Key Points
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Bone marrow-derived myeloid cells such as macrophages, neutrophils, eosinophils, mast cells and dendritic cells infiltrate malignant tumours in large numbers and are sometimes a prominent feature in the stroma of such tissues.
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A wide array of chemoattractants released by both malignant and stromal cells in tumours recruit myeloid cells from the tumour vasculature into tumours.
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Recent studies have shown these cells not only to be central in the regulation of inflammatory events and various immune mechanisms but also to have an important role in driving various crucial processes in tumorigenesis, including angiogenesis.
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Their role in tumour progression is often multifaceted and includes the production of pro-angiogenic growth factors and vascular-modulating enzymes. It may also extend to their possible trans-differentiation into endothelial cells in response to prolonged pro-angiogenic stimuli in tumours.
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Signals produced within the tumour microenvironment appear to stimulate many of the pro-angiogenic functions of these cells. For example, tumour-infiltrating macrophages are stimulated to act as a potent pro-angiogenic force in tumours by exposure to tumour hypoxia and/or such tumour cell-derived cytokines as vascular endothelial growth factor (VEGF), tumour necrosis factor α and angiopoietin 2.
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Antibodies (and other inhibitors) that block the uptake of pro-angiogenic myeloid cells such as monocytes into tumours are now being developed and tested in preclinical mouse models. For example, a neutralizing antibody to CCL2 markedly reduces both the number of tumour-associated macrophages and tumour angiogenesis.
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Some subpopulations of myeloid cells inhibit the anti-angiogenic response of tumours to antibodies targeting VEGF and placental growth factor in tumours. They have also been implicated in tumour responses to chemotherapy or radiation therapy.
Abstract
The use of various transgenic mouse models and analysis of human tumour biopsies has shown that bone marrow-derived myeloid cells, such as macrophages, neutrophils, eosinophils, mast cells and dendritic cells, have an important role in regulating the formation and maintenance of blood vessels in tumours. In this Review the evidence for each of these cell types driving tumour angiogenesis is outlined, along with the mechanisms regulating their recruitment and activation by the tumour microenvironment. We also discuss the therapeutic implications of recent findings that specific myeloid cell populations modulate the responses of tumours to agents such as chemotherapy and some anti-angiogenic therapies.
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References
de Visser, K. E. & Coussens, L. M. The inflammatory tumor microenvironment and its impact on cancer development. Contrib. Microbiol. 13, 118–137 (2006).
de Visser, K. E., Eichten, A. & Coussens, L. M. Paradoxical roles of the immune system during cancer development. Nature Rev. Cancer 6, 24–37 (2006).
Sierko, E. & Wojtukiewicz, M. Z. Platelets and angiogenesis in malignancy. Semin. Thromb. Hemost. 30, 95–108 (2004).
Bertolini, F., Shaked, Y., Mancuso, P. & Kerbel, R. S. The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nature Rev. Cancer 6, 835–845 (2006).
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).
Mantovani, A., Sozzani, S., Locati, M., Allavena, P. & Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23, 549–555 (2002).
Biswas, S. K. et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation). Blood 107, 2112–2122 (2006).
Saccani, A. et al. p50 nuclear factor-κB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res. 66, 11432–11440 (2006).
Biswas, S. K., Sica, A. & Lewis, C. E. Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. J. Immunol. 180, 2011–2017 (2008).
Bingle, L., Brown, N. J. & Lewis, C. E. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J. Pathol. 196, 254–265 (2002).
Yamashiro, S. et al. Tumor-derived monocyte chemoattractant protein-1 induces intratumoral infiltration of monocyte-derived macrophage subpopulation in transplanted rat tumors. Am. J. Pathol. 145, 856–867 (1994).
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).
Bottazzi, B., Walter, S., Govoni, D., Colotta, F. & Mantovani, A. Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth, and susceptibility to IL-2 therapy of a murine melanoma. J. Immunol. 148, 1280–1285 (1992).
Loberg, R. D. et al. CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. Neoplasia 9, 556–562 (2007).
Gazzaniga, S. et al. Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft. J. Invest. Dermatol. 127, 2031–2041 (2007). The paper shows that blocking the ability of tumours to recruit monocytes using an MCP-1 (CCL2) antibody inhibits tumour angiogenesis in a xenograft model. Their data highlight the CCL2–CCR2 axis as a target for new anti-angiogenic therapies.
Fischer, C. et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131, 463–475 (2007). This paper describes the effects of a neutralizing antibody to PlGF on tumour angiogenesis in various models and showed that, unlike VEGF inhibitors, this antibody did not induce tumour hypoxia but rather infiltration by pro-angiogenic macrophages. It also enhanced the effect of various chemotherapy agents in vivo.
