Role of inflammation-associated microenvironment in Tumorigenesis and Metastasis

Current Cancer Drug Targets

Volumn 14, Issue 1, 2014, Pages 30-45

  Gao, Feng ^a,b   Liang, Bin ^a   Reddy, Srinivasa T ^b   Farias Eisner, Robin ^b   Su, Xiulan ^a  

^a INNER MONGOLIA MEDICAL UNIVERSITY   (China)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Cancer therapy; Carcinogenesis; Drug resistance; Inflammation; Metastasis; Microenvironment

Indexed keywords

BEVACIZUMAB; CALGRANULIN A; CALGRANULIN B; CHEMOKINE RECEPTOR CXCR; COLONY STIMULATING FACTOR 1; CRENOLANIB; DIGOXIN; ENDOTHELIAL LEUKOCYTE ADHESION MOLECULE 1; GALUNISERTIB; GAMMA INTERFERON; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; ICRUCUMAB; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 4; INTERLEUKIN 6; LYMPHOTOXIN; MICRORNA; MONOCYTE CHEMOTACTIC PROTEIN 1; PADGEM PROTEIN; RITONAVIR; SCATTER FACTOR; SECONDARY LYMPHOID TISSUE CHEMOKINE; SORAFENIB; STROMAL CELL DERIVED FACTOR 1; TENASCIN; TRANSFORMING GROWTH FACTOR BETA1; TUMOR NECROSIS FACTOR ALPHA; UNINDEXED DRUG; VASCULAR CELL ADHESION MOLECULE 1; VASCULOTROPIN A;

ANGIOGENESIS; BREAST CANCER; CARCINOGENESIS; CELL ADHESION; CELL CYCLE; CELL INTERACTION; CELL MATURATION; CELL MIGRATION; CIRCULATING TUMOR CELL; DENDRITIC CELL; ENDOTHELIAL PROGENITOR CELL; EPITHELIAL MESENCHYMAL TRANSITION; EXTRACELLULAR MATRIX; FIBROBLAST; GASTROINTESTINAL STROMAL TUMOR; HUMAN; IMMUNE RESPONSE; INFLAMMATION; LEWIS CARCINOMA; LIVER CELL CARCINOMA; METASTASIS; NONHUMAN; OVARY CARCINOMA; PERICYTE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHENOTYPE; PROSTATE CARCINOMA; REVIEW; THROMBOCYTE ACTIVATION; THROMBOCYTE AGGREGATION; TREATMENT OUTCOME; TUMOR ASSOCIATED LEUKOCYTE; TUMOR GROWTH; TUMOR INVASION; TUMOR MICROENVIRONMENT;

BLOOD PLATELETS; CARCINOMA; CELL CYCLE; CELL MOVEMENT; DRUG RESISTANCE, NEOPLASM; EPITHELIAL-MESENCHYMAL TRANSITION; HUMANS; INFLAMMATION; MOLECULAR TARGETED THERAPY; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; TUMOR MICROENVIRONMENT;

EID: 84892497106     PISSN: 15680096     EISSN: 18735576     Source Type: Journal    
DOI: 10.2174/15680096113136660107     Document Type: Review

References (147)

1. Hanahan, D.; Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 2011, 144, 646-674.
2. Mintz, B.; Illmensee, K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc. Natl. Acad. Sci. U S A 1975, 72, 3585-3589.
3. Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 2004, 4, 71-78.
4. Condeelis, J.; Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 2006, 124, 263-266.
5. Coussens, L. M.; Werb, Z. Inflammation and cancer. Nature 2002, 420, 860-867.
6. Coussens, L. M.; Zitvogel, L.; Palucka, A. K. Neutralizing tumorpromoting chronic inflammation: a magic bullet? Science 2013, 339, 286-291.
7. Ohm, J. E.; Carbone, D. P. VEGF as a mediator of tumorassociated immunodeficiency. Immunol. Res. 2001, 23, 263-272.
8. Wang, H. W.; Joyce, J. A. Alternative activation of tumorassociated macrophages by IL-4: priming for protumoral functions. Cell Cycle 2010, 9, 4824-4835.
9. Zhang, Q. W.; Liu, L.; Gong, C. Y.; Shi, H. S.; Zeng, Y. H.; Wang, X. Z.; Zhao, Y. W.; Wei, Y. Q. Prognostic significance of tumorassociated macrophages in solid tumor: a meta-analysis of the literature. PLoS One 2012, 7, e50946.
10. Fujimoto, H.; Sangai, T.; Ishii, G.; Ikehara, A.; Nagashima, T.; Miyazaki, M.; Ochiai, A. Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int. J. Cancer 2009, 125, 1276-1284.
11. Priceman, S. J.; Sung, J. L.; Shaposhnik, Z.; Burton, J. B.; Torres-Collado, A. X.; Moughon, D. L.; Johnson, M.; Lusis, A. J.; Cohen, D. A.; Iruela-Arispe, M.L.; Wu, L. Targeting distinct tumorinfiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood 2010, 115, 1461-1471.
