Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).
Egeblad, M., Nakasone, E. S. & Werb, Z. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010).
Dotto, G. P., Weinberg, R. A. & Ariza, A. Malignant transformation of mouse primary keratinocytes by Harvey sarcoma virus and its modulation by surrounding normal cells. Proc. Natl Acad. Sci. USA 85, 6389–6393 (1988).
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).
Polanska, U. M. & Orimo, A. Carcinoma-associated fibroblasts: non-neoplastic tumour-promoting mesenchymal cells. J. Cell. Physiol. 8, 1651–1657 (2013).
Rinn, J. L., Bondre, C., Gladstone, H. B., Brown, P. O. & Chang, H. Y. Anatomic demarcation by positional variation in fibroblast gene expression programs. PLoS Genet. 2, e119 (2006).
Rudnick, J. A. et al. Functional heterogeneity of breast fibroblasts is defined by a prostaglandin secretory phenotype that promotes expansion of cancer-stem like cells. PLoS ONE 6, e24605 (2011).
Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol. 2, 737–744 (2000).
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).
Yamashita, M. et al. Role of stromal myofibroblasts in invasive breast cancer: stromal expression of alpha-smooth muscle actin correlates with worse clinical outcome. Breast Cancer 19, 170–176 (2012).
Fujita, H. et al. α-Smooth muscle actin expressing stroma promotes an aggressive tumor biology in pancreatic ductal adenocarcinoma. Pancreas 39, 1254–1262 (2010).
Vihinen, P. & Kähäri, V.-M. Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets. Int. J. Cancer 99, 157–166 (2002).
Calle, E. E. & Kaaks, R. R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Rev. Cancer 4, 579–591 (2004).
Ferrara, N. & Kerbel, R. S. Angiogenesis as a therapeutic target. Nature 438, 967–974 (2005).
Kalluri, R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nature Rev. Cancer 3, 422–433 (2003).
Rosenberg, R. D. & Aird, W. C. Vascular-bed–specific hemostasis and hypercoagulable states. N. Engl. J. Med. 340, 1555–1564 (1999).
Trédan, O., Galmarini, C. M., Patel, K. & Tannock, I. F. Drug resistance and the solid tumor microenvironment. J. Natl Cancer Inst. 99, 1441–1454 (2007).
Meert, A.-P. et al. The role of microvessel density on the survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br. J. Cancer 87, 694–701 (2002).
Des Guetz, G. et al. Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature. Br. J. Cancer 94, 1823–1832 (2006).
Uzzan, B., Nicolas, P., Cucherat, M. & Perret, G.-Y. Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. Cancer Res. 64, 2941–2955 (2004).
Hegde, P. S. et al. Predictive impact of circulating vascular endothelial growth factor in 4 phase III trials evaluating bevacizumab. Clin. Cancer Res. 19, 929–937 (2013).
Fridman, W.-H., Pagès, F., Sautès-Fridman, C. & Galon, J. The immune contexture in human tumours: impact on clinical outcome. Nature Rev. Cancer 12, 298–306 (2012).
Buckanovich, R. J. et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nature Med. 14, 28–36 (2008).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nature Rev. Cancer 12, 252–264 (2012).
Yang, L. et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6, 409–421 (2004).
Shojaei, F. et al. G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc. Natl Acad. Sci. USA 106, 6742–6747 (2009).
Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G. & Bar-Sagi, D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21, 836–847 (2012).
Bayne, L. J. et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822–835 (2012).
Motz, G. T. & Coukos, G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nature Rev. Immunol. 11, 702–711 (2011).
Gabrilovich, D. I., Ostrand-Rosenberg, S. S. & Bronte, V. V. Coordinated regulation of myeloid cells by tumours. Nature Rev. Immunol. 12, 253–268 (2012).
Nelson, B. H. CD20+ B cells: the other tumor-infiltrating lymphocytes. J. Immunol. 185, 4977–4982 (2010).
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).
Ammirante, M., Luo, J.-L., Grivennikov, S., Nedospasov, S. & Karin, M. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464, 302–305 (2010).
Coussens, L. M. et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999).
Yang, F.-C. et al. Nf1-dependent tumors require a microenvironment containing Nf1+/−- and c-kit-dependent bone marrow. Cell 135, 437–448 (2008).
Mantovani, A. & Sica, A. A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr. Opin. Immunol. 22, 231–237 (2010).
Finak, G. et al. Stromal gene expression predicts clinical outcome in breast cancer. Nature Med. 14, 518–527 (2008).
Tosolini, M. et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, Hh2, Treg, Th17) in patients with colorectal cancer. Cancer Res. 71, 1263–1271 (2011).
DeNardo, D. G. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).
Nielsen, J. S. et al. CD20+ tumor-infiltrating lymphocytes have an atypical CD27− memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin. Cancer Res. 18, 3281–3292 (2012).
Schmidt, M. et al. The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res. 68, 5405–5413 (2008).
Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).
Wagle, N. et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J. Clin. Oncol. 29, 3085–3096 (2011).
Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005).
Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).
Bean, J. et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl Acad. Sci. USA 104, 20932–20937 (2007).
Nazarian, R. et al. Melanomas acquire resistance to B-RAF (V600E) inhibition by RTK or N-RAS upregulation. Nature 468, 973–977 (2010).
Meads, M. B., Gatenby, R. A. & Dalton, W. S. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nature Rev. Cancer 9, 665–674 (2009).
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).
Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001).
Ohuchida, K. et al. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res. 64, 3215–3222 (2004).
Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).
The authors of this paper used co-cultures of tumour cells with fibroblast and stromal cell lines to screen for targeted therapy resistance, and identified secreted HFG as a mediator of resistance to BRAF inhibition in melanoma.
Wilson, T. R. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487, 505–509 (2012).
This article describes in vitro screening that illustrates the broad applicability of secreted growth factors as mediators of therapeutic resistance and identifies HFG as a mediator of therapeutic resistance to BRAF and HER2 inhibition.
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).
Sun, Y. et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nature Med. 18, 1359–1368 (2012).
This article highlights the crucial effect that therapeutic treatment has on the tumour stroma, which can influence drug response and resistance.
Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).
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).
Van der Veldt, A. A. M. et al. Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell 21, 82–91 (2012).
Gilbert, L. A. & Hemann, M. T. DNA damage-mediated induction of a chemoresistant niche. Cell 143, 355–366 (2010).
The authors of this article illustrate in an animal model how tissue responses to chemotherapy can create unique environments in vivo that support minimum residual disease and eventual cancer relapse.
Calabrese, C. et al. A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69–82 (2007).
This paper describes a potential role for the vascular niche in harbouring cancer stem cells.
Krishnamurthy, S. et al. Endothelial cell-initiated signaling promotes the survival and self-renewal of cancer stem cells. Cancer Res. 70, 9969–9978 (2010).
Lu, J. et al. Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell 23, 171–185 (2013).
Mao, Q. et al. A tumor hypoxic niche protects human colon cancer stem cells from chemotherapy. J. Cancer Res. Clin. Oncol. 139, 211–222 (2013).
Shojaei, F. et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nature Biotechnol. 25, 911–920 (2007).
This article describes how infiltrating immunosuppressive cells can impede anti-VEGF therapeutic efficacy.
Phan, V. T. et al. Oncogenic RAS pathway activation promotes resistance to anti-VEGF therapy through G-CSF-induced neutrophil recruitment. Proc. Natl Acad. Sci. USA 110, 6079–6084 (2013).
Xu, J. et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res. 73, 2782–2794 (2013).
Frederick, D. T. et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225–1231 (2013).
Rosenberg, S. A., Restifo, N. P., Yang, J. C., Morgan, R. A. & Dudley, M. E. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nature Rev. Cancer 8, 299–308 (2008).
Landsberg, J. et al. Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature 490, 412–416 (2012).
This report implicates treatment-induced inflammation as the cause of therapeutic resistance against an immunotherapy.
Coussens, L. M., Fingleton, B. & Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295, 2387–2392 (2002).
Michael, M. et al. Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer. J. Clin. Oncol. 17, 1802–1808 (1999).
Theunissen, J.-W. & de Sauvage, F. J. Paracrine Hedgehog signaling in cancer. Cancer Res. 69, 6007–6010 (2009).
Berlin, J. et al. A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer. Clin. Cancer Res. 19, 258–267 (2013).
Kaye, S. B. et al. A phase II, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission. Clin. Cancer Res. 18, 6509–6518 (2012).
Madden, J. I. Infinity Reports Update From Phase 2 Study of Saridegib Plus Gemcitabine in Patients with Metastatic Pancreatic Cancer http://phx.corporate-ir.net/phoenix.zhtml?c=121941&p=irol-newsArticle&ID=1653550&highlight= (Infinity Pharmaceuticals, 2012).
Catenacci, D. et al. A phase IB/randomized phase II study of gemcitabine (G) plus placebo (P) or vismodegib (V), a Hedgehog (Hh) pathway inhibitor, in patients (pts) with metastatic pancreatic cancer: Interim analysis of a University of Chicago phase II consortium study. J. Clin. Oncol. 30, (suppl.), abstr. 4022 (2012).
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).
Ferrara, N., Hillan, K. J., Gerber, H.-P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Rev. Drug Discov. 3, 391–400 (2004).
Sandler, A. et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355, 2542–2550 (2006).
Hurwitz, H. I. et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J. Clin. Oncol. 23, 3502–3508 (2005).
Yang, J. C. et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 349, 427–434 (2003).
Friedman, H. S. et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J. Clin. Oncol. 27, 4733–4740 (2009).
Vredenburgh, J. J. et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J. Clin. Oncol. 25, 4722–4729 (2007).
Perren, T. J. et al. A phase 3 trial of bevacizumab in ovarian cancer. N. Engl. J. Med. 365, 2484–2496 (2011).
Tewari, K. S. et al. Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group. J. Clin. Oncol. 31 (suppl.), abstr. 3 (2013)
Kindler, H. L. et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J. Clin. Oncol. 23, 8033–8040 (2005).
Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).
Pàez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009).
Singh, M. et al. Anti-VEGF antibody therapy does not promote metastasis in genetically engineered mouse tumour models. J. Pathol. 227, 417–430 (2012).
Miles, D. et al. Disease course patterns after discontinuation of bevacizumab: pooled analysis of randomized phase III trials. J. Clin. Oncol. 29, 83–88 (2011).
Blagoev, K. B. et al. Sunitinib does not accelerate tumor growth in patients with metastatic renal cell carcinoma. Cell Rep. 3, 277–281 (2013).
Chung, A. S. et al. Differential drug class-specific metastatic effects following treatment with a panel of angiogenesis inhibitors. J. Pathol. 227, 404–416 (2012).
de Groot, J. F. et al. Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol. 12, 233–242 (2010).
Lu, K. V. et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22, 21–35 (2012).
Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011).
Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).
Bargou, R. et al. Tumor regression in cancer patients by very low doses of a T-cell-engaging antibody. Science 321, 974–977 (2008).
Brischwein, K. et al. Strictly target cell-dependent activation of T cells by bispecific single-chain antibody constructs of the BiTE class. J. Immunother. 30, 798–807 (2007).
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).
Lake, R. A. & Robinson, B. W. S. Immunotherapy and chemotherapy — a practical partnership. Nature Rev. Cancer 5, 397–405 (2005).
Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Immunological aspects of cancer chemotherapy. Nature Rev. Immunol. 8, 59–73 (2008).
Ciampricotti, M., Hau, C.-S., Doornebal, C. W., Jonkers, J. & de Visser, K. E. Chemotherapy response of spontaneous mammary tumors is independent of the adaptive immune system. Nature Med. 18, 344–346 (2012).
Zitvogel, L. & Kroemer, G. Reply to: Chemotherapy response of spontaneous mammary tumors is independent of the adaptive immune system. Nature Med. 18, 346 (2012).
References 104 and 105 describe contradictory requirements for adaptive immunity in mediating chemotherapeutic responses in preclinical models of cancer.
Arlen, P. M. et al. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin. Cancer Res. 12, 1260–1269 (2006).
Hamzah, J. et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453, 410–414 (2008).
Johansson, A., Hamzah, J. J., Payne, C. J. C. & Ganss, R. R. Tumor-targeted TNFα stabilizes tumor vessels and enhances active immunotherapy. Proc. Natl Acad. Sci. USA 109, 7841–7846 (2012).
Shrimali, R. K. et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 70, 6171–6180 (2010).
Gabrilovich, D. I., Ishida, T., Nadaf, S., Ohm, J. E. & Carbone, D. P. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin. Cancer Res. 5, 2963–2970 (1999).
DeSilva, D. R. et al. Inhibition of mitogen-activated protein kinase kinase blocks T cell proliferation but does not induce or prevent anergy. J. Immunol. 160, 4175–4181 (1998).
Boni, A. et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 70, 5213–5219 (2010).
Singh, M. & Ferrara, N. Modeling and predicting clinical efficacy for drugs targeting the tumor milieu. Nature Biotechnol. 30, 648–657 (2012).
Yang, S. X. et al. Gene expression profile and angiogenic marker correlates with response to neoadjuvant bevacizumab followed by bevacizumab plus chemotherapy in breast cancer. Clin. Cancer Res. 14, 5893–5899 (2008).
Lambrechts, D., Lenz, H.-J., de Haas, S., Carmeliet, P. & Scherer, S. J. Markers of response for the antiangiogenic agent bevacizumab. J. Clin. Oncol. 31, 1219–1230 (2013).
Jubb, A. M. et al. Vascular phenotypes in primary non-small cell lung carcinomas and matched brain metastases. Br. J. Cancer 104, 1877–1881 (2011).
Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3, 75ra26 (2011).
Bennouna, J. et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 14, 29–37 (2013).
Cheever, M. A. et al. Translational Research Working Group developmental pathway for immune response modifiers. Clin. Cancer Res. 14, 5692–5699 (2008).
Deng, G., Lu, Y., Zlotnikov, G., Thor, A. D. & Smith, H. S. Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 274, 2057–2059 (1996).
Patocs, A. et al. Breast-cancer stromal cells with TP53 mutations and nodal metastases. N. Engl. J. Med. 357, 2543–2551 (2007).
Qiu, W. et al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nature Genet. 40, 650–655 (2008).
Giantonio, B. J. et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J. Clin. Oncol. 25, 1539–1544 (2007).
Fiegl, H. et al. Breast cancer DNA methylation profiles in cancer cells and tumor stroma: association with HER-2/neu status in primary breast cancer. Cancer Res. 66, 29–33 (2006).
Hu, M. et al. Distinct epigenetic changes in the stromal cells of breast cancers. Nature Genet. 37, 899–905 (2005).