Scotton, C., Milliken, D., Wilson, J., Raju, S. & Balkwill, F. Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours. Br. J. Cancer 85, 891–897 (2001).
Barleon, B. et al. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87, 3336–3343 (1996).
Hiratsuka, S., Minowa, O., Kuno, J., Noda, T. & Shibuya, M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc. Natl Acad. Sci. USA 95, 9349–9354 (1998).
Dineen, S. P. et al. Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice. Cancer Res. 68, 4340–4346 (2008).
Hiratsuka, S., Watanabe, A., Aburatani, H. & Maru, Y. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nature Cell Biol. 8, 1369–1375 (2006).
Knowles, H., Leek, R. & Harris, A. L. Macrophage infiltration and angiogenesis in human malignancy. Novartis Found. Symp. 256, 189–200 (2004).
Leek, R. D. et al. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 56, 4625–4629 (1996).
Onita, T. et al. Hypoxia-induced, perinecrotic expression of endothelial Per-ARNT-Sim domain protein-1/hypoxia-inducible factor-2α correlates with tumor progression, vascularization, and focal macrophage infiltration in bladder cancer. Clin. Cancer Res. 8, 471–480 (2002).
Takanami, I., Takeuchi, K. & Kodaira, S. Tumor-associated macrophage infiltration in pulmonary adenocarcinoma: association with angiogenesis and poor prognosis. Oncology 57, 138–142 (1999).
Valkovic, T. et al. Correlation between vascular endothelial growth factor, angiogenesis, and tumor-associated macrophages in invasive ductal breast carcinoma. Virchows Arch. 440, 583–588 (2002).
Li, C., Shintani, S., Terakado, N., Nakashiro, K. & Hamakawa, H. Infiltration of tumor-associated macrophages in human oral squamous cell carcinoma. Oncol. Rep. 9, 1219–1223 (2002).
Lin, E. Y. et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 66, 11238–11246 (2006). This study in transgenic murine mammary tumour model to show that TAM have a key role in promoting tumour angiogenesis, and thus in tumour development and metastasis.
Kimura, Y. N. et al. Inflammatory stimuli from macrophages and cancer cells synergistically promote tumor growth and angiogenesis. Cancer Sci. 98, 2009–2018 (2007).
Dirkx, A. E., Oude Egbrink, M. G., Wagstaff, J. & Griffioen, A. W. Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. J. Leukoc. Biol. 80, 1183–1196 (2006).
Hagemann, T. et al. Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J. Immunol. 176, 5023–5032 (2006).
Leek, R. D., Landers, R. J., Harris, A. L. & Lewis, C. E. Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast. Br. J. Cancer 79, 991–995 (1999).
Ohno, S. et al. Correlation of histological localization of tumor-associated macrophages with clinicopathological features in endometrial cancer. Anticancer Res. 24, 3335–3342 (2004).
Negus, R. P., Stamp, G. W., Hadley, J. & Balkwill, F. R. Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of C-C chemokines. Am. J. Pathol. 150, 1723–1734 (1997).
Bailey, C. et al. Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. Clin. Exp. Metastasis 24, 121–130 (2007).
Vaupel, P., Kelleher, D. K. & Hockel, M. Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy. Semin. Oncol. 28, 29–35 (2001).
Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).
Burke, B. et al. Expression of HIF-1α by human macrophages: implications for the use of macrophages in hypoxia-regulated cancer gene therapy. J. Pathol. 196, 204–212 (2002).
Talks, K. L. et al. The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages. Am. J. Pathol. 157, 411–421 (2000).
Lewis, C. E. & Murdoch, C. Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am. J. Pathol. 167, 627–635 (2005).
Elbarghati, L., Murdoch, C. & Lewis, C. E. Effects of hypoxia on transcription factor expression in human monocytes and macrophages. Immunobiology (in the press).
White, J. R. et al. Genetic amplification of the transcriptional response to hypoxia as a novel means of identifying regulators of angiogenesis. Genomics 83, 1–8 (2004).
Burke, B. et al. Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy. Am. J. Pathol. 163, 1233–1243 (2003).
Lewis, J. S., Landers, R. J., Underwood, J. C., Harris, A. L. & Lewis, C. E. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J. Pathol. 192, 150–158 (2000).
Bingle, L., Lewis, C. E., Corke, K. P., Reed, M. W. & Brown, N. J. Macrophages promote angiogenesis in human breast tumour spheroids in vivo. Br. J. Cancer 94, 101–107 (2006). The first paper to show that macrophages can stimulate the sprouting of blood vessels in normal tissues around an avascular tumour nodule. This has implications for the role of macrophages in early tumour development.
Luo, J. L. et al. Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin. Nature 446, 690–694 (2007).
Lynch, C. C. et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 7, 485–496 (2005).
Zampetaki, A., Mitsialis, S. A., Pfeilschifter, J. & Kourembanas, S. Hypoxia induces macrophage inflammatory protein-2 (MIP-2) gene expression in murine macrophages via NF-κB: the prominent role of p42/p44 and PI3 kinase pathways. FASEB J. 18, U808–U827 (2004).
Hagemann, T. et al. “Re-educating” tumor-associated macrophages by targeting NF-κB. J. Exp. Med. 205, 1261–1268 (2008).
Fernandez, P. B. et al. Endothelial-like cells derived from human CD14 positive monocytes. Differentiation 65, 287–300 (2000).
Kuwana, M. et al. Endothelial differentiation potential of human monocyte-derived multipotential cells. Stem Cells 24, 2733–2743 (2006).
De Palma, M. et al. Tie-2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8, 211–226 (2005). This paper shows that TIE2+ monocytes are an important pro-angiogenic myeloid cell in various murine tumour models.
Murdoch, C., Tazzyman, S., Webster, S. & Lewis, C. E. Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. J. Immunol. 178, 7405–7411 (2007). This paper is the first to show that angiopoietin 2 (especially in the presence of hypoxia) changes the phenotype of TIE2-expressing monocytes
Venneri, M. A. et al. Identification of proangiogenic Tie-2-expressing monocytes (TEMs) in human peripheral blood and cancer. Blood 109, 5276–5285 (2007).
Nowak, G. et al. Expression of vascular endothelial growth factor receptor-2 or Tie-2 on peripheral blood cells defines functionally competent cell populations capable of reendothelialization. Circulation 110, 3699–3707 (2004).
Gu, J. et al. Hypoxia-induced up-regulation of angiopoietin-2 in colorectal cancer. Oncol. Rep. 15, 779–783 (2006).
Stratmann, A., Risau, W. & Plate, K. H. Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am. J. Pathol. 153, 1459–1466 (1998).
Jin, D. K. et al. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nature Med. 12, 557–567 (2006). Identification of a distinct, pro-angiogenic myeloid cell population characterized by its expression of VEGFR1+CXCR4+ that can be mobilized from the bone marrow by platelet-derived CXCL12.
Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).
Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194–1201 (2001).
Ruan, J. et al. Magnitude of stromal hemangiogenesis correlates with histologic subtype of non-Hodgkin's lymphoma. Clin. Cancer Res. 12, 5622–5631 (2006).
Kryczek, I. et al. CXCL12 and vascular endothelial growth factor synergistically induce neoanglogenesis in human ovarian cancers. Cancer Res. 65, 465–472 (2005).
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).
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).
Movahedi, K. et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111, 4233–4244 (2008).
Sawanobori, Y. et al. Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood 111, 5457–5466 (2008).
Bronte, V. et al. Identification of a CD11b+/Gr-1+/CD31+ myeloid progenitor capable of activating or suppressing CD8+ T cells. Blood 96, 3838–3846 (2000).
Kusmartsev, S. & Gabrilovich, D. I. Immature myeloid cells and cancer-associated immune suppression. Cancer Immunol. Immunother. 51, 293–298 (2002).
Gabrilovich, D. I. et al. The terminology issue for myeloid-derived suppressor cells. Cancer Res. 67, 425 (2007).
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).
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. (doi: 10.1007/s00262-008-0523-4).
Hoechst, B. et al. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4+CD25+Foxp3+ T cells. Gastroenterology 21 Mar 2008 (doi:10.1053/j.gastro.2008.03.020).
Melani, C., Chiodoni, C., Forni, G. & Colombo, M. P. Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. Blood 102, 2138–2145 (2003).
Shojaei, F. et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450, 825–831 (2007).
Yang, L. et al. Abrogation of TGFβ signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13, 23–35 (2008).
LeCouter, J., Zlot, C., Tejada, M., Peale, F. & Ferrara, N. Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization. Proc. Natl Acad. Sci. USA 101, 16813–16818 (2004). References 75 & 76 demonstrate that the release of CD11b+Gr1+ cells from bone marrow and recruitment into the experimental tumours in mice is driven by distinct signals released by the tumour site (that is, TGFβ, Bv8 and EG-VEGF).
Lin, R., LeCouter, J., Kowalski, J. & Ferrara, N. Characterization of endocrine gland-derived vascular endothelial growth factor signaling in adrenal cortex capillary endothelial cells. J. Biol. Chem. 277, 8724–8729 (2002).
Soga, T. et al. Molecular cloning and characterization of prokineticin receptors. Biochim. Biophys. Acta 1579, 173–179 (2002).
Pan, P. Y. et al. Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function. Blood 111, 219–228 (2008).
Dolcetti, L. et al. Myeloid-derived suppressor cell role in tumor-related inflammation. Cancer Lett. 22 Apr 2008 (doi:10.1016/j.canlet.2008.03.012).
Sinha, P., Clements, V. K., Miller, S. & Ostrand-Rosenberg, S. Tumor immunity: a balancing act between T cell activation, macrophage activation and tumor-induced immune suppression. Cancer Immunol. Immunother. 54, 1137–1142 (2005).
Nagaraj, S. & Gabrilovich, D. I. Myeloid-derived suppressor cells. Adv. Exp. Med. Biol. 601, 213–223 (2007).
Sinha, P., Clements, V. K., Bunt, S. K., Albelda, S. M. & Ostrand-Rosenberg, S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J. Immunol. 179, 977–983 (2007).
Kusmartsev, S. & Gabrilovich, D. I. Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol. Immunother. 55, 237–245 (2006).
Eck, M., Schmausser, B., Scheller, K., Brandlein, S. & Muller-Hermelink, H. K. Pleiotropic effects of CXC chemokines in gastric carcinoma: differences in CXCL8 and CXCL1 expression between diffuse and intestinal types of gastric carcinoma. Clin. Exp. Immunol. 134, 508–515 (2003).
Nielsen, B. S. et al. 92 kDa type IV collagenase (MMP-9) is expressed in neutrophils and macrophages but not in malignant epithelial cells in human colon cancer. Int. J. Cancer 65, 57–62 (1996).
Bellocq, A. et al. Neutrophil alveolitis in bronchioloalveolar carcinoma: induction by tumor-derived interleukin-8 and relation to clinical outcome. Am. J. Pathol. 152, 83–92 (1998).
Gijsbers, K. et al. GCP-2/CXCL6 synergizes with other endothelial cell-derived chemokines in neutrophil mobilization and is associated with angiogenesis in gastrointestinal tumors. Exp. Cell Res. 303, 331–342 (2005).
Luan, J. et al. Mechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression. J. Leukoc. Biol. 62, 588–597 (1997).
Arenberg, D. A. et al. Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. J. Clin. Invest. 102, 465–472 (1998).
Xie, K. Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev. 12, 375–391 (2001).
Xu, L., Xie, K., Mukaida, N., Matsushima, K. & Fidler, I. J. Hypoxia-induced elevation in interleukin-8 expression by human ovarian carcinoma cells. Cancer Res. 59, 5822–5829 (1999).
Shi, Q., Xiong, Q., Le, X. & Xie, K. Regulation of interleukin-8 expression by tumor-associated stress factors. J. Interferon Cytokine Res. 21, 553–566 (2001).
Lee, L. F. et al. IL-8 reduced tumorigenicity of human ovarian cancer in vivo due to neutrophil infiltration. J. Immunol. 164, 2769–2775 (2000). This article showed that overexpression of CXCL8 (IL8) by tumours in mice attracts neutrophils to the tumour site.
Keane, M. P., Belperio, J. A., Xue, Y. Y., Burdick, M. D. & Strieter, R. M. Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer. J. Immunol. 172, 2853–2860 (2004).
Moepps, B., Nuesseler, E., Braun, M. & Gierschik, P. A homolog of the human chemokine receptor CXCR1 is expressed in the mouse. Mol. Immunol. 43, 897–914 (2006).
Fan, X. et al. Murine CXCR1 is a functional receptor for GCP-2/CXCL6 and interleukin-8/CXCL8. J. Biol. Chem. 282, 11658–11666 (2007).
Mentzel, T. et al. The association between tumour progression and vascularity in myxofibrosarcoma and myxoid/round cell liposarcoma. Virchows Arch. 438, 13–22 (2001).
Benelli, R. et al. Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation. FASEB J. 16, 267–269 (2002).
Van, C. E. et al. Tumor angiogenesis induced by granulocyte chemotactic protein-2 as a countercurrent principle. Am. J. Pathol. 159, 1405–1414 (2001).
Nozawa, H., Chiu, C. & Hanahan, D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc. Natl Acad. Sci. USA 103, 12493–12498 (2006).
Coussens, L. M., Tinkle, C. L., Hanahan, D. & Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103, 481–490 (2000). This paper was the first to use various transgenic mouse models to show the importance of MMP9 expression by bone marrow-derived cells (neutrophils, macrophages and mast cells) to squamous carcinogenesis.
Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol. 2, 737–744 (2000). This paper showed that neutrophil-derived MMP9 is a major contributor to the angiogenic switch and works by modulating the extracellular matrix and releasing bio-active VEGF
Masure, S., Proost, P., Van, D. J. & Opdenakker, G. Purification and identification of 91-kDa neutrophil gelatinase. Release by the activating peptide interleukin-8. Eur. J. Biochem. 198, 391–398 (1991).
Ardi, V. C., Kupriyanova, T. A., Deryugina, E. I. & Quigley, J. P. Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc. Natl Acad. Sci. USA 104, 20262–20267 (2007).
McCourt, M., Wang, J. H., Sookhai, S. & Redmond, H. P. Proinflammatory mediators stimulate neutrophil-directed angiogenesis. Arch. Surg. 134, 1325–1331 (1999).
Queen, M. M., Ryan, R. E., Holzer, R. G., Keller-Peck, C. R. & Jorcyk, C. L. Breast cancer cells stimulate neutrophils to produce oncostatin M: potential implications for tumor progression. Cancer Res. 65, 8896–8904 (2005).
Cassatella, M. A. Neutrophil-derived proteins: selling cytokines by the pound. Adv. Immunol. 73, 369–509 (1999).
Van den Steen, P. E., Proost, P., Wuyts, A., Van, D. J. & Opdenakker, G. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood 96, 2673–2681 (2000).
Koehne, P. et al. Lack of hypoxic stimulation of VEGF secretion from neutrophils and platelets. Am. J. Physiol. Heart Circ. Physiol. 279, H817–H824 (2000).
Gleich, G. J., Adolphson, C. R. & Leiferman, K. M. The biology of the eosinophilic leukocyte. Annu. Rev. Med. 44, 85–101 (1993).
Looi, L. M. Tumor-associated tissue eosinophilia in nasopharyngeal carcinoma. A pathologic study of 422 primary and 138 metastatic tumors. Cancer 59, 466–470 (1987).
Dorta, R. G. et al. Tumour-associated tissue eosinophilia as a prognostic factor in oral squamous cell carcinomas. Histopathology 41, 152–157 (2002).
Nielsen, H. J. et al. Independent prognostic value of eosinophil and mast cell infiltration in colorectal cancer tissue. J. Pathol. 189, 487–495 (1999).
Teruya-Feldstein, J. et al. Differential chemokine expression in tissues involved by Hodgkin's disease: direct correlation of eotaxin expression and tissue eosinophilia. Blood 93, 2463–2470 (1999). One of the first studies to correlate the presence of increased numbers of eosinophils with high expression of the eosinophil chemoattractant eotaxin in human tumours.
Jose, P. J. et al. Eotaxin: cloning of an eosinophil chemoattractant cytokine and increased mRNA expression in allergen-challenged guinea-pig lungs. Biochem. Biophys. Res. Commun. 205, 788–794 (1994).
Daugherty, B. L. et al. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J. Exp. Med. 183, 2349–2354 (1996).
Lorena, S. C., Oliveira, D. T., Dorta, R. G., Landman, G. & Kowalski, L. P. Eotaxin expression in oral squamous cell carcinomas with and without tumour associated tissue eosinophilia. Oral Dis. 9, 279–283 (2003).
Puxeddu, I. et al. Human peripheral blood eosinophils induce angiogenesis. Int. J. Biochem. Cell Biol. 37, 628–636 (2005).
Horiuchi, T. & Weller, P. F. Expression of vascular endothelial growth factor by human eosinophils: upregulation by granulocyte macrophage colony-stimulating factor and interleukin-5. Am. J. Respir. Cell. Mol. Biol. 17, 70–77 (1997).
Simson, L. et al. Regulation of carcinogenesis by IL-5 and CCL11: a potential role for eosinophils in tumor immune surveillance. J. Immunol. 178, 4222–4229 (2007).
Munitz, A. & Levi-Schaffer, F. Eosinophils: 'new' roles for 'old' cells. Allergy 59, 268–275 (2004).
Ohno, I. et al. Eosinophils as a source of matrix metalloproteinase-9 in asthmatic airway inflammation. Am. J. Respir. Cell. Mol. Biol. 16, 212–219 (1997).
Salcedo, R. et al. Eotaxin (CCL11) induces in vivo angiogenic responses by human CCR3+ endothelial cells. J. Immunol. 166, 7571–7578 (2001).
Cormier, S. A. et al. Eosinophil infiltration of solid tumors is an early and persistent inflammatory host response. J. Leukoc. Biol. 79, 1131–1139 (2006).
Metz, M. & Maurer, M. Mast cells — key effector cells in immune responses. Trends Immunol. 28, 234–241 (2007).
Baghestanian, M. et al. Activation of human mast cells through stem cell factor receptor (KIT) is associated with expression of bcl-2. Int. Arch. Allergy Immunol. 129, 228–236 (2002).
Drew, E., Merkens, H., Chelliah, S., Doyonnas, R. & McNagny, K. M. CD34 is a specific marker of mature murine mast cells. Exp. Hematol. 30, 1211 (2002).
Diaconu, N. C., Kaminska, R., Naukkarinen, A., Harvima, R. J. & Harvima, I. T. The increase in tryptase- and chymase-positive mast cells is associated with partial inactivation of chymase and increase in protease inhibitors in basal cell carcinoma. J. Eur. Acad. Dermatol. Venereol. 21, 908–915 (2007).
Dundar, E. et al. The significance and relationship between mast cells and tumour angiogenesis in non-small cell lung carcinoma. J. Int. Med. Res. 36, 88–95 (2008).
Sawatsubashi, M. et al. Association of vascular endothelial growth factor and mast cells with angiogenesis in laryngeal squamous cell carcinoma. Virchows Arch. 436, 243–248 (2000).
Tuna, B., Yorukoglu, K., Unlu, M., Mungan, M. U. & Kirkali, Z. Association of mast cells with microvessel density in renal cell carcinomas. Eur. Urol. 50, 530–534 (2006).
Ribatti, D. et al. Angiogenesis and mast cells in human breast cancer sentinel lymph nodes with and without micrometastases. Histopathology 51, 837–842 (2007).
Yano, H. et al. Mast cell infiltration around gastric cancer cells correlates with tumor angiogenesis and metastasis. Gastric Cancer 2, 26–32 (1999).
Elpek, G. O. et al. The prognostic relevance of angiogenesis and mast cells in squamous cell carcinoma of the oesophagus. J. Clin. Pathol. 54, 940–944 (2001).
Lamaroon, A. et al. Increase of mast cells and tumor angiogenesis in oral squamous cell carcinoma. J. Oral Pathol. Med. 32, 195–199 (2003).
Acikalin, M. F. et al. Tumour angiogenesis and mast cell density in the prognostic assessment of colorectal carcinomas. Dig. Liver Dis. 37, 162–169 (2005).
Ribatti, D. et al. Neovascularization and mast cells with tryptase activity increase simultaneously with pathologic progression in human endometrial cancer. Am. J. Obstet. Gynecol. 193, 1961–1965 (2005).
Ribatti, D. et al. Tumor vascularity and tryptase-positive mast cells correlate with a poor prognosis in melanoma. Eur. J. Clin. Invest. 33, 420–425 (2003).
Ribatti, D. et al. Bone marrow angiogenesis and mast cell density increase simultaneously with progression of human multiple myeloma. Br. J. Cancer 79, 451–455 (1999).
Ribatti, D. et al. The role of mast cells in tumour angiogenesis. Br. J. Haematol. 115, 514–521 (2001).
Crivellato, E., Nico, B. & Ribatti, D. Mast cells and tumour angiogenesis: New insight from experimental carcinogenesis. Cancer Lett. 2 May 2008 (doi:10.1016/j.canlet.2008.03.031).
Meininger, C. J. et al. The c-kit receptor ligand functions as a mast cell chemoattractant. Blood 79, 958–963 (1992).
Wershil, B. K., Tsai, M., Geissler, E. N., Zsebo, K. M. & Galli, S. J. The rat c-kit ligand, stem cell factor, induces c-kit receptor-dependent mouse mast cell activation in vivo. Evidence that signaling through the c-kit receptor can induce expression of cellular function. J. Exp. Med. 175, 245–255 (1992).
Zhang, W., Stoica, G., Tasca, S. I., Kelly, K. A. & Meininger, C. J. Modulation of tumor angiogenesis by stem cell factor. Cancer Res. 60, 6757–6762 (2000). This paper showed that SCF significantly contributed to the accumulation of mast cells in a rodent tumour model, and that this was correlated with increased vascularity.
Matsuura, N. & Zetter, B. R. Stimulation of mast cell chemotaxis by interleukin 3. J. Exp. Med. 170, 1421–1426 (1989).
Reed, J. A., McNutt, N. S., Bogdany, J. K. & Albino, A. P. Expression of the mast cell growth factor interleukin-3 in melanocytic lesions correlates with an increased number of mast cells in the perilesional stroma: implications for melanoma progression. J. Cutan. Pathol. 23, 495–505 (1996).
Cuttitta, F. et al. Adrenomedullin functions as an important tumor survival factor in human carcinogenesis. Microsc. Res. Tech. 57, 110–119 (2002).
Zudaire, E. et al. Adrenomedullin is a cross-talk molecule that regulates tumor and mast cell function during human carcinogenesis. Am. J. Pathol. 168, 280–291 (2006).
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).
Juremalm, M. & Nilsson, G. Chemokine receptor expression by mast cells. Chem. Immunol. Allergy 87, 130–144 (2005).
Starkey, J. R., Crowle, P. K. & Taubenberger, S. Mast-cell-deficient W/Wv mice exhibit a decreased rate of tumor angiogenesis. Int. J. Cancer 42, 48–52 (1988).
Coussens, L. M. et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999). This study used the HPV16 transgenic mouse model of skin cancer to show that, first, infiltration by mast cells coincides with the angiogenic switch in premalignant lesions and, second, that the latter is abated in a mast-cell-deficient mice.
Soucek, L. et al. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nature Med. 13, 1211–1218 (2007).
Theoharides, T. C., Kempuraj, D., Tagen, M., Conti, P. & Kalogeromitros, D. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol. Rev. 217, 65–78 (2007).
Ho, K. L. Ultrastructure of cerebellar capillary hemangioblastoma. II. Mast cells and angiogenesis. Acta Neuropathol. 64, 308–318 (1984).
Nico, B., Mangieri, D., Crivellato, E., Vacca, A. & Ribatti, D. Mast cells contribute to vasculogenic mimicry in multiple myeloma. Stem Cells Dev. 17, 19–22 (2008).
Nakayama, T., Yao, L. & Tosato, G. Mast cell-derived angiopoietin-1 plays a critical role in the growth of plasma cell tumors. J. Clin. Invest. 114, 1317–1325 (2004).
Jeong, H. J. et al. Expression of proinflammatory cytokines via HIF-1α and NFκB activation on desferrioxamine-stimulated HMC-1 cells. Biochem. Biophys. Res. Commun. 306, 805–811 (2003).
Fujita, Y. et al. Involvement of adrenomedullin induced by hypoxia in angiogenesis in human renal cell carcinoma. Int. J. Urol. 9, 285–295 (2002).
Garayoa, M. et al. Hypoxia-inducible factor-1 (HIF-1) up-regulates adrenomedullin expression in human tumor cell lines during oxygen deprivation: a possible promotion mechanism of carcinogenesis. Mol. Endocrinol. 14, 848–862 (2000).
Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).
O'Neill, H. C. et al. Dendritic cell development in long-term spleen stromal cultures. Stem Cells 22, 475–486 (2004).
Colonna, M., Trinchieri, G. & Liu, Y. J. Plasmacytoid dendritic cells in immunity. Nature Immunol. 5, 1219–1226 (2004).
Kadowaki, N. et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J. Exp. Med. 194, 863–869 (2001).
Gabrilovich, D. et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92, 4150–4166 (1998).
Ghiringhelli, F. et al. Tumor cells convert immature myeloid dendritic cells into TGFβ-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J. Exp. Med. 202, 919–929 (2005).
Troy, A. J., Summers, K. L., Davidson, P. J., Atkinson, C. H. & Hart, D. N. Minimal recruitment and activation of dendritic cells within renal cell carcinoma. Clin. Cancer Res. 4, 585–593 (1998).
Fricke, I. & Gabrilovich, D. I. Dendritic cells and tumor microenvironment: a dangerous liaison. Immunol. Invest. 35, 459–483 (2006).
Gabrilovich, D. I. et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nature Med. 2, 1096–1103 (1996).
Dikov, M. M. et al. Vascular endothelial growth factor effects on nuclear factor-κB activation in hematopoietic progenitor cells. Cancer Res. 61, 2015–2021 (2001).
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. Nature Med. 10, 950–958 (2004). This paper shows that β -defensin recruits iDC into tumours and with the support of VEGF renders the DC in an immature state. These iDC were shown to differentiate into endothelial-like cells, migrate to blood vessels and promote tumour growth support.
Curiel, T. J. et al. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Res. 64, 5535–5538 (2004).
Okunishi, K. et al. A novel role of hepatocyte growth factor as an immune regulator through suppressing dendritic cell function. J. Immunol. 175, 4745–4753 (2005).
Feijoo, E. et al. Dendritic cells delivered inside human carcinomas are sequestered by interleukin-8. Int. J. Cancer 116, 275–281 (2005).
Caux, C. et al. Activation of human dendritic cells through CD40 cross-linking. J. Exp. Med. 180, 1263–1272 (1994).
Naldini, A. et al. Cutting edge: IL-1β mediates the proangiogenic activity of osteopontin-activated human monocytes. J. Immunol. 177, 4267–4270 (2006).
Scimone, M. L. et al. Migration of polymorphonuclear leucocytes is influenced by dendritic cells. Immunology 114, 375–385 (2005).
Conejo-Garcia, J. R. et al. Vascular leukocytes contribute to tumor vascularization. Blood 105, 679–681 (2005). This paper describes a novel population of cells which express MDC and EC markers in human ovarian cancers. These cells were shown to assemble new blood vessels in vivo when implanted into mice.
Gottfried, E. et al. Differentiation of human tumour-associated dendritic cells into endothelial-like cells: an alternative pathway of tumour angiogenesis. Scand. J. Immunol. 65, 329–335 (2007).
Laxmanan, S. et al. Vascular endothelial growth factor impairs the functional ability of dendritic cells through Id pathways. Biochem. Biophys. Res. Commun. 334, 193–198 (2005).
Alard, P., Clark, S. L. & Kosiewicz, M. M. Mechanisms of tolerance induced by TGF beta-treated APC: CD4 regulatory T cells prevent the induction of the immune response possibly through a mechanism involving TGFβ. Eur. J. Immunol. 34, 1021–1030 (2004).
Pockaj, B. A. et al. Reduced T-cell and dendritic cell function is related to cyclooxygenase-2 overexpression and prostaglandin E2 secretion in patients with breast cancer. Ann. Surg. Oncol. 11, 328–339 (2004).
Puig-Kroger, A. et al. Peritoneal dialysis solutions inhibit the differentiation and maturation of human monocyte-derived dendritic cells: effect of lactate and glucose-degradation products. J. Leukoc. Biol. 73, 482–492 (2003).
Konno, S. et al. Interleukin-10 and Th2 cytokines differentially regulate osteopontin expression in human monocytes and dendritic cells. J. Interferon Cytokine Res. 26, 562–567 (2006).
Ricciardi, A. et al. Transcriptome of hypoxic immature dendritic cells: modulation of chemokine/receptor expression. Mol. Cancer Res. 6, 175–185 (2008). This study describes the changes in gene expression that occur in iDC exposed to hypoxia, including various genes that could hold back DC maturation and promote tumour angiogenesis.
Luo, Y. et al. Targeting tumor-associated macrophages as a novel strategy against breast cancer. J. Clin. Invest. 116, 2132–2141 (2006).
Aharinejad, S. et al. Colony-stimulating factor-1 antisense treatment suppresses growth of human tumor xenografts in mice. Cancer Res. 62, 5317–5324 (2002).
Loberg, R. D. et al. Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Res. 67, 9417–9424 (2007).
Pahler, J. C. et al. Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response. Neoplasia 10, 329–339 (2008).
Shojaei, F. et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nature Biotechnol. 25, 911–920 (2007). This study showed for the first time that tumour-infiltrating CD11b+Gr1+ myeloid cells can help to protect tumours from the anti-angiogenic effects of a VEGF antibody.
Hanahan, D. and Bergers, G. Modes of resistance to anti-angiogenic therapy. Nature Rev. Cancer (in the press).
McDonnell, C. O. et al. Effect of neoadjuvant chemoradiotherapy on angiogenesis in oesophageal cancer. Br. J. Surg. 90, 1373–1378 (2003).
Ahn, G. O. & Brown, J. M. Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell 13, 193–205 (2008).
Acknowledgements
The authors gratefully acknowledge the support of Yorkshire Cancer Research, UK, Cancer Research UK, Breast Cancer Campaign, UK and Prostate Cancer Campaign, UK for their work in this area. They also thank S. Ostrand-Rosenberg for her helpful advice on the MDSC section. M.M. is the recipient of the 2008 BACR–AstraZeneca Young Scientist Frank Rose Award. We apologize to any investigators whose papers could not be cited owing to space limitations.
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Glossary
- T-helper-1 cell response
-
(TH1 response). A TH1 immune response is mediated by pro-inflammatory cytokines such as IFNγ, IL1β and TNFα. It promotes cellular immune responses against intracellular infections and malignancy.
- T-helper-2 cell response
-
(TH2 response). A TH2 response involves production of cytokines, such as IL4, that stimulate antibody production. TH2 cytokines promote secretory immune responses of mucosal surfaces to extracellular pathogens and allergic reactions.
- Clodronate liposomes
-
Liposomes encapsulating the agent clodronate. Monocytes and macrophages readily engulf these structures by endocytosis. The lipid bilayer is then broken down by phospholipases in lysosomes and clodronate is released into the cell where it then induces apoptosis in the host cell.
- Gene-directed enzyme–pro-drug therapy
-
Delivery of a gene encoding a non-mammalian enzyme into a specific cell population. The enzyme converts a systemically delivered pro-drug into an active cytotoxic agent only in the cells that express the enzyme.
- Endocrine-gland-derived VEGF
-
EG-VEGF, also known as prokineticin 1 (PK1), is a cytokine that resembles VEGF in that it promotes angiogenesis and vascular permeability; the two proteins are structurally dissimilar and work through different receptors.
- Rat aortic ring assay
-
An organ culture assay in which a rat aorta is cut into segments before being placed in a matrix such as Matrigel or a collagen gel. The explants are monitored for the outgrowth of vessel-like extensions from the aorta.
- CAM assay
-
An angiogenesis assay in which the shell of a fertilized chick egg is cut open and the embryo with intact chorioallantoic membrane (CAM) incubated in a Petri dish until blood vessels in the CAM become visible. Test substances or cells are then placed on the membrane and their effects on vessel formation in the CAM examined by microscopy.
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Murdoch, C., Muthana, M., Coffelt, S. et al. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8, 618–631 (2008). https://doi.org/10.1038/nrc2444
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DOI: https://doi.org/10.1038/nrc2444
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