12. Qian, B. Z.; Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 2010, 141, 39-51.
13. Lin, E. Y.; Nguyen, A. V.; Russell, R. G.; Pollard, J. W. Colonystimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 2001, 193, 727-740.
14. Karin, M.; Greten, F. R. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 2005, 5, 749-759.
15. Tanaka, H.; Shinto, O.; Yashiro, M.; Yamazoe, S.; Iwauchi, T.; Muguruma, K.; Kubo, N.; Ohira, M.; Hirakawa, K. Transforming growth factor beta signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity. Oncol. Rep. 2010, 24, 1637-1643.
16. Yang, L.; Huang, J.; Ren, X.; Gorska, A. E.; Chytil, A.; Aakre, M.; Carbone, D. P.; Matrisian, L. M.; Richmond, A.; Lin, P. C.; Moses, H. L. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 2008, 13, 23-35.
17. Yang, W. C.; Ma, G.; Chen, S. H.; Pan, P. Y. Polarization and reprogramming of myeloid-derived suppressor cells. J. Mol. Cell Biol. 2013, 5, 207-209.
18. 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 2013, 138, 105-115.
19. Rosborough, B. R.; Castellaneta, A.; Natarajan, S.; Thomson, A.W.; Turnquist, H.R. Histone deacetylase inhibition facilitates GM-CSF-mediated expansion of myeloid-derived suppressor cells in vitro and in vivo. J. Leukoc. Biol. 2012, 91, 701-709.
20. Morales, J. K.; Kmieciak, M.; Knutson, K. L.; Bear, H. D.; Manjili, M. H. GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1-bone marrow progenitor cells into myeloid-derived suppressor cells. Breast Cancer Res. Treat. 2010, 123, 39-49.
21. Sica, A.; Bronte, V. Altered macrophage differentiation and immune dysfunction in tumor development. J. Clin. Invest. 2007, 117, 1155-1166.
22. Bierie, B.; Moses, H. L. Transforming growth factor beta (TGFbeta) and inflammation in cancer. Cytokine Growth Factor Rev. 2010, 21, 49-59.
23. Polanska, U. M.; Orimo, A. Carcinoma-associated fibroblasts: nonneoplastic tumour-promoting mesenchymal cells. J. Cell Physiol. 2013, 228, 1651-1657.
24. Olumi, A. F.; Grossfeld, G. D.; Hayward, S. W.; Carroll, P. R.; Tlsty, T. D.; Cunha, G. R. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999, 59, 5002-5011.
25. Bhowmick, N. A.; Chytil, A.; Plieth, D.; Gorska, A. E.; Dumont, N.; Shappell, S.; Washington, M. K.; Neilson, E. G.; Moses, H. L. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004, 303, 848-851.
26. Kojima, Y.; Acar, A.; Eaton, E. N.; Mellody, K. T.; Scheel, C.; Ben-Porath, I.; Onder, T. T.; Wang, Z. C.; Richardson, A. L.; Weinberg, R. A.; Orimo, A. Autocrine TGF-beta and stromal cellderived factor-1 (SDF-1) signaling drives the evolution of tumorpromoting mammary stromal myofibroblasts. Proc. Natl. Acad. Sci. U S A 2010, 107, 20009-20014.
27. Kalluri, R.; Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 2006, 6, 392-401.
28. Nagaharu, K.; Zhang, X.; Yoshida, T.; Katoh, D.; Hanamura, N.; Kozuka, Y.; Ogawa, T.; Shiraishi, T.; Imanaka-Yoshida, K. Tenascin C induces epithelial-mesenchymal transition-like change accompanied by SRC activation and focal adhesion kinase phosphorylation in human breast cancer cells. Am. J. Pathol. 2011, 178, 754-763.
29. Orimo, A.; Gupta, P. B.; Sgroi, D. C.; Arenzana-Seisdedos, F.; Delaunay, T.; Naeem, R.; Carey, V. J.; Richardson, A. L.; Weinberg, R. A. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005, 121, 335-348.
30. Raz, Y.; Erez, N. An inflammatory vicious cycle: Fibroblasts and immune cell recruitment in cancer. Exp. Cell Res. 2013, 13, S0014-4827.
31. Martinez-Outschoorn, U. E.; Trimmer, C.; Lin, Z.; Whitaker-Menezes, D.; Chiavarina, B.; Zhou, J.; Wang, C.; Pavlides, S.; Martinez-Cantarin, M. P.; Capozza, F.; Witkiewicz, A. K.; Flomenberg, N.; Howell, A.; Pestell, R. G.; Caro, J.; Lisanti, M. P.; Sotgia, F. Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFkappaB activation in the tumor stromal microenvironment. Cell Cycle 2010, 9, 3515-3533.
