J. & Koo, J. S. Adipocyte biology in breast cancer: from silent bystander to active facilitator. Prog. Lipid Res. 69, 11–20 (2017).
Kozin, S. V. et al. Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res. 70, 5679–5685 (2010).
Ribas, A. Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 5, 915–919 (2015).
Roca, H. et al. Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer. PLoS ONE 8, e76773 (2013).
Mammoto, T. & Ingber, D. E. Mechanical control of tissue and organ development. Development 137, 1407–1420 (2010).
Hynes, R. O. & Naba, A. Overview of the matrisome — an inventory of extracellular matrix constituents and functions. Cold Spring Harb. Perspect. Biol. 4, a004903 (2012).
Bonnans, C., Chou, J. & Werb, Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 15, 786–801 (2014).
Hynes, R. O. The extracellular matrix: not just pretty fibrils. Science 326, 1216–1219 (2009).
Laurent, G. J., Chambers, R. C., Hill, M. R. & McAnulty, R. J. Regulation of matrix turnover: fibroblasts, forces, factors and fibrosis. Biochem. Soc. Trans. 35, 647–651 (2007).
Alberts, B. et al. Molecular Biology of the Cell. 2nd edn (Garland Publishing, 1989).
Alexander, J. & Cukierman, E. Stromal dynamic reciprocity in cancer: intricacies of fibroblastic-ECM interactions. Curr. Opin. Cell Biol. 42, 80–93 (2016).
Buckley, C. D. et al. Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation. Trends Immunol. 22, 199–204 (2001).
Smith, R. S., Smith, T. J., Blieden, T. M. & Phipps, R. P. Fibroblasts as sentinel cells. Synthesis of chemokines and regulation of inflammation. Am. J. Pathol. 151, 317–322 (1997).
Schneider, E. L., Mitsui, Y., Au, K. S. & Shorr, S. S. Tissue-specific differences in cultured human diploid fibroblasts. Exp. Cell Res. 108, 1–6 (1977).
Zamansky, G. B., Arundel, C., Nagasawa, H. & Little, J. B. Adaptation of human diploid fibroblasts in vitro to serum from different sources. J. Cell Sci. 61, 289–297 (1983).
Porter, K. E. & Turner, N. A. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol. Ther. 123, 255–278 (2009).
Baum, J. & Duffy, H. S. Fibroblasts and myofibroblasts: what are we talking about? J. Cardiovasc. Pharmacol. 57, 376–379 (2011).
Bochaton-Piallat, M. L., Gabbiani, G. & Hinz, B. The myofibroblast in wound healing and fibrosis: answered and unanswered questions. F1000Res 5, 752 (2016).
Hinz, B. et al. The myofibroblast: one function, multiple origins. Am. J. Pathol. 170, 1807–1816 (2007).
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).
Shiga, K. et al. Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers 7, 2443–2458 (2015).
Tuxhorn, J. A. et al. Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling. Clin. Cancer Res. 8, 2912–2923 (2002).
Nombela-Arrieta, C., Ritz, J. & Silberstein, L. E. The elusive nature and function of mesenchymal stem cells. Nat. Rev. Mol. Cell Biol. 12, 126–131 (2011).
Friedenstein, A. J., Chailakhjan, R. K. & Lalykina, K. S. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 3, 393–403 (1970).
Friedenstein, A. J., Piatetzky-Shapiro, I. I. & Petrakova, K. V. Osteogenesis in transplants of bone marrow cells. J. Embryol. Exp. Morphol. 16, 381–390 (1966).
Friedenstein, A. J., Gorskaja, J. F. & Kulagina, N. N. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp. Hematol. 4, 267–274 (1976).
Piersma, A. H. et al. Characterization of fibroblastic stromal cells from murine bone marrow. Exp. Hematol. 13, 237–243 (1985).
Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).
Rickard, D. J., Sullivan, T. A., Shenker, B. J., Leboy, P. S. & Kazhdan, I. Induction of rapid osteoblast differentiation in rat bone marrow stromal cell cultures by dexamethasone and BMP-2. Dev. Biol. 161, 218–228 (1994).
Wakitani, S., Saito, T. & Caplan, A. I. Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle Nerve 18, 1417–1426 (1995).
Horwitz, E. M. et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 7, 393–395 (2005).
Lindner, U., Kramer, J., Rohwedel, J. & Schlenke, P. Mesenchymal stem or stromal cells: toward a better understanding of their biology? Transfus. Med. Hemother 37, 75–83 (2010).
Paunescu, V. et al. Tumour-associated fibroblasts and mesenchymal stem cells: more similarities than differences. J. Cell. Mol. Med. 15, 635–646 (2011).
Haniffa, M. A. et al. Adult human fibroblasts are potent immunoregulatory cells and functionally equivalent to mesenchymal stem cells. J. Immunol. 179, 1595–1604 (2007).
Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat. Biotechnol. 26, 101–106 (2008).
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).
Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2006).
Alt, E. et al. Fibroblasts share mesenchymal phenotypes with stem cells, but lack their differentiation and colony-forming potential. Biol. Cell 103, 197–208 (2011).
Battula, V. L. et al. Connective tissue growth factor regulates adipocyte differentiation of mesenchymal stromal cells and facilitates leukemia bone marrow engraftment. Blood 122, 357–366 (2013).
Erices, A., Conget, P. & Minguell, J. J. Mesenchymal progenitor cells in human umbilical cord blood. Br. J. Haematol. 109, 235–242 (2000).
Zvaifler, N. J. et al. Mesenchymal precursor cells in the blood of normal individuals. Arthritis Res. 2, 477–488 (2000).
Galotto, M. et al. Stromal damage as consequence of high-dose chemo/radiotherapy in bone marrow transplant recipients. Exp. Hematol. 27, 1460–1466 (1999).
Sanchez-Abarca, L. I. et al. Uptake and delivery of antigens by mesenchymal stromal cells. Cytotherapy 15, 673–678 (2013).
Yagi, H. et al. Mesenchymal stem cells: Mechanisms of immunomodulation and homing. Cell Transplant 19, 667–679 (2010).
Moroni, L. & Fornasari, P. M. Human mesenchymal stem cells: a bank perspective on the isolation, characterization and potential of alternative sources for the regeneration of musculoskeletal tissues. J. Cell. Physiol. 228, 680–687 (2013).
Wu, L., Cai, X., Zhang, S., Karperien, M. & Lin, Y. Regeneration of articular cartilage by adipose tissue derived mesenchymal stem cells: perspectives from stem cell biology and molecular medicine. J. Cell. Physiol. 228, 938–944 (2013).
Ducy, P., Schinke, T. & Karsenty, G. The osteoblast: a sophisticated fibroblast under central surveillance. Science 289, 1501–1504 (2000).
Seeman, E. & Delmas, P. D. Bone quality—the material and structural basis of bone strength and fragility. N. Engl. J. Med. 354, 2250–2261 (2006).
Mackie, E. J. Osteoblasts: novel roles in orchestration of skeletal architecture. Int. J. Biochem. Cell Biol. 35, 1301–1305 (2003).
Caetano-Lopes, J., Canhao, H. & Fonseca, J. E. Osteoblasts and bone formation. Acta Reumatol. Port. 32, 103–110 (2007).
Gori, F. et al. The expression of osteoprotegerin and RANK ligand and the support of osteoclast formation by stromal-osteoblast lineage cells is developmentally regulated. Endocrinology 141, 4768–4776 (2000).
Harada, S. & Rodan, G. A. Control of osteoblast function and regulation of bone mass. Nature 423, 349–355 (2003).
Muir, H. The chondrocyte, architect of cartilage. Biomechanics, structure, function and molecular biology of cartilage matrix macromolecules. Bioessays 17, 1039–1048 (1995).
Mackie, E. J., Ahmed, Y. A., Tatarczuch, L., Chen, K. S. & Mirams, M. Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int. J. Biochem. Cell Biol. 40, 46–62 (2008).
Urban, J. P. The chondrocyte: a cell under pressure. Br. J. Rheumatol 33, 901–908 (1994).
Massague, J. & Obenauf, A. C. Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016).
Pienta, K. J., McGregor, N., Axelrod, R. & Axelrod, D. E. Ecological therapy for cancer: defining tumors using an ecosystem paradigm suggests new opportunities for novel cancer treatments. Transl Oncol. 1, 158–164 (2008).
Ostman, A. & Augsten, M. Cancer-associated fibroblasts and tumor growth — bystanders turning into key players. Curr. Opin. Genet. Dev. 19, 67–73 (2009).
Cunha, G. R., Bigsby, R. M., Cooke, P. S. & Sugimura, Y. Stromal-epithelial interactions in adult organs. Cell Differ. 17, 137–148 (1985).
Cunha, G. R., Donjacour, A. A. & Sugimura, Y. Stromal-epithelial interactions and heterogeneity of proliferative activity within the prostate. Biochem. Cell Biol. 64, 608–614 (1986).
Ozdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).
Bhowmick, N. A. et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303, 848–851 (2004).
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).
Calon, A. et al. Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571–584 (2012).
Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).
Shimoda, M., Jackson, H. W. & Khokha, R. Tumor suppression by stromal TIMPs. Mol. Cell Oncol. 3, e975082 (2016).
Cruz-Munoz, W. & Khokha, R. The role of tissue inhibitors of metalloproteinases in tumorigenesis and metastasis. Crit. Rev. Clin. Lab. Sci. 45, 291–338 (2008).
Shimoda, M. et al. Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nat. Cell Biol. 16, 889–901 (2014).
Tjomsland, V. et al. Profile of MMP and TIMP expression in human pancreatic stellate cells: regulation by IL-1α and TGFβ and implications for migration of pancreatic cancer cells. Neoplasia 18, 447–456 (2016).
Bloomston, M., Shafii, A., Zervos, E. E. & Rosemurgy, A. S. TIMP-1 overexpression in pancreatic cancer attenuates tumor growth, decreases implantation and metastasis, and inhibits angiogenesis. J. Surg. Res. 102, 39–44 (2002).
Langley, R. R. & Fidler, I. J. The seed and soil hypothesis revisited — the role of tumor-stroma interactions in metastasis to different organs. Int. J. Cancer 128, 2527–2535 (2011).
Fidler, I. J. et al. Modulation of tumor cell response to chemotherapy by the organ environment. Cancer Metastasis Rev. 13, 209–222 (1994).
Couillard, J., Demers, M., Lavoie, G. & St-Pierre, Y. The role of DNA hypomethylation in the control of stromelysin gene expression. Biochem. Biophys. Res. Commun. 342, 1233–1239 (2006).
Hanson, J. A. et al. Gene promoter methylation in prostate tumor-associated stromal cells. J. Natl Cancer Inst. 98, 255–261 (2006).
Lin, H. J. et al. Breast cancer-associated fibroblasts confer AKT1-mediated epigenetic silencing of Cystatin M in epithelial cells. Cancer Res. 68, 10257–10266 (2008).
Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).
Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).
Micallef, L. et al. The myofibroblast, multiple origins for major roles in normal and pathological tissue repair. Fibrogen. Tissue Repair 5, S5 (2012).
Neuzillet, C. et al. Stromal expression of SPARC in pancreatic adenocarcinoma. Cancer Metastasis Rev. 32, 585–602 (2013).
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).
Chiquet-Ehrismann, R., Mackie, E. J., Pearson, C. A. & Sakakura, T. Tenascin: an extracellular matrix protein involved in tissue interactions during fetal development and oncogenesis. Cell 47, 131–139 (1986).
Kyutoku, M. et al. Role of periostin in cancer progression and metastasis: inhibition of breast cancer progression and metastasis by anti-periostin antibody in a murine model. Int. J. Mol. Med. 28, 181–186 (2011).
Mackie, E. J. et al. Tenascin is a stromal marker for epithelial malignancy in the mammary gland. Proc. Natl Acad. Sci. USA 84, 4621–4625 (1987).
Ouyang, G. et al. Upregulated expression of periostin by hypoxia in non-small-cell lung cancer cells promotes cell survival via the Akt/PKB pathway. Cancer Lett. 281, 213–219 (2009).
Ruan, K., Bao, S. & Ouyang, G. The multifaceted role of periostin in tumorigenesis. Cell. Mol. Life Sci. 66, 2219–2230 (2009).
Mouw, J. K. et al. Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat. Med. 20, 360–367 (2014).
Kim, W. et al. The integrin-coupled signaling adaptor p130Cas suppresses Smad3 function in transforming growth factor-beta signaling. Mol. Biol. Cell 19, 2135–2146 E07-10-0991 (2008).
Liu, J. & Agarwal, S. Mechanical signals activate vascular endothelial growth factor receptor-2 to upregulate endothelial cell proliferation during inflammation. J. Immunol. 185, 1215–1221 (2010).
Pylayeva, Y. et al. Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling. J. Clin. Invest. 119, 252–266 (2009).
Tomakidi, P. et al. Defects of basement membrane and hemidesmosome structure correlate with malignant phenotype and stromal interactions in HaCaT-Ras xenografts. Differentiation 64, 263–275 (1999).
Kaukonen, R. et al. Normal stroma suppresses cancer cell proliferation via mechanosensitive regulation of JMJD1a-mediated transcription. Nat. Commun. 7, 12237 (2016).
Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).
Boire, A. et al. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120, 303–313 (2005).
Sternlicht, M. D. et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98, 137–146 (1999).
Hotary, K. B. et al. Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell 114, 33–45 (2003).
Tang, D. et al. High expression of Galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer. International journal of cancer. Int. J. Cancer 130, 2337–2348 (2012).
Luttenberger, T. et al. Platelet-derived growth factors stimulate proliferation and extracellular matrix synthesis of pancreatic stellate cells: implications in pathogenesis of pancreas fibrosis. Lab. Invest. 80, 47–55 (2000).
Joesting, M. S. et al. Identification of SFRP1 as a candidate mediator of stromal-to-epithelial signaling in prostate cancer. Cancer Res. 65, 10423–10430 (2005).
Bragado, P. et al. TGF-beta2 dictates disseminated tumour cell fate in target organs through TGF-beta-RIII and p38alpha/beta signalling. Nat. Cell Biol. 15, 1351–1361 (2013).
Carstens, J. L. et al. FGFR1-WNT-TGF-beta signaling in prostate cancer mouse models recapitulates human reactive stroma. Cancer Res. 74, 609–620 (2014).
Claffey, K. P. et al. Fibroblast growth factor 2 activation of stromal cell vascular endothelial growth factor expression and angiogenesis. Lab. Invest. 81, 61–75 (2001).
Korc, M. & Friesel, R. E. The role of fibroblast growth factors in tumor growth. Curr. Cancer Drug Targets 9, 639–651 (2009).
Crawford, Y. et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell 15, 21–34 (2009).
Pietras, K., Pahler, J., Bergers, G. & Hanahan, D. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med. 5, e19 (2008).
Fukumura, D. et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 94, 715–725 (1998).
Erez, N., Truitt, M., Olson, P., Arron, S. T. & Hanahan, D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner. Cancer Cell 17, 135–147 (2010).
Prabhu, V. V., Warfel, N. A. & El-Deiry, W. S. CTGF-mediated autophagy-senescence transition in tumor stroma promotes anabolic tumor growth and metastasis. Cell Cycle 11, 2592–2593 (2012).
Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).
Sun, Y. X. et al. Expression and activation of alpha v beta 3 integrins by SDF-1/CXC12 increases the aggressiveness of prostate cancer cells. Prostate 67, 61–73 (2007).
Sun, Y. X. et al. Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo. J. Cell. Biochem. 89, 462–473 (2003).
LeBedis, C., Chen, K., Fallavollita, L., Boutros, T. & Brodt, P. Peripheral lymph node stromal cells can promote growth and tumorigenicity of breast carcinoma cells through the release of IGF-I and EGF. International journal of cancer. J. Int. Cancer 100, 2–8 (2002).
Sainaghi, P. P. et al. Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor. J. Cell. Physiol. 204, 36–44 (2005).
Shiozawa, Y. et al. GAS6/AXL axis regulates prostate cancer invasion, proliferation, and survival in the bone marrow niche. Neoplasia 12, 116–127 (2010).
Taichman, R. S. et al. GAS6 receptor status is associated with dormancy and bone metastatic tumor formation. PLoS ONE 8, e61873 (2013).
Quante, M. et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19, 257–272 (2011).
Hugo, H. J. et al. Contribution of fibroblast and mast cell (afferent) and tumor (efferent) IL-6 effects within the tumor microenvironment. Cancer Microenviron. 5, 83–93 (2012).
Cheng, N., Chytil, A., Shyr, Y., Joly, A. & Moses, H. L. Transforming growth factor-beta signaling-deficient fibroblasts enhance hepatocyte growth factor signaling in mammary carcinoma cells to promote scattering and invasion. Mol. Cancer Res. 6, 1521–1533 (2008).
Tait, L. R. et al. Dynamic stromal-epithelial interactions during progression of MCF10DCIS.com xenografts. International journal of cancer. J. Int. Cancer 120, 2127–2134 (2007).
Rajaram, M., Li, J., Egeblad, M. & Powers, R. S. System-wide analysis reveals a complex network of tumor-fibroblast interactions involved in tumorigenicity. PLoS Genet. 9, e1003789 (2013).
Elkhattouti, A., Hassan, M. & Gomez, C. R. Stromal fibroblast in age-related cancer: role in tumorigenesis and potential as novel therapeutic target. Front. Oncol. 5, 158 (2015).
Pazolli, E. et al. Chromatin remodeling underlies the senescence-associated secretory phenotype of tumor stromal fibroblasts that supports cancer progression. Cancer Res. 72, 2251–2261 (2012).
Luo, X. et al. Stromal-initiated changes in the bone promote metastatic niche development. Cell Rep. 14, 82–92 (2016).
Pazolli, E. et al. Senescent stromal-derived osteopontin promotes preneoplastic cell growth. Cancer Res. 69, 1230–1239 (2009).
Ao, Z. et al. Identification of cancer-associated fibroblasts in circulating blood from patients with metastatic breast cancer. Cancer Res. 75, 4681–4687 (2015).
Jones, M. L., Siddiqui, J., Pienta, K. J. & Getzenberg, R. H. Circulating fibroblast-like cells in men with metastatic prostate cancer. Prostate 73, 176–181 (2013).
Bystricky, B. et al. Relationship between circulating tumor cells and annexin A2 in early breast cancer patients. Anticancer Res. 37, 2727–2734 (2017).
Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 9, 285–293 (2009).
Bergfeld, S. A., Blavier, L. & DeClerck, Y. A. Bone marrow-derived mesenchymal stromal cells promote survival and drug resistance in tumor cells. Mol. Cancer Ther. 13, 962–975 (2014).
Worthley, D. L. et al. Bone marrow cells as precursors of the tumor stroma. Exp. Cell Res. 319, 1650–1656 (2013).
Brennen, W. N., Chen, S., Denmeade, S. R. & Isaacs, J. T. Quantification of mesenchymal stem cells (MSCs) at sites of human prostate cancer. Oncotarget 4, 106–117 (2013).
Arina, A. et al. Tumor-associated fibroblasts predominantly come from local and not circulating precursors. Proc. Natl Acad. Sci. USA 113, 7551–7556 (2016).
Jung, Y. et al. Annexin 2-CXCL12 interactions regulate metastatic cell targeting and growth in the bone marrow. Mol. Cancer Res. 13, 197–207 (2015).
Mishra, A., Shiozawa, Y., Pienta, K. J. & Taichman, R. S. Homing of cancer cells to the bone. Cancer Microenviron. 4, 221–235 (2011).
Shiozawa, Y. et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J. Clin. Invest. 121, 1298–1312 (2011).
Wobus, M. et al. Breast carcinoma cells modulate the chemoattractive activity of human bone marrow-derived mesenchymal stromal cells by interfering with CXCL12. International journal of cancer. Int. J. Cancer 136, 44–54 (2015).
Wang, N. et al. Prostate cancer cells preferentially home to osteoblast-rich areas in the early stages of bone metastasis — evidence from in vivo models. J. Bone Miner. Res. 29, 2688–2696 (2014).
Shimo, T. et al. The role of sonic hedgehog signaling in osteoclastogenesis and jaw bone destruction. PLoS ONE 11, e0151731 (2016).
Heller, E. et al. Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment. Cancer Res. 72, 897–907 (2012).
Johnson, R. W. et al. TGF-beta promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling. Cancer Res. 71, 822–831 (2011).
Mundy, G. R. Metastasis to bone: causes, consequences and therapeutic opportunities. Nature reviews. Cancer 2, 584–593 (2002).
Guise, T. A. The vicious cycle of bone metastases. J. Musculoskelet. Neuronal Interact. 2, 570–572 (2002).
Jeong, H. M., Cho, S. W. & Park, S. I. Osteoblasts are the centerpiece of the metastatic bone microenvironment. Endocrinol. Metab. 31, 485–492 (2016).
Li, X. Q. et al. ITGBL1 Is a Runx2 transcriptional target and promotes breast cancer bone metastasis by activating the TGFβ signaling pathway. Cancer Res. 75, 3302–3313 (2015).
Sottnik, J. L., Dai, J., Zhang, H., Campbell, B. & Keller, E. T. Tumor-induced pressure in the bone microenvironment causes osteocytes to promote the growth of prostate cancer bone metastases. Cancer Res. 75, 2151–2158 (2015).
Cunha, G. R. Epithelio-mesenchymal interactions in primordial gland structures which become responsive to androgenic stimulation. Anat. Rec. 172, 179–195 (1972).
Cunha, G. R. Tissue interactions between epithelium and mesenchyme of urogenital and integumental origin. Anat. Rec. 172, 529–541 (1972).
Cunha, G. R. The role of androgens in the epithelio-mesenchymal interactions involved in prostatic morphogenesis in embryonic mice. Anat. Rec. 175, 87–96 (1973).
Aboseif, S., El-Sakka, A., Young, P. & Cunha, G. Mesenchymal reprogramming of adult human epithelial differentiation. Differentiation 65, 113–118 (1999).
Hayward, S. W. et al. Malignant transformation in a nontumorigenic human prostatic epithelial cell line. Cancer Res. 61, 8135–8142 (2001).
Barcellos-Hoff, M. H. & Ravani, S. A. Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res. 60, 1254–1260 (2000).
Yasuda, K. et al. Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity. Lab. Invest. 94, 1355–1369 (2014).
Zhao, X. L. et al. High-mobility group box 1 released by autophagic cancer-associated fibroblasts maintains the stemness of luminal breast cancer cells. J. Pathol. 243, 376–389 (2017).
Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 12, 468–476 (2010).
Del Pozo Martin, Y. et al. Mesenchymal cancer cell-stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization. Cell Rep. 13, 2456–2469 (2015).
Du, H. & Che, G. Genetic alterations and epigenetic alterations of cancer-associated fibroblasts. Oncol. Lett. 13, 3–12 (2017).
Kurose, K. et al. Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat. Genet. 32, 355–357 (2002).
Kurose, K. et al. Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour-microenvironment interactions. Hum. Mol. Genet. 10, 1907–1913 (2001).
Tanwar, P. S., Zhang, L., Roberts, D. J. & Teixeira, J. M. Stromal deletion of the APC tumor suppressor in mice triggers development of endometrial cancer. Cancer Res. 71, 1584–1596 (2011).
Kode, A. et al. Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts. Nature 506, 240–244 (2014).
Calvo, F. et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat. Cell Biol. 15, 637–646 (2013).
Procopio, M. G. et al. Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. Nat. Cell Biol. 17, 1193–1204 (2015).
Scherz-Shouval, R. et al. The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell 158, 564–578 (2014).
Tyekucheva, S. et al. Stromal and epithelial transcriptional map of initiation progression and metastatic potential of human prostate cancer. Nat. Commun. 8, 420 (2017).
Bauer, M. et al. Heterogeneity of gene expression in stromal fibroblasts of human breast carcinomas and normal breast. Oncogene 29, 1732–1740 (2010).
Nakagawa, H. et al. Role of cancer-associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles. Oncogene 23, 7366–7377 (2004).
Sato, N., Maehara, N. & Goggins, M. Gene expression profiling of tumor-stromal interactions between pancreatic cancer cells and stromal fibroblasts. Cancer Res. 64, 6950–6956 (2004).
Singer, C. F. et al. Differential gene expression profile in breast cancer-derived stromal fibroblasts. Breast Cancer Res. Treatment 110, 273–281 (2008).
Horie, M. et al. TBX4 is involved in the super-enhancer-driven transcriptional programs underlying features specific to lung fibroblasts. Am. J. Physiol. Lung Cell. Mol. Physiol. 314, L177–L191 (2018).
Marks, D. L., Olson, R. L. & Fernandez-Zapico, M. E. Epigenetic control of the tumor microenvironment. Epigenomics 8, 1671–1687 (2016).
Mathot, P. et al. DNA methylation signal has a major role in the response of human breast cancer cells to the microenvironment. Oncogenesis 6, e390 (2017).
Rodriguez-Canales, J. et al. Identification of a unique epigenetic sub-microenvironment in prostate cancer. J. Pathol. 211, 410–419 (2007).
Albrengues, J. et al. Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nat. Commun. 6, 10204 (2015).
Albrengues, J. et al. LIF mediates proinvasive activation of stromal fibroblasts in cancer. Cell Rep. 7, 1664–1678 (2014).
Jiang, L. et al. Global hypomethylation of genomic DNA in cancer-associated myofibroblasts. Cancer Res. 68, 9900–9908 (2008).
Velaei, K., Samadi, N., Barazvan, B. & Soleimani Rad, J. Tumor microenvironment-mediated chemoresistance in breast cancer. Breast 30, 92–100 (2016).
Ayala, G. et al. Reactive stroma as a predictor of biochemical-free recurrence in prostate cancer. Clin. Cancer Res. 9, 4792–4801 (2003).
Mhawech-Fauceglia, P. et al. Stromal expression of fibroblast activation protein alpha (FAP) predicts platinum resistance and shorter recurrence in patients with epithelial ovarian cancer. Cancer Microenviron. 8, 23–31 (2015).
Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).
Damiano, J. S., Hazlehurst, L. A. & Dalton, W. S. Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and gamma-irradiation. Leukemia 15, 1232–1239 (2001).
Hazlehurst, L. A. & Dalton, W. S. Mechanisms associated with cell adhesion mediated drug resistance (CAM-DR) in hematopoietic malignancies. Cancer Metastasis Rev. 20, 43–50 (2001).
Hazlehurst, L. A., Damiano, J. S., Buyuksal, I., Pledger, W. J. & Dalton, W. S. Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene 19, 4319–4327 (2000).
Landowski, T. H., Olashaw, N. E., Agrawal, D. & Dalton, W. S. Cell adhesion-mediated drug resistance (CAM-DR) is associated with activation of NF-kappa B (RelB/p50) in myeloma cells. Oncogene 22, 2417–2421 (2003).
Hazlehurst, L. A., Argilagos, R. F. & Dalton, W. S. Beta1 integrin mediated adhesion increases Bim protein degradation and contributes to drug resistance in leukaemia cells. Br. J. Haematol. 136, 269–275 (2007).
Lwin, T. et al. Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas. Blood 110, 1631–1638 (2007).
Jain, R. K. Transport of molecules in the tumor interstitium: a review. Cancer Res. 47, 3039–3051 (1987).
Young, J. S., Lumsden, C. E. & Stalker, A. L. The significance of the tissue pressure of normal testicular and of neoplastic (Brown-Pearce carcinoma) tissue in the rabbit. J. Pathol. Bacteriol. 62, 313–333 (1950).
DuFort, C. C., DelGiorno, K. E. & Hingorani, S. R. Mounting pressure in the microenvironment: fluids, solids, and cells in pancreatic ductal adenocarcinoma. Gastroenterology 150, 1545–1557.e2 (2016).
Provenzano, P. P. & Hingorani, S. R. Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. Br. J. Cancer 108, 1–8 (2013).
Wegner, C. S. et al. Dynamic contrast-enhanced MRI of the microenvironment of pancreatic adenocarcinoma xenografts. Acta Oncol. 56, 1754–1762 (2017).
Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012).
Ozerdem, U. & Hargens, A. R. A simple method for measuring interstitial fluid pressure in cancer tissues. Microvasc. Res. 70, 116–120 (2005).
Munson, J. M., Bellamkonda, R. V. & Swartz, M. A. Interstitial flow in a 3D microenvironment increases glioma invasion by a CXCR4-dependent mechanism. Cancer Res. 73, 1536–1546 (2013).
Hirth, J. et al. The effect of an individual’s cytochrome CYP3A4 activity on docetaxel clearance. Clin. Cancer Res. 6, 1255–1258 (2000).
Alonso, S. et al. Human bone marrow niche chemoprotection mediated by cytochrome P450 enzymes. Oncotarget 6, 14905–14912 (2015).
Alonso, S. et al. Hedgehog and retinoid signaling alters multiple myeloma microenvironment and generates bortezomib resistance. J. Clin. Invest. 126, 4460–4468 (2016).
Xu, K. et al. Autophagy induction contributes to the resistance to methotrexate treatment in rheumatoid arthritis fibroblast-like synovial cells through high mobility group box chromosomal protein 1. Arthritis Res. Ther. 17, 374 (2015).
Huber, R. M. et al. DNA damage induces GDNF secretion in the tumor microenvironment with paracrine effects promoting prostate cancer treatment resistance. Oncotarget 6, 2134–2147 (2015).
Sun, Y. et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat. Med. 18, 1359–1368 (2012).
Gilbert, L. A. & Hemann, M. T. DNA damage-mediated induction of a chemoresistant niche. Cell 143, 355–366 (2010).
Steinbichler, T. B., Metzler, V., Pritz, C., Riechelmann, H. & Dudas, J. Tumor-associated fibroblast-conditioned medium induces CDDP resistance in HNSCC cells. Oncotarget 7, 2508–2518 (2016).
Peiris-Pages, M., Sotgia, F. & Lisanti, M. P. Chemotherapy induces the cancer-associated fibroblast phenotype, activating paracrine Hedgehog-GLI signalling in breast cancer cells. Oncotarget 6, 10728–10745 (2015).
Hu, Y. et al. Fibroblast-derived exosomes contribute to chemoresistance through priming cancer stem cells in colorectal cancer. PLoS ONE 10, e0125625 (2015).
Wang, W. et al. Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell 165, 1092–1105 (2016).
Baskar, R., Lee, K. A., Yeo, R. & Yeoh, K. W. Cancer and radiation therapy: current advances and future directions. Int. J. Med. Sci. 9, 193–199 (2012).
Cordes, N. Integrin-mediated cell-matrix interactions for prosurvival and antiapoptotic signaling after genotoxic injury. Cancer Lett. 242, 11–19 (2006).
Cordes, N., Seidler, J., Durzok, R., Geinitz, H. & Brakebusch, C. β1-integrin-mediated signaling essentially contributes to cell survival after radiation-induced genotoxic injury. Oncogene 25, 1378–1390 (2006).
Hellevik, T. et al. Cancer-associated fibroblasts from human NSCLC survive ablative doses of radiation but their invasive capacity is reduced. Radiat. Oncol. 7, 59 (2012).
Mantoni, T. S., Lunardi, S., Al-Assar, O., Masamune, A. & Brunner, T. B. Pancreatic stellate cells radioprotect pancreatic cancer cells through beta1-integrin signaling. Cancer Res. 71, 3453–3458 (2011).
Park, C. C., Zhang, H. J., Yao, E. S., Park, C. J. & Bissell, M. J. Beta1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts. Cancer Res. 68, 4398–4405 (2008).
Puthawala, K. et al. Inhibition of integrin alpha(v)beta6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis. Am. J. Respir. Crit. Care Med. 177, 82–90 (2008).
Chargari, C., Clemenson, C., Martins, I., Perfettini, J. L. & Deutsch, E. Understanding the functions of tumor stroma in resistance to ionizing radiation: emerging targets for pharmacological modulation. Drug Resist. Updat. 16, 10–21 (2013).
Kamochi, N. et al. Irradiated fibroblast-induced bystander effects on invasive growth of squamous cell carcinoma under cancer-stromal cell interaction. Cancer Sci. 99, 2417–2427 (2008).
Ohuchida, K. et al. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res. 64, 3215–3222 (2004).
Mitsuhashi, A. et al. Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab. Nat. Commun. 6, 8792 (2015).
Yoshida, T. et al. Podoplanin-positive cancer-associated fibroblasts in the tumor microenvironment induce primary resistance to EGFR-TKIs in lung adenocarcinoma with EGFR mutation. Clin. Cancer Res. 21, 642–651 (2015).
Mueller, K. L. et al. Fibroblast-secreted hepatocyte growth factor mediates epidermal growth factor receptor tyrosine kinase inhibitor resistance in triple-negative breast cancers through paracrine activation of Met. Breast Cancer Res. 14, R104 (2012).
Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).
Hirata, E. et al. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin beta1/FAK signaling. Cancer Cell 27, 574–588 (2015).
Singh, M. et al. Stromal androgen receptor in prostate development and cancer. Am. J. Pathol. 184, 2598–2607 (2014).
Schweizer, M. T. et al. Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study. Sci. Transl Med. 7, 269ra2 (2015).
Wikstrom, P., Marusic, J., Stattin, P. & Bergh, A. Low stroma androgen receptor level in normal and tumor prostate tissue is related to poor outcome in prostate cancer patients. Prostate 69, 799–809 (2009).
Li, Y. et al. Decrease in stromal androgen receptor associates with androgen-independent disease and promotes prostate cancer cell proliferation and invasion. J. Cell. Mol. Med. 12, 2790–2798 (2008).
Holton, S. E., Bergamaschi, A., Katzenellenbogen, B. S. & Bhargava, R. Integration of molecular profiling and chemical imaging to elucidate fibroblast-microenvironment impact on cancer cell phenotype and endocrine resistance in breast cancer. PLOS ONE 9, e96878 (2014).
Witkiewicz, A. K. et al. An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am. J. Pathol. 174, 2023–2034 (2009).
Mercier, I. et al. Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy. Cancer Biol. Ther. 7, 1212–1225 (2008).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
Gajewski, T. F., Schreiber, H. & Fu, Y. X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014–1022 (2013).
Silzle, T., Randolph, G. J., Kreutz, M. & Kunz-Schughart, L. A. The fibroblast: sentinel cell and local immune modulator in tumor tissue. International journal of cancer. J. Int. Cancer 108, 173–180 (2004).
Talts, J. F., Wirl, G., Dictor, M., Muller, W. J. & Fassler, R. Tenascin-C modulates tumor stroma and monocyte/macrophage recruitment but not tumor growth or metastasis in a mouse strain with spontaneous mammary cancer. J. Cell Sci. 112, 1855–1864 (1999).
Salmon, H. et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin. Invest. 122, 899–910 (2012).
Martinet, L. et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res. 71, 5678–5687 (2011).
Singh, S., Ross, S. R., Acena, M., Rowley, D. A. & Schreiber, H. Stroma is critical for preventing or permitting immunological destruction of antigenic cancer cells. J. Exp. Med. 175, 139–146 (1992).
Kraman, M. et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330, 827–830 (2010).
Li, X. et al. Stromal PD-L1 expression is associated with better disease-free survival in triple-negative breast cancer. Am. J. Clin. Pathol. 146, 496–502 (2016).
Miyoshi, H. et al. PD-L1 expression on neoplastic or stromal cells is respectively a poor or good prognostic factor for adult T-cell leukemia/lymphoma. Blood 128, 1374–1381 (2016).
Pines, M., Knopov, V., Genina, O., Lavelin, I. & Nagler, A. Halofuginone, a specific inhibitor of collagen type I synthesis, prevents dimethylnitrosamine-induced liver cirrhosis. J. Hepatol. 27, 391–398 (1997).
Zion, O. et al. Inhibition of transforming growth factor beta signaling by halofuginone as a modality for pancreas fibrosis prevention. Pancreas 38, 427–435 (2009).
Juarez, P. et al. Halofuginone inhibits the establishment and progression of melanoma bone metastases. Cancer Res. 72, 6247–6256 (2012).
Kultti, A. et al. 4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3. Exp. Cell Res. 315, 1914–1923 (2009).
Hajime, M. et al. Inhibitory effect of 4-methylesculetin on hyaluronan synthesis slows the development of human pancreatic cancer in vitro and in nude mice. International journal of cancer. J. Int. Cancer 120, 2704–2709 (2007).
Wong, K. M., Horton, K. J., Coveler, A. L., Hingorani, S. R. & Harris, W. P. Targeting the tumor stroma: the biology and clinical development of pegylated recombinant human hyaluronidase (PEGPH20). Curr. Oncol. Rep. 19, 47 (2017).
Erler, J. T. et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009).
Erler, J. T. et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440, 1222–1226 (2006).
Cox, T. R. et al. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res. 73, 1721–1732 (2013).
Gilkes, D. M. et al. Collagen prolyl hydroxylases are essential for breast cancer metastasis. Cancer Res. 73, 3285–3296 (2013).
Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).
Miller, B. W. et al. Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol. Med. 7, 1063–1076 (2015).
Sherman, M. H. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159, 80–93 (2014).
Chronopoulos, A. et al. ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion. Nat. Commun. 7, 12630 (2016).
Alvarez, R. et al. Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br. J. Cancer 109, 926–933 (2013).
Von Hoff, D. D. et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J. Clin. Oncol. 29, 4548–4554 (2011).
Bonomi, A. et al. Human amniotic mesenchymal stromal cells (hAMSCs) as potential vehicles for drug delivery in cancer therapy: an in vitro study. Stem Cell Res. Ther. 6, 155 (2015).
Levy, O. et al. A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer. Biomaterials 91, 140–150 (2016).
Kidd, S. et al. Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging. Stem Cells 27, 2614–2623 (2009).
Brennen, W. N., Denmeade, S. R. & Isaacs, J. T. Mesenchymal stem cells as a vector for the inflammatory prostate microenvironment. Endocr. Relat. Cancer 20, R269–R290 (2013).
Clezardin, P. Mechanisms of action of bisphosphonates in oncology: a scientific concept evolving from antiresorptive to anticancer activities. Bonekey Rep. 2, 267 (2013).
Weilbaecher, K. N., Guise, T. A. & McCauley, L. K. Cancer to bone: a fatal attraction. Nat. Rev. Cancer 11, 411–425 (2011).
Terpos, E. et al. Bone antiresorptive agents in the treatment of bone metastases associated with solid tumours or multiple myeloma. Bonekey Rep. 4, 744 (2015).
Dhesy-Thind, S. et al. Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: a cancer care Ontario and American Society of Clinical Oncology Practice Guideline. J. Clin. Oncol. 35, 2062–2081 (2017).
Shore, N. D. Radium-223 dichloride for metastatic castration-resistant prostate cancer: the urologist’s perspective. Urology 85, 717–724 (2015).
Nilsson, S. et al. Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases. Clin. Genitourin. Cancer 11, 20–26 (2013).
Liu, R., Li, H., Liu, L., Yu, J. & Ren, X. Fibroblast activation protein: a potential therapeutic target in cancer. Cancer Biol. Ther. 13, 123–129 (2012).
Hofheinz, R. D. et al. Stromal antigen targeting by a humanised monoclonal antibody: an early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer. Onkologie 26, 44–48 (2003).
Scott, A. M. et al. A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin. Cancer Res. 9, 1639–1647 (2003).
Mersmann, M. et al. Human antibody derivatives against the fibroblast activation protein for tumor stroma targeting of carcinomas. Int. J. Cancer 92, 240–248 (2001).
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).
Erickson, H. K. et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 66, 4426–4433 (2006).
Ostermann, E. et al. Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin. Cancer Res. 14, 4584–4592 (2008).
Fischer, E. et al. Radioimmunotherapy of fibroblast activation protein positive tumors by rapidly internalizing antibodies. Clin. Cancer Res. 18, 6208–6218 (2012).
LeBeau, A. M., Brennen, W. N., Aggarwal, S. & Denmeade, S. R. Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin. Mol. Cancer Ther. 8, 1378–1386 (2009).
Froeling, F. E. et al. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-beta-catenin signaling to slow tumor progression. Gastroenterology 141, 1486–1497 (2011).
Guan, J. et al. Retinoic acid inhibits pancreatic cancer cell migration and EMT through the downregulation of IL-6 in cancer associated fibroblast cells. Cancer Lett. 345, 132–139 (2014).
Ghiaur, G. et al. Regulation of human hematopoietic stem cell self-renewal by the microenvironment’s control of retinoic acid signaling. Proc. Natl Acad. Sci. USA 110, 16121–16126 (2013).
Mehra, R. et al. Characterization of bone metastases from rapid autopsies of prostate cancer patients. Clin. Cancer Res. 17, 3924–3932 (2011).
Bai, A. et al. GP369, an FGFR2-IIIb-specific antibody, exhibits potent antitumor activity against human cancers driven by activated FGFR2 signaling. Cancer Res. 70, 7630–7639 (2010).
Chae, Y. K. et al. Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application. Oncotarget 8, 16052–16074 (2017).
Katoh, M. & Nakagama, H. FGF receptors: cancer biology and therapeutics. Med. Res. Rev. 34, 280–300 (2014).
Bello, E. et al. E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res. 71, 1396–1405 (2011).
Gozgit, J. M. et al. Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol. Cancer Ther. 11, 690–699 (2012).
Biswas, S. et al. Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J. Clin. Invest. 117, 1305–1313 (2007).
Domanska, U. M. et al. CXCR4 inhibition enhances radiosensitivity, while inducing cancer cell mobilization in a prostate cancer mouse model. Clin. Exp. Metastasis 31, 829–839 (2014).
Domanska, U. M. et al. CXCR4 inhibition with AMD3100 sensitizes prostate cancer to docetaxel chemotherapy. Neoplasia 14, 709–718 (2012).
Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).
Jackson, H. J., Rafiq, S. & Brentjens, R. J. Driving CAR T-cells forward. Nat. Rev. Clin. Oncol. 13, 370–383 (2016).
Stromnes, I. M. et al. T cells engineered against a native antigen can surmount immunologic and physical barriers to treat pancreatic ductal adenocarcinoma. Cancer Cell 28, 638–652 (2015).
Wang, L. C. et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol. Res. 2, 154–166 (2014).
Kakarla, S. et al. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol. Ther. 21, 1611–1620 (2013).
Chen, M. et al. A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts. Sci. Rep. 5, 14421 (2015).
Gottschalk, S., Yu, F., Ji, M., Kakarla, S. & Song, X. T. A vaccine that co-targets tumor cells and cancer associated fibroblasts results in enhanced antitumor activity by inducing antigen spreading. PLOS ONE 8, e82658 (2013).
Loeffler, M., Kruger, J. A., Niethammer, A. G. & Reisfeld, R. A. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J. Clin. Invest. 116, 1955–1962 (2006).
Wen, Y. et al. Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model. Cancer Sci. 101, 2325–2332 (2010).
Mantovani, A. et al. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).
Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13 (2014).
Long, K. B. et al. IFNγ and CCL2 cooperate to redirect tumor-infiltrating monocytes to degrade fibrosis and enhance chemotherapy efficacy in pancreatic carcinoma. Cancer Discov. 6, 400–413 (2016).
Winograd, R. et al. Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. Cancer Immunol. Res. 3, 399–411 (2015).
Zippelius, A., Schreiner, J., Herzig, P. & Muller, P. Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment. Cancer Immunol. Res. 3, 236–244 (2015).
Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011).
Tada, H. et al. Reprogrammed chondrocytes engineered to produce IL-12 provide novel ex vivo immune-gene therapy for cancer. Immunotherapy 9, 239–248 (2017).
Danaei, G. et al. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet 366, 1784–1793 (2005).
Mandelker, D. et al. Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA versus guideline-based germline testing. JAMA 318, 825–835 (2017).
Tomasetti, C. & Vogelstein, B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78–81 (2015).
Dry, J. R., Yang, M. & Saez-Rodriguez, J. Looking beyond the cancer cell for effective drug combinations. Genome Med. 8, 125 (2016).
Micke, P. & Ostman, A. Tumour-stroma interaction: cancer-associated fibroblasts as novel targets in anti-cancer therapy? Lung Cancer 45 (Suppl. 2), S163–S175 (2004).
Zhang, P., Lehmann, B. D., Shyr, Y. & Guo, Y. The utilization of formalin fixed-paraffin-embedded specimens in high throughput genomic studies. Int. J. Genom. 2017, 1926304 (2017).
Dietrich, D. et al. Analysis of DNA methylation of multiple genes in microdissected cells from formalin-fixed and paraffin-embedded tissues. J. Histochem. Cytochem. 57, 477–489 (2009).
Paulsson, J. & Micke, P. Prognostic relevance of cancer-associated fibroblasts in human cancer. Semin. Cancer Biol. 25, 61–68 (2014).
Liao, Y., Ni, Y., He, R., Liu, W. & Du, J. Clinical implications of fibroblast activation protein-alpha in non-small cell lung cancer after curative resection: a new predictor for prognosis. J. Cancer Res. Clin. Oncol. 139, 1523–1528 (2013).
Edlund, K. et al. CD99 is a novel prognostic stromal marker in non-small cell lung cancer Int. J. Cancer 131, 2264–2273 (2012).
Ishikawa, S. et al. Matrix metalloproteinase-2 status in stromal fibroblasts, not in tumor cells, is a significant prognostic factor in non-small-cell lung cancer. Clin. Cancer Res. 10, 6579–6585 (2004).
Ono, S. et al. Podoplanin-positive cancer-associated fibroblasts could have prognostic value independent of cancer cell phenotype in stage I lung squamous cell carcinoma: usefulness of combining analysis of both cancer cell phenotype and cancer-associated fibroblast phenotype. Chest 143, 963–970 (2013).
Saito, R. A. et al. Forkhead box F1 regulates tumor-promoting properties of cancer-associated fibroblasts in lung cancer. Cancer Res. 70, 2644–2654 (2010).
Monti, D. et al. Pilot study demonstrating metabolic and anti-proliferative effects of in vivo anti-oxidant supplementation with N-acetylcysteine in breast cancer. Semin. Oncol. 44, 226–232 (2017).
Chang, H. Y. et al. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol. 2, E7 (2004).
Chen, J. L. et al. Stromal responses among common carcinomas correlated with clinicopathologic features. Clin. Cancer Res. 19, 5127–5135 (2013).
Finak, G. et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat. Med. 14, 518–527 (2008).
Navab, R. et al. Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer. Proc. Natl Acad. Sci. USA 108, 7160–7165 (2011).
Planche, A. et al. Identification of prognostic molecular features in the reactive stroma of human breast and prostate cancer. PLoS ONE 6, e18640 (2011).
The work of K.C.P., K.C.V., and A.E.d.G. is supported by National Cancer Institute (NCI) grants U54CA143803, CA163124, CA093900, and CA143055, as well as by the Prostate Cancer Foundation and the Patrick C. Walsh Fund. The work of K.C.V. is supported by NCI grant F32CA206394. The authors are grateful to S. Amend for editing the manuscript.
The authors declare no competing interests.
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Valkenburg, K.C., de Groot, A.E. & Pienta, K.J. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol 15, 366–381 (2018). https://doi.org/10.1038/s41571-018-0007-1
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