Abstract
Influencing cancer cell invasion is one of the many ways, tumor-associated macrophages (TAM) can foster tumor progression. Penetration of the basement membrane and movement of tumor cells through tissues usually require enhanced motile capacity as well as reorganization of the invaded structures via pericellular proteolysis. Malignant cells secrete chemo- and cytokines to attract macrophages, which are then polarized into the TAM-phenotype and, in turn, produce a huge arsenal of factors with pro-invasive activity. Among these factors are members of several pro-migratory signaling cascades, such as the EGF/CSF-1 loop, TNFα, the CXCR4/CXCL12 axis as well as other chemokines and their receptors. Para- as well as autocrine activation of these pathways directly stimulates tumor cell motility and, additionally, induces tissue remodeling by the upregulation of proteases. Thus, TAM are key actors at the tumor–host boundary, influencing invasion directly by the activation of migration-associated signaling as well as indirectly through supply of critical downstream effectors.
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Abraham D, Zins K, Sioud M, Lucas T, Schafer R, Stanley ER, Aharinejad S (2010) Stromal cell-derived CSF-1 blockade prolongs xenograft survival of CSF-1-negative neuroblastoma. Int J Cancer 126:1339–1352
Ai X, Do AT, Lozynska O, Kusche-Gullberg M, Lindahl U, Emerson CP Jr (2003) QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling. J Cell Biol 162:341–351
Aman A, Piotrowski T (2008) Wnt/beta-catenin and Fgf signaling control collective cell migration by restricting chemokine receptor expression. Dev Cell 15:749–761
Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4:540–550
Balkwill F (2009) Tumour necrosis factor and cancer. Nat Rev Cancer 9:361–371
Baran B, Bechyne I, Siedlar M, Szpak K, Mytar B, Sroka J, Laczna E, Madeja Z, Zembala M, Czyz J (2009) Blood monocytes stimulate migration of human pancreatic carcinoma cells in vitro: the role of tumour necrosis factor - alpha. Eur J Cell Biol 88:743–752
Barbieri F, Bajetto A, Florio T (2010) Role of chemokine network in the development and progression of ovarian cancer: a potential novel pharmacological target. J Oncol 2010:426956
Bates RC, Mercurio AM (2003) Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell 14:1790–1800
Blumenthal A, Ehlers S, Lauber J, Buer J, Lange C, Goldmann T, Heine H, Brandt E, Reiling N (2006) The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation. Blood 108:965–973
Brabletz T, Hlubek F, Spaderna S, Schmalhofer O, Hiendlmeyer E, Jung A, Kirchner T (2005) Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs 179:56–65
Buccione R, Caldieri G, Ayala I (2009) Invadopodia: specialized tumor cell structures for the focal degradation of the extracellular matrix. Cancer Metastasis Rev 28:137–149
Chung AS, Kao WJ (2009) Fibroblasts regulate monocyte response to ECM-derived matrix: the effects on monocyte adhesion and the production of inflammatory, matrix remodeling, and growth factor proteins. J Biomed Mater Res A 89:841–853
Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127:469–480
Coussens LM, Werb Z (1996) Matrix metalloproteinases and the development of cancer. Chem Biol 3:895–904
DeNardo DG, Johansson M, Coussens LM (2008) Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev 27:11–18
Filderman AE, Bruckner A, Kacinski BM, Deng N, Remold HG (1992) Macrophage colony-stimulating factor (CSF-1) enhances invasiveness in CSF-1 receptor-positive carcinoma cell lines. Cancer Res 52:3661–3666
Fodde R, Brabletz T (2007) Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol 19:150–158
Fridlender ZG, Kapoor V, Buchlis G, Cheng G, Sun J, Wang LC, Singhal S, Snyder LA, Albelda SM (2011) CCL2 blockade inhibits lung cancer tumor growth by altering macrophage phenotype and activating CD8+ Cells. Am J Respir Cell Mol Biol 44:230–237
Friedl P (2004) Prespecification and plasticity: shifting mechanisms of cell migration. Curr Opin Cell Biol 16:14–23
Friedl P, Gilmour D (2009) Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 10:445–457
Fujimoto H, Sangai T, Ishii G, Ikehara A, Nagashima T, Miyazaki M, Ochiai A (2009) Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer 125:1276–1284
Gjoen T, Seljelid R, Kolset SO (1989) Binding of metastatic colon carcinoma cells to liver macrophages. J Leukoc Biol 45:362–369
Gocheva V, Zeng W, Ke D, Klimstra D, Reinheckel T, Peters C, Hanahan D, Joyce JA (2006) Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes Dev 20:543–556
Gocheva V, Wang HW, Gadea BB, Shree T, Hunter KE, Garfall AL, Berman T, Joyce JA (2010) IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 24:241–255
Gorden DL, Fingleton B, Crawford HC, Jansen DE, Lepage M, Matrisian LM (2007) Resident stromal cell-derived MMP-9 promotes the growth of colorectal metastases in the liver microenvironment. Int J Cancer 121:495–500
Goswami S, Sahai E, Wyckoff JB, Cammer M, Cox D, Pixley FJ, Stanley ER, Segall JE, Condeelis JS (2005) Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res 65:5278–5283
Grimshaw MJ, Hagemann T, Ayhan A, Gillett CE, Binder C, Balkwill FR (2004) A role for endothelin-2 and its receptors in breast tumor cell invasion. Cancer Res 64:2461–2468
Hagemann T, Robinson SC, Schulz M, Trumper L, Balkwill FR, Binder C (2004) Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis 25:1543–1549
Hagemann T, Wilson J, Kulbe H, Li NF, Leinster DA, Charles K, Klemm F, Pukrop T, Binder C, Balkwill FR (2005) Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. J Immunol 175:1197–1205
Hagemann T, Wilson J, Burke F, Kulbe H, Li NF, Pluddemann A, Charles K, Gordon S, Balkwill FR (2006) Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J Immunol 176:5023–5032
Haro H, Crawford HC, Fingleton B, Shinomiya K, Spengler DM, Matrisian LM (2000) Matrix metalloproteinase-7-dependent release of tumor necrosis factor-alpha in a model of herniated disc resorption. J Clin Invest 105:143–150
Helbig G, Christopherson KW, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, Broxmeyer HE, Nakshatri H (2003) NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem 278:21631–21638
Hernandez L, Smirnova T, Kedrin D, Wyckoff J, Zhu L, Stanley ER, Cox D, Muller WJ, Pollard JW, Van RN, Segall JE (2009) The EGF/CSF-1 paracrine invasion loop can be triggered by heregulin beta1 and CXCL12. Cancer Res 69:3221–3227
Heuff G, van de Loosdrecht AA, Betjes MG, Beelen RH, Meijer S (1995) Isolation and purification of large quantities of fresh human Kupffer cells, which are cytotoxic against colon carcinoma. Hepatology 21:740–745
Hiratsuka S, Nakamura K, Iwai S, Murakami M, Itoh T, Kijima H, Shipley JM, Senior RM, Shibuya M (2002) MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2:289–300
Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, Shibuya M, Akira S, Aburatani H, Maru Y (2008) The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol 10:1349–1355
Jodele S, Blavier L, Yoon JM, DeClerck YA (2006) Modifying the soil to affect the seed: role of stromal-derived matrix metalloproteinases in cancer progression. Cancer Metastasis Rev 25:35–43
Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827
Kedrin D, van Rheenen J, Hernandez L, Condeelis J, Segall JE (2007) Cell motility and cytoskeletal regulation in invasion and metastasis. J Mammary Gland Biol Neoplasia 12:143–152
Kim S, Takahashi H, Lin WW, Descargues P, Grivennikov S, Kim Y, Luo JL, Karin M (2009) Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457:102–106
Kulbe H, Hagemann T, Szlosarek PW, Balkwill FR, Wilson JL (2005) The inflammatory cytokine tumor necrosis factor-alpha regulates chemokine receptor expression on ovarian cancer cells. Cancer Res 65:10355–10362
Kulbe H, Thompson R, Wilson JL, Robinson S, Hagemann T, Fatah R, Gould D, Ayhan A, Balkwill F (2007) The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Res 67:585–592
Kurayoshi M, Yamamoto H, Izumi S, Kikuchi A (2007) Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling. Biochem J 402:515–523
Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56:4625–4629
Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M, Zhou X, Xia W, Hortobagyi GN, Yu D, Hung MC (2004) Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell 6:459–469
Lin EY, Nguyen AV, Russell RG, Pollard JW (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193:727–740
Lin EY, Gouon-Evans V, Nguyen AV, Pollard JW (2002) The macrophage growth factor CSF-1 in mammary gland development and tumor progression. J Mammary Gland Biol Neoplasia 7:147–162
Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ, Pollard JW (2003) Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 163:2113–2126
Lin CY, Lin CJ, Chen KH, Wu JC, Huang SH, Wang SM (2006) Macrophage activation increases the invasive properties of hepatoma cells by destabilization of the adherens junction. FEBS Lett 580:3042–3050
Mantovani A, Bottazzi B, Colotta F, Sozzani S, Ruco L (1992) The origin and function of tumor-associated macrophages. Immunol Today 13:265–270
Markovic DS, Glass R, Synowitz M, Rooijen N, Kettenmann H (2005) Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2. J Neuropathol Exp Neurol 64:754–762
Mikels AJ, Nusse R (2006) Wnts as ligands: processing, secretion and reception. Oncogene 25:7461–7468
Montcouquiol M, Crenshaw EB III, Kelley MW (2006) Noncanonical Wnt signaling and neural polarity. Annu Rev Neurosci 29:363–386
Moore RJ, Owens DM, Stamp G, Arnott C, Burke F, East N, Holdsworth H, Turner L, Rollins B, Pasparakis M, Kollias G, Balkwill F (1999) Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 5:828–831
Mukai M, Shinkai K, Tateishi R, Mori Y, Akedo H (1987) Macrophage potentiation of invasive capacity of rat ascites hepatoma cells. Cancer Res 47:2167–2171
Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56
Nauts HC, Swift WE, Coley BL (1946) The Treatment of Malignant Tumors by Bacterial Toxins As Developed by the Late Coley, William, B., Reviewed in the Light of Modern Research. Cancer Res 6:205–216
Ojalvo LS, Whittaker CA, Condeelis JS, Pollard JW (2010) Gene expression analysis of macrophages that facilitate tumor invasion supports a role for Wnt-signaling in mediating their activity in primary mammary tumors. J Immunol 184:702–712
Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS (2009) Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res 69:9498–9506
Pereira C, Schaer DJ, Bachli EB, Kurrer MO, Schoedon G (2008) Wnt5A/CaMKII signaling contributes to the inflammatory response of macrophages and is a target for the antiinflammatory action of activated protein C and interleukin-10. Arterioscler Thromb Vasc Biol 28:504–510
Pereira CP, Bachli EB, Schoedon G (2009) The wnt pathway: a macrophage effector molecule that triggers inflammation. Curr Atheroscler Rep 11:236–242
Porcile C, Bajetto A, Barbieri F, Barbero S, Bonavia R, Biglieri M, Pirani P, Florio T, Schettini G (2005) Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation. Exp Cell Res 308:241–253
Prieve MG, Moon RT (2003) Stromelysin-1 and mesothelin are differentially regulated by Wnt-5a and Wnt-1 in C57mg mouse mammary epithelial cells. BMC Dev Biol 3:2
Pukrop T, Binder C (2008) The complex pathways of Wnt 5a in cancer progression. J Mol Med 86:259–266
Pukrop T, Klemm F, Hagemann T, Gradl D, Schulz M, Siemes S, Trumper L, Binder C (2006) Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines. Proc Natl Acad Sci USA 103:5454–5459
Pukrop T, Dehghani F, Chuang H-N, Lohaus R, Bayanga K, Heermann S, Regen T, van Rossum D, Klemm F, Schulz M, Siam L, Hoffmann A, Trümper L, Stadelmann Chr, Bechmann I, Hanisch U-K, Binder C (2010) Microglia promote colonization of brain tissue by breast cancer cells in a Wnt-dependent way. Glia 58:1477–1489
Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51
Robinson SC, Coussens LM (2005) Soluble mediators of inflammation during tumor development. Adv Cancer Res 93:159–187
Sabeh F, Shimizu-Hirota R, Weiss SJ (2009) Protease-dependent versus -independent cancer cell invasion programs: three-dimensional amoeboid movement revisited. J Cell Biol 185:11–19
Schenk S, Quaranta V (2003) Tales from the crypt[ic] sites of the extracellular matrix. Trends Cell Biol 13:366–375
Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, Vago L, Mantovani A, Melillo G, Sica A (2003) Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 198:1391–1402
Scott KA, Moore RJ, Arnott CH, East N, Thompson RG, Scallon BJ, Shealy DJ, Balkwill FR (2003) An anti-tumor necrosis factor-alpha antibody inhibits the development of experimental skin tumors. Mol Cancer Ther 2:445–451
Scotton CJ, Wilson JL, Scott K, Stamp G, Wilbanks GD, Fricker S, Bridger G, Balkwill FR (2002) Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res 62:5930–5938
Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42:717–727
Smith K, Bui TD, Poulsom R, Kaklamanis L, Williams G, Harris AL (1999) Up-regulation of macrophage wnt gene expression in adenoma-carcinoma progression of human colorectal cancer. Br J Cancer 81:496–502
Steele RJ, Eremin O, Brown M, Hawkins RA (1984) A high macrophage content in human breast cancer is not associated with favourable prognostic factors. Br J Surg 71:456–458
Sturm JW, Magdeburg R, Berger K, Petruch B, Samel S, Bonninghoff R, Keese M, Hafner M, Post S (2003) Influence of TNFA on the formation of liver metastases in a syngenic mouse model. Int J Cancer 107:11–21
Swallow CJ, Murray MP, Guillem JG (1996) Metastatic colorectal cancer cells induce matrix metalloproteinase release by human monocytes. Clin Exp Metastasis 14:3–11
Vasiljeva O, Papazoglou A, Kruger A, Brodoefel H, Korovin M, Deussing J, Augustin N, Nielsen BS, Almholt K, Bogyo M, Peters C, Reinheckel T (2006) Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer. Cancer Res 66:5242–5250
Wallingford JB, Habas R (2005) The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity. Development 132:4421–4436
Wang W, Goswami S, Lapidus K, Wells AL, Wyckoff JB, Sahai E, Singer RH, Segall JE, Condeelis JS (2004) Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors. Cancer Res 64:8585–8594
Wesolowska A, Kwiatkowska A, Slomnicki L, Dembinski M, Master A, Sliwa M, Franciszkiewicz K, Chouaib S, Kaminska B (2008) Microglia-derived TGF-beta as an important regulator of glioblastoma invasion–an inhibition of TGF-beta-dependent effects by shRNA against human TGF-beta type II receptor. Oncogene 27:918–930
Westermarck J, Kahari VM (1999) Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 13:781–792
Wiesen JF, Werb Z (1996) The role of stromelysin-1 in stromal-epithelial interactions and cancer. Enzyme Protein 49:174–181
Wu YJ, La Pierre DP, Wu J, Yee AJ, Yang BB (2005) The interaction of versican with its binding partners. Cell Res 15:483–494
Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, Zhou BP (2009) Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15:416–428
Wyckoff J, Wang W, Lin EY, Wang Y, Pixley F, Stanley ER, Graf T, Pollard JW, Segall J, Condeelis J (2004) A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 64:7022–7029
Wyckoff JB, Wang Y, Lin EY, Li JF, Goswami S, Stanley ER, Segall JE, Pollard JW, Condeelis J (2007) Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67:2649–2656
Xu L, Duda DG, di Tomaso E, Ancukiewicz M, Chung DC, Lauwers GY, Samuel R, Shellito P, Czito BG, Lin PC, Poleski M, Bentley R, Clark JW, Willett CG, Jain RK (2009) Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res 69:7905–7910
Xue C, Wyckoff J, Liang F, Sidani M, Violini S, Tsai KL, Zhang ZY, Sahai E, Condeelis J, Segall JE (2006) Epidermal growth factor receptor overexpression results in increased tumor cell motility in vivo coordinately with enhanced intravasation and metastasis. Cancer Res 66:192–197
Yamaguchi H, Lorenz M, Kempiak S, Sarmiento C, Coniglio S, Symons M, Segall J, Eddy R, Miki H, Takenawa T, Condeelis J (2005) Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin. J Cell Biol 168:441–452
Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14:818–829
Zabel BA, Wang Y, Lewen S, Berahovich RD, Penfold ME, Zhang P, Powers J, Summers BC, Miao Z, Zhao B, Jalili A, Janowska-Wieczorek A, Jaen JC, Schall TJ (2009) Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands. J Immunol 183:3204–3211
Zheng B, Lavoie C, Tang TD, Ma P, Meerloo T, Beas A, Farquhar MG (2004) Regulation of epidermal growth factor receptor degradation by heterotrimeric Galphas protein. Mol Biol Cell 15:5538–5550
Zins K, Abraham D, Sioud M, Aharinejad S (2007) Colon cancer cell-derived tumor necrosis factor-alpha mediates the tumor growth-promoting response in macrophages by up-regulating the colony-stimulating factor-1 pathway. Cancer Res 67:1038–1045
Zlotnik A (2006) Chemokines and cancer. Int J Cancer 119:2026–2029
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Binder, C. (2011). The Role of Tumour-Associated Macrophages in Malignant Invasion. In: Lawrence, T., Hagemann, T. (eds) Tumour-Associated Macrophages. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0662-4_3
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