32. Shurin, G. V.; Ma, Y.; Shurin, M. R. Immunosuppressive mechanisms of regulatory dendritic cells in cancer. Cancer Microenviron. 2013, 6, 159-167.
33. Lu, L.; Pan, K.; Zheng, H. X.; Li, J. J.; Qiu, H. J.; Zhao, J. J.; Weng, D. S.; Pan, Q. Z.; Wang, D. D.; Jiang, S. S.; Chang, A. E.; Li, Q.; Xia, J. C. IL-17A promotes immune cell recruitment in human esophageal cancers and the infiltrating dendritic cells represent a positive prognostic marker for patient survival. J. Immunother. 2013, 36, 451-458.
34. Nieman, K. M.; Romero, I. L.; Van Houten, B.; Lengyel, E. Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim. Biophys. Acta 2013, 1831, 1533-1541.
35. Vucenik, I.; Stains, J. P. Obesity and cancer risk: evidence, mechanisms, and recommendations. Ann. N. Y. Acad. Sci. 2012, 1271, 37-43.
36. Liu, J.; Zhang, Y.; Zhao, J.; Yang, Z.; Li, D.; Katirai, F.; Huang, B. Mast cell: insight into remodeling a tumor microenvironment. Cancer Metastasis Rev. 2011, 30, 177-184.
37. Stojanovic, A.; Correia, M. P.; Cerwenka, A. Shaping of NK cell responses by the tumor microenvironment. Cancer Microenviron. 2013, 6, 135-146.
38. Park, Y. J.; Song, B.; Kim, Y. S.; Kim, E. K.; Lee, J. M.; Lee, G. E.; Kim, J. O.; Kim, Y. J.; Chang, W. S.; Kang, C. Y. Tumor microenvironmental conversion of natural killer cells into myeloid-derived suppressor cells. Cancer Res. 2013, 73, 5669-5681.
39. Ishiguro, K.; Yoshida, T.; Yagishita, H.; Numata, Y.; Okayasu, T. Epithelial and stromal genetic instability contributes to genesis of colorectal adenomas. Gut 2006, 55, 695-702.
40. Weber, F.; Shen, L.; Fukino, K.; Patocs, A.; Mutter, G. L.; Caldes, T.; Eng, C. Total-genome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. Am. J. Hum. Genet. 2006, 78, 961-972.
41. Campbell, I.; Polyak, K.; Haviv, I. Clonal mutations in the cancerassociated fibroblasts: the case against genetic coevolution. Cancer Res. 2009, 69, 6765-6768; discussion 6769.
42. Friedl, P.; Wolf, K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat. Rev. Cancer 2003, 3, 362-374.
43. Polacheck, W. J.; Zervantonakis, I. K.; Kamm, R. D. Tumor cell migration in complex microenvironments. Cell Mol. Life Sci. 2013, 70, 1335-1356.
44. De Craene, B.; Berx, G. Regulatory networks defining EMT during cancer initiation and progression. Nat. Rev. Cancer 2013, 13, 97-110.
45. Yu, M.; Bardia, A.; Wittner, B. S.; Stott, S. L.; Smas, M. E.; Ting, D. T.; Isakoff, S. J.; Ciciliano, J. C.; Wells, M. N.; Shah, A. M.; Concannon, K. F.; Donaldson, M. C.; Sequist, L. V.; Brachtel, E.; Sgroi, D.; Baselga, J.; Ramaswamy, S.; Toner, M.; Haber, D. A.; Maheswaran, S. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 2013, 339, 580-584.
46. Erez, N.; Coussens, L. M. Leukocytes as paracrine regulators of metastasis and determinants of organ-specific colonization. Int. J. Cancer 2011, 128, 2536-2544.
47. Condeelis, J.; Segall, J. E. Intravital imaging of cell movement in tumours. Nat. Rev. Cancer 2003, 3, 921-930.
48. Park, J.; Schwarzbauer, J. E. Mammary epithelial cell interactions with fibronectin stimulate epithelial-mesenchymal transition. Oncogene 2013, 118. doi: 10.1038/onc.2013.118.
49. Vlaicu, P.; Mertins, P.; Mayr, T.; Widschwendter, P.; Ataseven, B.; Hogel, B.; Eiermann, W.; Knyazev, P.; Ullrich, A. Monocytes/macrophages support mammary tumor invasivity by cosecreting lineage-specific EGFR ligands and a STAT3 activator. BMC Cancer 2013, 13, 197.
50. Cardoso, A. P.; Pinto, M. L.; Pinto, A. T.; Oliveira, M. I.; Pinto, M. T.; Goncalves, R.; Relvas, J. B.; Figueiredo, C.; Seruca, R.; Mantovani, A.; Mareel, M.; Barbosa, M. A.; Oliveira, M. J. Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y, c-Src, Erk1/2 and Akt phosphorylation and smallGTPase activity. Oncogene 2013, 154. doi: 10.1038/onc.2013. 154.
51. Hussain, F.; Freissmuth, M.; Volkel, D.; Thiele, M.; Douillard, P.; Antoine, G.; Thurner, P.; Ehrlich, H.; Schwarz, H. P.; Scheiflinger, F.; Kerschbaumer, R. J. Human anti-macrophage migration inhibitory factor antibodies inhibit growth of human prostate cancer cells in vitro and in vivo. Mol. Cancer Ther. 2013, 12, 1223-1234.
52. Schober, A.; Knarren, S.; Lietz, M.; Lin, E. A.; Weber, C. Crucial role of stromal cell-derived factor-1alpha in neointima formation after vascular injury in apolipoprotein E-deficient mice. Circulation 2003, 108, 2491-2497.
53. Luo, Y.; Lan, L.; Jiang, Y. G.; Zhao, J. H.; Li, M. C.; Wei, N. B.; Lin, Y. H. Epithelial-mesenchymal transition and migration of prostate cancer stem cells is driven by cancer-associated fibroblasts in an HIF-1alpha/beta-catenin-dependent pathway. Mol. Cells 2013, 36, 138-144.
54. Joyce, J. A.; and Pollard, J. W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 2009, 9, 239-252.
55. Pathak, A.; and Kumar, S. Biophysical regulation of tumor cell invasion: moving beyond matrix stiffness. Integr. Biol. (Camb) 2011, 3, 267-278.
56. Greenberg, J. I.; Shields, D. J.; Barillas, S. G.; Acevedo, L. M.; Murphy, E.; Huang, J.; Scheppke, L.; Stockmann, C.; Johnson, R. S.; Angle, N.; Cheresh, D.A. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 2008, 456, 809-813.
57. Brudno, Y.; Ennett-Shepard, A. B.; Chen, R. R.; Aizenberg, M.; Mooney, D. J. Enhancing microvascular formation and vessel maturation through temporal control over multiple pro-angiogenic and pro-maturation factors. Biomaterials 2013, 34, 9201-9209.
58. Marignol, L.; Rivera-Figueroa, K.; Lynch, T.; Hollywood, D. Hypoxia, notch signalling, and prostate cancer. Nat. Rev. Urol. 2013, 10, 405-413.
59. Saharinen, P.; Alitalo, K. The yin, the yang, and the angiopoietin-1. J. Clin. Invest. 2011, 121, 2157-2159.
60. Outtz, H. H.; Tattersall, I. W.; Kofler, N. M.; Steinbach, N.; Kitajewski, J. Notch1 controls macrophage recruitment and Notch signaling is activated at sites of endothelial cell anastomosis during retinal angiogenesis in mice. Blood 2011, 118, 3436-3439.
61. Lin, E. Y.; Li, J. F.; Bricard, G.; Wang, W.; Deng, Y.; Sellers, R.; Porcelli, S. A.; Pollard, J. W. Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages. Mol. Oncol. 2007, 1, 288-302.
62. Amit-Cohen, B. C.; Rahat, M. M.; Rahat, M. A. Tumor cellmacrophage interactions increase angiogenesis through secretion of EMMPRIN. Front. Physiol. 2013, 4, 178.
63. Coussens, L. M.; Tinkle, C. L.; Hanahan, D.; Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 2000, 103, 481-490.
64. Bergers, G.; Brekken, R.; McMahon, G.; Vu, T. H.; Itoh, T.; Tamaki, K.; Tanzawa, K.; Thorpe, P.; Itohara, S.; Werb, Z.; Hanahan, D. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell. Biol. 2000, 2, 737-744.
65. Wyckoff, J. B.; Wang, Y.; Lin, E. Y.; Li, J. F.; Goswami, S.; Stanley, E. R.; Segall, J. E.; Pollard, J. W.; Condeelis, J. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 2007, 67, 2649-2656.
66. Du, R.; Lu, K. V.; Petritsch, C.; Liu, P.; Ganss, R.; Passegue, E.; Song, H.; Vandenberg, S.; Johnson, R. S.; Werb, Z.; Bergers, G. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 2008, 13, 206-220.
67. Lyden, D.; Hattori, K.; Dias, S.; Costa, C.; Blaikie, P.; Butros, L.; Chadburn, A.; Heissig, B.; Marks, W.; Witte, L.; Wu, Y.; Hicklin, D.; Zhu, Z.; Hackett, N. R.; Crystal, R. G.; Moore, M. A.; Hajjar, K. A.; Manova, K.; Benezra, R.; Rafii, S. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat. Med. 2001, 7, 1194-1201.
68. Mellick, A. S.; Plummer, P. N.; Nolan, D. J.; Gao, D.; Bambino, K.; Hahn, M.; Catena, R.; Turner, V.; McDonnell, K.; Benezra, R.; Brink, R.; Swarbrick, A.; Mittal, V. Using the transcription factor inhibitor of DNA binding 1 to selectively target endothelial progenitor cells offers novel strategies to inhibit tumor angiogenesis and growth. Cancer Res. 2010, 70, 7273-7282.
69. Le Bourhis, X.; Romon, R.; Hondermarck, H. Role of endothelial progenitor cells in breast cancer angiogenesis: from fundamental research to clinical ramifications. Breast Cancer Res. Treat. 2010, 120, 17-24.
70. Gille, J.; Heidenreich, R.; Pinter, A.; Schmitz, J.; Boehme, B.; Hicklin, D. J.; Henschler, R.; Breier, G. Simultaneous blockade of VEGFR-1 and VEGFR-2 activation is necessary to efficiently inhibit experimental melanoma growth and metastasis formation. Int. J. Cancer 2007, 120, 1899-1908.
71. Timar, J.; Tovari, J.; Raso, E.; Meszaros, L.; Bereczky, B.; Lapis, K. Platelet-mimicry of cancer cells: epiphenomenon with clinical significance. Oncology 2005, 69, 185-201.
72. Bambace, N. M.; Holmes, C. E. The platelet contribution to cancer progression. J. Thromb. Haemost. 2011, 9, 237-249.
73. Jain, S.; Harris, J.; Ware, J. Platelets: linking hemostasis and cancer. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 2362-2367.
74. Varon, D.; Hayon, Y.; Dashevsky, O.; Shai, E. Involvement of platelet derived microparticles in tumor metastasis and tissue regeneration. Thromb. Res. 2012, 130 Suppl 1, S98-99.
75. Chatterjee, M.; Gawaz, M. Platelet-Derived CXCL12 (SDF-1alpha): Basic Mechanisms and Clinical Implications. J. Thromb. Haemost. 2013, doi: 10.1111/jth. 12404.
76. Kawada, K.; Taketo, M. M. Significance and mechanism of lymph node metastasis in cancer progression. Cancer Res. 2011, 71, 1214-1218.
77. Tammela, T.; Alitalo, K. Lymphangiogenesis: Molecular mechanisms and future promise. Cell 2010, 140, 460-476.
78. Kerjaschki, D.; Bago-Horvath, Z.; Rudas, M.; Sexl, V.; Schneckenleithner, C.; Wolbank, S.; Bartel, G.; Krieger, S.; Kalt, R.; Hantusch, B.; Keller, T.; Nagy-Bojarszky, K.; Huttary, N.; Raab, I.; Lackner, K.; Krautgasser, K.; Schachner, H.; Kaserer, K.; Rezar, S.; Madlener, S.; Vonach, C.; Davidovits, A.; Nosaka, H.; Hammerle, M.; Viola, K.; Dolznig, H.; Schreiber, M.; Nader, A.; Mikulits, W.; Gnant, M.; Hirakawa, S.; Detmar, M.; Alitalo, K.; Nijman, S.; Offner, F.; Maier, T. J.; Steinhilber, D.; Krupitza, G. Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse. J. Clin. Invest. 2011, 121, 2000-2012.
79. Hirbe, A. C.; Morgan, E. A.; Weilbaecher, K. N. The CXCR4/SDF-1 chemokine axis: a potential therapeutic target for bone metastases? Curr. Pharm. Des. 2010, 16, 1284-1290.
80. Shiozawa, Y.; Pedersen, E. A.; Havens, A. M.; Jung, Y.; Mishra, A.; Joseph, J.; Kim, J. K.; Patel, L. R.; Ying, C.; Ziegler, A. M.; Pienta, M. J.; Song, J.; Wang, J.; Loberg, R. D.; Krebsbach, P. H.; Pienta, K. J.; Taichman, R. S. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J. Clin. Invest. 2011, 121, 1298-1312.
81. Kerr, B. A.; McCabe, N. P.; Feng, W.; Byzova, T. V. Platelets govern pre-metastatic tumor communication to bone. Oncogene 2013, 32, 4319-4324.
82. Kaplan, R. N.; Riba, R. D.; Zacharoulis, S.; Bramley, A. H.; Vincent, L.; Costa, C.; MacDonald, D. D.; Jin, D. K.; Shido, K.; Kerns, S. A.; Zhu, Z.; Hicklin, D.; Wu, Y.; Port, J. L.; Altorki, N.; Port, E. R.; Ruggero, D.; Shmelkov, S. V.; Jensen, K. K.; Rafii, S. and Lyden, D. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005, 438, 820-827.
83. Nguyen, D. X.; Bos, P. D.; Massague, J. Metastasis: from dissemination to organ-specific colonization. Nat. Rev. Cancer 2009, 9, 274-284.
84. Muller, A.; Homey, B.; Soto, H.; Ge, N.; Catron, D.; Buchanan, M. E.; McClanahan, T.; Murphy, E.; Yuan, W.; Wagner, S. N.; Barrera, J. L.; Mohar, A.; Verastegui, E.; Zlotnik, A. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001, 410, 50-56.
85. Kostic, A.; Lynch, C. D.; Sheetz, M. P. Differential matrix rigidity response in breast cancer cell lines correlates with the tissue tropism. PLoS One 2009, 4, e6361.
86. Psaila, B.; Lyden, D. The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 2009, 9, 285-293.
87. Sceneay, J.; Smyth, M. J.; Moller, A. The pre-metastatic niche: finding common ground. Cancer Metastasis Rev. 2013. May 1. [Epub ahead of print].
88. Erler, J. T.; Bennewith, K. L.; Nicolau, M.; Dornhofer, N.; Kong, C.; Le, Q. T.; Chi, J. T.; Jeffrey, S. S.; Giaccia, A. J. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006, 440, 1222-1226.
89. Erler, J. T.; Bennewith, K. L.; Cox, T. R.; Lang, G.; Bird, D.; Koong, A.; Le, Q. T.; Giaccia, A. J. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 2009, 15, 35-44.
90. Hiratsuka, S.; Watanabe, A; Aburatani, H.; Maru, Y. Tumourmediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat. Cell Biol. 2006, 8, 1369-1375.
91. Hiratsuka, S.; Duda, D. G.; Huang, Y.; Goel, S.; Sugiyama, T.; Nagasawa, T.; Fukumura, D.; Jain, R. K. C-X-C receptor type 4 promotes metastasis by activating p38 mitogen-activated protein kinase in myeloid differentiation antigen (Gr-1)-positive cells. Proc. Natl. Acad. Sci. U S A 2011, 108, 302-307.
92. Hiratsuka, S.; Watanabe, A.; Sakurai, Y.; Akashi-Takamura, S.; Ishibashi, S.; Miyake, K.; Shibuya, M.; Akira, S.; Aburatani, H.; Maru, Y. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat. Cell Biol. 2008, 10, 1349-1355.
93. Yan, H. H.; Pickup, M.; Pang, Y.; Gorska, A. E.; Li, Z.; Chytil, A.; Geng, Y.; Gray, J. W.; Moses, H. L.; Yang, L. Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Res. 2010, 70, 6139-6149.
94. Yang, L.; Pang, Y.; Moses, H. L. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010, 31, 220-227.
95. Sceneay, J.; Parker, B. S.; Smyth, M. J.; Moller, A. Hypoxia-driven immunosuppression contributes to the pre-metastatic niche. Oncoimmunology 2013, 2, e22355.
96. Hiratsuka, S.; Nakamura, K.; Iwai, S.; Murakami, M.; Itoh, T.; Kijima, H.; Shipley, J. M.; Senior, R. M.; Shibuya, M. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2002, 2, 289-300.
97. Niida, S.; Kondo, T.; Hiratsuka, S.; Hayashi, S.; Amizuka, N.; Noda, T.; Ikeda, K.; Shibuya, M. VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice. Proc. Natl. Acad. Sci. U S A 2005, 102, 14016-14021.
98. Kim, S.; Takahashi, H.; Lin, W. W.; Descargues, P.; Grivennikov, S.; Kim, Y.; Luo, J. L.; Karin, M. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 2009, 457, 102-106.
99. Hiratsuka, S.; Goel, S.; Kamoun, W. S.; Maru, Y.; Fukumura, D.; Duda, D. G.; Jain, R. K. Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation. Proc. Natl. Acad. Sci. U S A 2011, 108, 3725-3730.
100. Kitamura, T.; Fujishita, T.; Loetscher, P.; Revesz, L.; Hashida, H.; Kizaka-Kondoh, S.; Aoki, M.; Taketo, M. M. Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model. Proc. Natl. Acad. Sci. U S A 2010, 107, 13063-13068.
101. Padua, D.; Zhang, X. H.; Wang, Q.; Nadal, C.; Gerald, W. L.; Gomis, R. R.; Massague, J. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 2008, 133, 66-77.
102. 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 2013, 24, 130-137.
103. Oskarsson, T.; Acharyya, S.; Zhang, X. H.; Vanharanta, S.; Tavazoie, S. F.; Morris, P. G.; Downey, R. J.; Manova-Todorova, K.; Brogi, E.; Massague, J. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat. Med. 2011, 17, 867-874.
104. Qian, B.; Deng, Y.; Im, J. H.; Muschel, R. J.; Zou, Y.; Li, J.; Lang, R. A.; Pollard, J. W. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One 2009, 4, e6562.
105. Tsai, J. H.; Donaher, J. L.; Murphy, D. A.; Chau, S.; Yang, J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 2012, 22, 725-736.
106. Chao, Y. L.; Shepard, C. R.; Wells, A. Breast carcinoma cells reexpress E-cadherin during mesenchymal to epithelial reverting transition. Mol. Cancer 2010, 9, 179.
107. Korpal, M.; Ell, B. J.; Buffa, F. M.; Ibrahim, T.; Blanco, M. A.; Celia-Terrassa, T.; Mercatali, L.; Khan, Z.; Goodarzi, H.; Hua, Y.; Wei, Y.; Hu, G.; Garcia, B. A.; Ragoussis, J.; Amadori, D.; Harris, A. L.; Kang, Y. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat. Med. 2011, 17, 1101-1108.
108. Leontovich, A. A.; Zhang, S.; Quatraro, C.; Iankov, I.; Veroux, P. F.; Gambino, M. W.; Degnim, A.; McCubrey, J.; Ingle, J.; Galanis, E.; D'Assoro, A. B. Raf-1 oncogenic signaling is linked to activation of mesenchymal to epithelial transition pathway in metastatic breast cancer cells. Int. J. Oncol. 2012, 40, 1858-1864.
109. Sheng, W.; Wang, G.; La Pierre, D. P.; Wen, J.; Deng, Z.; Wong, C. K.; Lee, D. Y.; Yang, B. B. Versican mediates mesenchymalepithelial transition. Mol. Biol. Cell 2006, 17, 2009-2020.
110. Gao, D.; Joshi, N.; Choi, H.; Ryu, S.; Hahn, M.; Catena, R.; Sadik, H.; Argani, P.; Wagner, P.; Vahdat, L. T.; Port, J. L.; Stiles, B.; Sukumar, S.; Altorki, N. K.; Rafii, S.; Mittal, V. Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Res. 2012, 72, 1384-1394.
111. Lang, S. H.; Sharrard, R. M.; Stark, M.; Villette, J. M.; Maitland, N. J. Prostate epithelial cell lines form spheroids with evidence of glandular differentiation in three-dimensional Matrigel cultures. Br. J. Cancer 2001, 85, 590-599.
112. Aguirre-Ghiso, J. A. Models, mechanisms and clinical evidence for cancer dormancy. Nat. Rev. Cancer 2007, 7, 834-846.
113. Tanaka, T.; Nangaku, M. Angiogenesis and hypoxia in the kidney. Nat. Rev. Nephrol. 2013, 9, 211-222.
114. McAllister, S. S.; Gifford, A. M.; Greiner, A. L.; Kelleher, S. P.; Saelzler, M. P.; Ince, T. A.; Reinhardt, F.; Harris, L. N.; Hylander, B. L.; Repasky, E. A.; Weinberg, R. A. Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell 2008, 133, 994-1005.
115. Ostman, A. The tumor microenvironment controls drug sensitivity. Nat. Med. 2012, 18, 1332-1334.
116. Paraiso, K. H.; Smalley, K. S. Fibroblast-mediated drug resistance in cancer. Biochem. Pharmacol. 2013, 85, 1033-1041.
117. Sun, Y.; Campisi, J.; Higano, C.; Beer, T. M.; Porter, P.; Coleman, I.; True, L.; Nelson, P. S. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat. Med. 2012, 18, 1359-1368.
118. Straussman, R.; Morikawa, T.; Shee, K.; Barzily-Rokni, M.; Qian, Z. R.; Du, J.; Davis, A.; Mongare, M. M.; Gould, J.; Frederick, D. T.; Cooper, Z. A.; Chapman, P. B.; Solit, D. B.; Ribas, A.; Lo, R. S.; Flaherty, K. T.; Ogino, S.; Wargo, J. A.; Golub, T. R. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012, 487, 500-504.
119. Zhang, W.; Zhu, X. D.; Sun, H. C.; Xiong, Y. Q.; Zhuang, P. Y.; Xu, H. X.; Kong, L. Q.; Wang, L.; Wu, W. Z.; Tang, Z. Y. Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin. Cancer Res. 2010, 16, 3420-3430.
120. Fischer, C.; Jonckx, B.; Mazzone, M.; Zacchigna, S.; Loges, S.; Pattarini, L.; Chorianopoulos, E.; Liesenborghs, L.; Koch, M.; De Mol, M.; Autiero, M.; Wyns, S.; Plaisance, S.; Moons, L.; van Rooijen, N.; Giacca, M.; Stassen, J. M.; Dewerchin, M.; Collen, D.; Carmeliet, P. Anti-PlGF inhibits growth of VEGF(R)-inhibitorresistant tumors without affecting healthy vessels. Cell 2007, 131, 463-475.
121. Finke, J.; Ko, J.; Rini, B.; Rayman, P.; Ireland, J; Cohen, P. MDSC as a mechanism of tumor escape from sunitinib mediated antiangiogenic therapy. Int. Immunopharmacol. 2011, 11, 856-861.
122. Lu, T.; Ramakrishnan, R.; Altiok, S.; Youn, J. I.; Cheng, P.; Celis, E.; Pisarev, V.; Sherman, S.; Sporn, M. B.; Gabrilovich, D. Tumorinfiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J. Clin. Invest. 2011, 121, 4015-4029.
123. Albini, A.; Sporn, M. B. The tumour microenvironment as a target for chemoprevention. Nat. Rev. Cancer 2007, 7, 139-147.
124. Singh, M.; Ferrara, N. Modeling and predicting clinical efficacy for drugs targeting the tumor milieu. Nat. Biotechnol. 2012, 30, 648-657.
125. Gerald, D.; Chintharlapalli, S.; Augustin, H. G.; Benjamin, L. E. Angiopoietin-2: an attractive target for improved antiangiogenic tumor therapy. Cancer Res. 2013, 73, 1649-1657.
126. Bergers, G.; Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 2008, 8, 592-603.
127. Moreno Garcia, V.; Basu, B.; Molife, L. R.; Kaye, S. B. Combining antiangiogenics to overcome resistance: rationale and clinical experience. Clin. Cancer Res. 2012, 18, 3750-3761.
128. Azad, N. S.; Posadas, E. M.; Kwitkowski, V. E.; Steinberg, S. M.; Jain, L.; Annunziata, C. M.; Minasian, L.; Sarosy, G.; Kotz, H. L.; Premkumar, A.; Cao, L.; McNally, D.; Chow, C.; Chen, H. X.; Wright, J. J.; Figg, W. D.; Kohn, E. C. Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J. Clin. Oncol. 2008, 26, 3709-3714.
129. Castellano, D.; Capdevila, J.; Sastre, J.; Alonso, V.; Llanos, M.; Garcia-Carbonero, R.; Manzano Mozo, J. L.; Sevilla, I.; Duran, I.; Salazar, R. Sorafenib and bevacizumab combination targeted therapy in advanced neuroendocrine tumour: A phase II study of Spanish Neuroendocrine Tumour Group (GETNE0801). Eur. J. Cancer 2013, 6, S0959-8049(13)00549-2.
130. Tang, X.; Mo, C.; Wang, Y.; Wei, D.; Xiao, H. Anti-tumour strategies aiming to target tumour-associated macrophages. Immunology 2013, 138, 93-104.
131. Micke, P.; Ostman, A. Exploring the tumour environment: cancerassociated fibroblasts as targets in cancer therapy. Expert Opin. Ther. Targets 2005, 9, 1217-1233.
132. Denardo, D. G.; Brennan, D. J.; Rexhepaj, E.; Ruffell, B.; Shiao, S. L.; Madden, S. F.; Gallagher, W. M.; Wadhwani, N.; Keil, S. D.; Junaid, S. A.; Rugo, H. S.; Hwang, E. S.; Jirstrom, K.; West, B. L.; Coussens, L. M. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011, 1, 54-67.
133. Fend, L.; Accart, N.; Kintz, J.; Cochin, S.; Reymann, C.; Le Pogam, F.; Marchand, J. B.; Menguy, T.; Slos, P.; Rooke, R.; Fournel, S.; Bonnefoy, J. Y.; Preville, X.; Haegel, H. Therapeutic effects of anti-CD115 monoclonal antibody in mouse cancer models through dual inhibition of tumor-associated macrophages and osteoclasts. PLoS One 2013, 8, e73310.
134. Haegel, H.; Thioudellet, C.; Hallet, R.; Geist, M.; Menguy, T.; Le Pogam, F.; Marchand, J. B.; Toh, M. L.; Duong, V.; Calcei, A.; Settelen, N.; Preville, X.; Hennequi, M.; Grellier, B.; Ancian, P.; Rissanen, J.; Clayette, P.; Guillen, C.; Rooke, R.; Bonnefoy, J. Y. A unique anti-CD115 monoclonal antibody which inhibits osteolysis and skews human monocyte differentiation from M2-polarized macrophages toward dendritic cells. MAbs 2013, 5, 736-747.
135. Santos, A. M.; Jung, J.; Aziz, N.; Kissil, J. L.; Pure, E. Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J. Clin. Invest. 2009, 119, 3613-3625.
136. Brennen, W. N.; Rosen, D. M.; Wang, H.; Isaacs, J. T.; Denmeade, S. R. Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. J. Natl. Cancer Inst. 2012, 104, 1320-1334.
137. Shields, J. D.; Kourtis, I. C.; Tomei, A. A.; Roberts, J. M.; Swartz, M. A. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science 2010, 328, 749-752.
138. Pikarsky, E.; Porat, R. M.; Stein, I.; Abramovitch, R.; Amit, S.; Kasem, S.; Gutkovich-Pyest, E.; Urieli-Shoval, S.; Galun, E.; Ben-Neriah, Y. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 2004, 431, 461-466.
139. Nakanishi, C.; Toi, M. Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat. Rev. Cancer 2005, 5, 297-309.
140. Joyce, J. A. Therapeutic targeting of the tumor microenvironment. