Joyce, J.A. & Pollard, J.W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9, 239–252 (2009).
Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).
Hanahan, D. & Coussens, L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).
Hanahan, D. & Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Weis, S.M. & Cheresh, D.A. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat. Med. 17, 1359–1370 (2011).
Lindau, D., Gielen, P., Kroesen, M., Wesseling, P. & Adema, G.J. The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology 138, 105–115 (2013).
Shiao, S.L., Ganesan, A.P., Rugo, H.S. & Coussens, L.M. Immune microenvironments in solid tumors: new targets for therapy. Genes Dev. 25, 2559–2572 (2011).
Mantovani, A., Cassatella, M.A., Costantini, C. & Jaillon, S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat. Rev. Immunol. 11, 519–531 (2011).
Khazaie, K. et al. The significant role of mast cells in cancer. Cancer Metastasis Rev. 30, 45–60 (2011).
De Palma, M. & Naldini, L. Tie2-expressing monocytes (TEMs): novel targets and vehicles of anticancer therapy? Biochim. Biophys. Acta 1796, 5–10 (2009).
Palucka, K. & Banchereau, J. Cancer immunotherapy via dendritic cells. Nat. Rev. Cancer 12, 265–277 (2012).
Grivennikov, S.I., Greten, F.R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).
Sangiovanni, A. et al. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology 126, 1005–1014 (2004).
Beaugerie, L. et al. Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease. Gastroenterology 145, 166–175 (2013).
Barcellos-Hoff, M.H., Lyden, D. & Wang, T.C. The evolution of the cancer niche during multistage carcinogenesis. Nat. Rev. Cancer 13, 511–518 (2013).
de Martel, C. et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 13, 607–615 (2012).
Stewart, T., Tsai, S.C., Grayson, H., Henderson, R. & Opelz, G. Incidence of de-novo breast cancer in women chronically immunosuppressed after organ transplantation. Lancet 346, 796–798 (1995).
Gallagher, B., Wang, Z., Schymura, M.J., Kahn, A. & Fordyce, E.J. Cancer incidence in New York State acquired immunodeficiency syndrome patients. Am. J. Epidemiol. 154, 544–556 (2001).
Schulz, T.F. Cancer and viral infections in immunocompromised individuals. Int. J. Cancer 125, 1755–1763 (2009).
Vajdic, C.M. & van Leeuwen, M.T. Cancer incidence and risk factors after solid organ transplantation. Int. J. Cancer 125, 1747–1754 (2009).
Biswas, S.K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 (2010).
Flavell, R.A., Sanjabi, S., Wrzesinski, S.H. & Licona-Limon, P. The polarization of immune cells in the tumour environment by TGFβ. Nat. Rev. Immunol. 10, 554–567 (2010).
Wang, H.W. & Joyce, J.A. Alternative activation of tumor-associated macrophages by IL-4: priming for protumoral functions. Cell Cycle 9, 4824–4835 (2010).
Hagemann, T. et al. “Re-educating” tumor-associated macrophages by targeting NF-κB. J. Exp. Med. 205, 1261–1268 (2008).
Pyonteck, S.M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 (2013).
Cook, J. & Hagemann, T. Tumour-associated macrophages and cancer. Curr. Opin. Pharmacol. 13, 595–601 (2013).
Bissell, M.J. & Hines, W.C. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17, 320–329 (2011).
Egeblad, M., Nakasone, E.S. & Werb, Z. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010).
Qian, B.Z. & Pollard, J.W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).
Condeelis, J. & Pollard, J.W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).
Goswami, S. et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res. 65, 5278–5283 (2005).
Coniglio, S.J. et al. Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol. Med. 18, 519–527 (2012).
Joyce, J.A. et al. Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell 5, 443–453 (2004).
Gocheva, V. et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev. 24, 241–255 (2010).
Shree, T. et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. 25, 2465–2479 (2011).
Mosser, D.M. & Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).
Lewis, C. & Murdoch, C. Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am. J. Pathol. 167, 627–635 (2005).
Escribese, M.M., Casas, M. & Corbi, A.L. Influence of low oxygen tensions on macrophage polarization. Immunobiology 217, 1233–1240 (2012).
Shime, H. et al. Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors. Proc. Natl. Acad. Sci. USA 109, 2066–2071 (2012).
Cai, X. et al. Re-polarization of tumor-associated macrophages to pro-inflammatory M1 macrophages by microRNA-155. J. Mol. Cell Biol. 4, 341–343 (2012).
Motz, G.T. & Coukos, G. Deciphering and reversing tumor immune suppression. Immunity 39, 61–73 (2013).
Almand, B. et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J. Immunol. 166, 678–689 (2001).
Talmadge, J.E. & Gabrilovich, D.I. History of myeloid-derived suppressor cells. Nat. Rev. Cancer 13, 739–752 (2013).
Gabrilovich, D.I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).
Mazzoni, A. et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J. Immunol. 168, 689–695 (2002).
Gabrilovich, D.I., Velders, M.P., Sotomayor, E.M. & Kast, W.M. Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J. Immunol. 166, 5398–5406 (2001).
Sinha, P., Clements, V.K. & Ostrand-Rosenberg, S. Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease. J. Immunol. 174, 636–645 (2005).
Liu, C. et al. Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor-bearing host. Blood 109, 4336–4342 (2007).
Diaz-Montero, C.M. et al. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol. Immunother. 58, 49–59 (2009).
Shirota, Y., Shirota, H. & Klinman, D.M. Intratumoral injection of CpG oligonucleotides induces the differentiation and reduces the immunosuppressive activity of myeloid-derived suppressor cells. J. Immunol. 188, 1592–1599 (2012).
Whiteside, T.L., Schuler, P. & Schilling, B. Induced and natural regulatory T cells in human cancer. Expert Opin. Biol. Ther. 12, 1383–1397 (2012).
Gasteiger, G. et al. IL-2–dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells. J. Exp. Med. 210, 1179–1187 (2013).
Bates, G.J. et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J. Clin. Oncol. 24, 5373–5380 (2006).
Fu, J. et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132, 2328–2339 (2007).
Frey, D.M. et al. High frequency of tumor-infiltrating FOXP3+ regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int. J. Cancer 126, 2635–2643 (2010).
von Boehmer, H. & Daniel, C. Therapeutic opportunities for manipulating TReg cells in autoimmunity and cancer. Nat. Rev. Drug Discov. 12, 51–63 (2013).
Fridman, W.H., Pages, F., Sautes-Fridman, C. & Galon, J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer 12, 298–306 (2012).
Blatner, N.R. et al. Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer. Sci. Transl. Med. 4, 164ra159 (2012).
Rech, A.J. et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci. Transl. Med. 4, 134ra162 (2012).
Tomasek, J.J., Gabbiani, G., Hinz, B., Chaponnier, C. & Brown, R.A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 3, 349–363 (2002).
Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 6, 392–401 (2006).
Olumi, A.F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).
Dumont, N. et al. Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. Neoplasia 15, 249–262 (2013).
Marsh, T., Pietras, K. & McAllister, S.S. Fibroblasts as architects of cancer pathogenesis. Biochim. Biophys. Acta 1832, 1070–1078 (2013).
Zeisberg, E.M., Potenta, S., Xie, L., Zeisberg, M. & Kalluri, R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 67, 10123–10128 (2007).
Petersen, O.W. et al. Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am. J. Pathol. 162, 391–402 (2003).
Orr, B. et al. Identification of stromally expressed molecules in the prostate by tag-profiling of cancer-associated fibroblasts, normal fibroblasts and fetal prostate. Oncogene 31, 1130–1142 (2012).
Zeisberg, M. et al. BMP-7 counteracts TGF-β1–induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 9, 964–968 (2003).
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).
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).
Zhang, X.H. et al. Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell 154, 1060–1073 (2013).
Bergamaschi, A. et al. Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome. J. Pathol. 214, 357–367 (2008).
Naba, A. et al. The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices. Mol. Cell. Proteomics 11, M111.014647 (2012).
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).
Du, R. et al. HIF1α induces the recruitment of bone marrow–derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220 (2008).
Semenza, G.L. Cancer-stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis. Oncogene 32, 4057–4063 (2013).
Zhu, W. et al. Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp. Mol. Pathol. 80, 267–274 (2006).
Ho, I.A. et al. Human bone marrow–derived mesenchymal stem cells suppress human glioma growth through inhibition of angiogenesis. Stem Cells 31, 146–155 (2013).
Roodhart, J.M. et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 20, 370–383 (2011).
Cuiffo, B.G. & Karnoub, A.E. Mesenchymal stem cells in tumor development: emerging roles and concepts. Cell Adh. Migr. 6, 220–230 (2012).
Alitalo, A. & Detmar, M. Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene 31, 4499–4508 (2012).
Schoppmann, S.F. et al. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am. J. Pathol. 161, 947–956 (2002).
Kerjaschki, D. et al. Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nat. Med. 12, 230–234 (2006).
Zumsteg, A. et al. Myeloid cells contribute to tumor lymphangiogenesis. PLoS ONE 4, e7067 (2009).
Hunter, K.E. et al. Heparanase promotes lymphangiogenesis and tumor invasion in pancreatic neuroendocrine tumors. Oncogene published online, doi:10.1038/onc.2013.142 (6 May 2013).
Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 9, 285–293 (2009).
Mani, S.A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).
Thiery, J.P., Acloque, H., Huang, R.Y. & Nieto, M.A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).
Gao, D. et al. Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Res. 72, 1384–1394 (2012).
Chao, Y., Wu, Q., Acquafondata, M., Dhir, R. & Wells, A. Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases. Cancer Microenviron. 5, 19–28 (2012).
Chaffer, C.L., Thompson, E.W. & Williams, E.D. Mesenchymal to epithelial transition in development and disease. Cells Tissues Organs 185, 7–19 (2007).
Bonde, A.K., Tischler, V., Kumar, S., Soltermann, A. & Schwendener, R.A. Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors. BMC Cancer 12, 35 (2012).
Gay, L.J. & Felding-Habermann, B. Contribution of platelets to tumour metastasis. Nat. Rev. Cancer 11, 123–134 (2011).
Labelle, M., Begum, S. & Hynes, R.O. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal–like transition and promotes metastasis. Cancer Cell 20, 576–590 (2011).
Nishimura, K., Semba, S., Aoyagi, K., Sasaki, H. & Yokozaki, H. Mesenchymal stem cells provide an advantageous tumor microenvironment for the restoration of cancer stem cells. Pathobiology 79, 290–306 (2012).
Condeelis, J. & Segall, J.E. Intravital imaging of cell movement in tumours. Nat. Rev. Cancer 3, 921–930 (2003).
Wyckoff, J.B. et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 67, 2649–2656 (2007).
van Zijl, F. et al. Hepatic tumor-stroma crosstalk guides epithelial to mesenchymal transition at the tumor edge. Oncogene 28, 4022–4033 (2009).
Chouaib, S. et al. Hypoxia promotes tumor growth in linking angiogenesis to immune escape. Front. Immunol. 3, 21 (2012).
Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226–230 (2011).
Corzo, C.A. et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 207, 2439–2453 (2010).
Halama, N. et al. Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res. 71, 5670–5677 (2011).
Murdoch, C., Giannoudis, A. & Lewis, C.E. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 104, 2224–2234 (2004).
Nguyen, D.X., Bos, P.D. & Massague, J. Metastasis: from dissemination to organ-specific colonization. Nat. Rev. Cancer 9, 274–284 (2009).
Condeelis, J. & Weissleder, R. In vivo imaging in cancer. Cold Spring Harb. Perspect. Biol. 2, a003848 (2010).
Sidani, M., Wyckoff, J., Xue, C., Segall, J.E. & Condeelis, J. Probing the microenvironment of mammary tumors using multiphoton microscopy. J. Mammary Gland Biol. Neoplasia 11, 151–163 (2006).
Robinson, B.D. et al. Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin. Cancer Res. 15, 2433–2441 (2009).
Lucci, A. et al. Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol. 13, 688–695 (2012).
Krishnamurthy, S. et al. Detection of minimal residual disease in blood and bone marrow in early stage breast cancer. Cancer 116, 3330–3337 (2010).
Stoecklein, N.H. et al. Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. Cancer Cell 13, 441–453 (2008).
Redente, E.F. et al. Tumor progression stage and anatomical site regulate tumor-associated macrophage and bone marrow–derived monocyte polarization. Am. J. Pathol. 176, 2972–2985 (2010).
Chambers, A.F. et al. Critical steps in hematogenous metastasis: an overview. Surg. Oncol. Clin. N. Am. 10, 243–255, vii (2001).
Palumbo, J.S. et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell–mediated elimination of tumor cells. Blood 105, 178–185 (2005).
Ruggeri, Z.M. & Mendolicchio, G.L. Adhesion mechanisms in platelet function. Circ. Res. 100, 1673–1685 (2007).
Schumacher, D., Strilic, B., Sivaraj, K.K., Wettschureck, N. & Offermanns, S. Platelet-derived nucleotides promote tumor-cell transendothelial migration and metastasis via P2Y2 receptor. Cancer Cell 24, 130–137 (2013).
Taucher, S. et al. Impact of pretreatment thrombocytosis on survival in primary breast cancer. Thromb. Haemost. 89, 1098–1106 (2003).
Brown, K.M., Domin, C., Aranha, G.V., Yong, S. & Shoup, M. Increased preoperative platelet count is associated with decreased survival after resection for adenocarcinoma of the pancreas. Am. J. Surg. 189, 278–282 (2005).
Brockmann, M.A. et al. Preoperative thrombocytosis predicts poor survival in patients with glioblastoma. Neuro-oncol. 9, 335–342 (2007).
Kaplan, R.N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).
Chen, Q., Zhang, X.H. & Massague, J. Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 20, 538–549 (2011).
Lu, X. et al. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α4β1-positive osteoclast progenitors. Cancer Cell 20, 701–714 (2011).
Erler, J.T. et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440, 1222–1226 (2006).
Sceneay, J. et al. Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res. 72, 3906–3911 (2012).
Malanchi, I. et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481, 85–89 (2012).
Peinado, H. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18, 883–891 (2012).
Luga, V. et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151, 1542–1556 (2012).
Lugini, L. et al. Immune surveillance properties of human NK cell–derived exosomes. J. Immunol. 189, 2833–2842 (2012).
Morse, M.A. et al. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J. Transl. Med. 3, 9 (2005).
Escudier, B. et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of the first phase I clinical trial. J. Transl. Med. 3, 10 (2005).
Näslund, T.I., Gehrmann, U., Qazi, K.R., Karlsson, M.C. & Gabrielsson, S. Dendritic cell–derived exosomes need to activate both T and B cells to induce antitumor immunity. J. Immunol. 190, 2712–2719 (2013).
Granot, Z. et al. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20, 300–314 (2011).
Catena, R. et al. Bone marrow–derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discov. 3, 578–589 (2013).
Aguirre-Ghiso, J.A. Models, mechanisms and clinical evidence for cancer dormancy. Nat. Rev. Cancer 7, 834–846 (2007).
Schreiber, R.D., Old, L.J. & Smyth, M.J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).
Hensel, J.A., Flaig, T.W. & Theodorescu, D. Clinical opportunities and challenges in targeting tumour dormancy. Nat. Rev. Clin. Oncol. 10, 41–51 (2013).
Naumov, G.N., Akslen, L.A. & Folkman, J. Role of angiogenesis in human tumor dormancy: animal models of the angiogenic switch. Cell Cycle 5, 1779–1787 (2006).
Ghajar, C.M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807–817 (2013).
Conejo-Garcia, J.R. et al. Tumor-infiltrating dendritic cell precursors recruited by a β-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat. Med. 10, 950–958 (2004).
Gao, D. et al. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 319, 195–198 (2008).
Lyden, D. et al. Impaired recruitment of bone-marrow–derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat. Med. 7, 1194–1201 (2001).
Purhonen, S. et al. Bone marrow–derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc. Natl. Acad. Sci. USA 105, 6620–6625 (2008).
Dawson, M.R., Duda, D.G., Fukumura, D. & Jain, R.K. VEGFR1-activity–independent metastasis formation. Nature 461, E4 (2009).
Kerbel, R.S. et al. Endothelial progenitor cells are cellular hubs essential for neoangiogenesis of certain aggressive adenocarcinomas and metastatic transition but not adenomas. Proc. Natl. Acad. Sci. U S A 105, E54; author reply E55 (2008).
Pierga, J.Y. et al. Clinical significance of proliferative potential of occult metastatic cells in bone marrow of patients with breast cancer. Br. J. Cancer 89, 539–545 (2003).
Braun, S. et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N. Engl. J. Med. 342, 525–533 (2000).
Naumov, G.N. et al. Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res. 62, 2162–2168 (2002).
Liu, D., Aguirre Ghiso, J., Estrada, Y. & Ossowski, L. EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell 1, 445–457 (2002).
Ranganathan, A.C., Adam, A.P. & Aguirre-Ghiso, J.A. Opposing roles of mitogenic and stress signaling pathways in the induction of cancer dormancy. Cell Cycle 5, 1799–1807 (2006).
Lujambio, A. et al. Non–cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013).
Gao, H. et al. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150, 764–779 (2012).
Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).
Koebel, C.M. et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450, 903–907 (2007).
Khong, H.T. & Restifo, N.P. Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat. Immunol. 3, 999–1005 (2002).
Vanneman, M. & Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12, 237–251 (2012).
Yoshikawa, K. et al. Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head. Cancer Sci. 103, 2012–2020 (2012).
Qian, B. et al. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS ONE 4, e6562 (2009).
Qian, B.Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).
Mantovani, G. et al. Tumor-associated lympho-monocytes from neoplastic effusions are immunologically defective in comparison with patient autologous PBMCs but are capable of releasing high amounts of various cytokines. Int. J. Cancer 71, 724–731 (1997).
Gil-Bernabé, A.M. et al. Recruitment of monocytes/macrophages by tissue factor–mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood 119, 3164–3175 (2012).
Palumbo, J.S. Mechanisms linking tumor cell–associated procoagulant function to tumor dissemination. Semin. Thromb. Hemost. 34, 154–160 (2008).
Amirkhosravi, A. et al. Tissue factor pathway inhibitor reduces experimental lung metastasis of B16 melanoma. Thromb. Haemost. 87, 930–936 (2002).
Marusyk, A., Almendro, V. & Polyak, K. Intra-tumour heterogeneity: a looking glass for cancer? Nat. Rev. Cancer 12, 323–334 (2012).
Garraway, L.A. & Lander, E.S. Lessons from the cancer genome. Cell 153, 17–37 (2013).
Fang, H. & Declerck, Y.A. Targeting the tumor microenvironment: from understanding pathways to effective clinical trials. Cancer Res. 73, 4965–4977 (2013).
Carmeliet, P. & Jain, R.K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).
Sharma, P., Wagner, K., Wolchok, J.D. & Allison, J.P. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat. Rev. Cancer 11, 805–812 (2011).
Restifo, N.P., Dudley, M.E. & Rosenberg, S.A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269–281 (2012).
Hodi, F.S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Hwu, P. Treating cancer by targeting the immune system. N. Engl. J. Med. 363, 779–781 (2010).
Wolchok, J.D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).
Hamid, O. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013).
Vonderheide, R.H. & Glennie, M.J. Agonistic CD40 antibodies and cancer therapy. Clin. Cancer Res. 19, 1035–1043 (2013).
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).
Coussens, L.M., Zitvogel, L. & Palucka, A.K. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339, 286–291 (2013).
DeNardo, D.G. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).
Germano, G. et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23, 249–262 (2013).
Murdoch, C., Muthana, M., Coffelt, S.B. & Lewis, C.E. The role of myeloid cells in the promotion of tumour angiogenesis. Nat. Rev. Cancer 8, 618–631 (2008).
Fridlender, Z.G. & Albelda, S.M. Tumor-associated neutrophils: friend or foe? Carcinogenesis 33, 949–955 (2012).
Vivier, E., Tomasello, E., Baratin, M., Walzer, T. & Ugolini, S. Functions of natural killer cells. Nat. Immunol. 9, 503–510 (2008).
Bos, P.D. & Rudensky, A.Y. Treg cells in cancer: a case of multiple personality disorder. Sci. Transl. Med. 4, 164fs144 (2012).
Mahmoud, S.M. et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J. Clin. Oncol. 29, 1949–1955 (2011).
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).
Calle, E.E., Rodriguez, C., Walker-Thurmond, K. & Thun, M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 348, 1625–1638 (2003).
Behan, J.W. et al. Adipocytes impair leukemia treatment in mice. Cancer Res. 69, 7867–7874 (2009).
Morris, P.G. et al. Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev. Res. (Phila.) 4, 1021–1029 (2011).
Nieman, K.M. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 17, 1498–1503 (2011).
Zhang, Y. et al. Stromal progenitor cells from endogenous adipose tissue contribute to pericytes and adipocytes that populate the tumor microenvironment. Cancer Res. 72, 5198–5208 (2012).
Katayama, Y. et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407–421 (2006).
Yamazaki, S. et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147, 1146–1158 (2011).
Liebig, C. et al. Perineural invasion is an independent predictor of outcome in colorectal cancer. J. Clin. Oncol. 27, 5131–5137 (2009).
Ayala, G.E. et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin. Cancer Res. 14, 7593–7603 (2008).
Demir, I.E., Friess, H. & Ceyhan, G.O. Nerve-cancer interactions in the stromal biology of pancreatic cancer. Front. Physiol. 3, 97 (2012).
Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013).
Liao, X. et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N. Engl. J. Med. 367, 1596–1606 (2012).
Holmgaard, R.B., Zamarin, D., Munn, D.H., Wolchok, J.D. & Allison, J.P. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J. Exp. Med. 210, 1389–1402 (2013).
Landsberg, J. et al. Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature 490, 412–416 (2012).
De Palma, M. & Lewis, C.E. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23, 277–286 (2013).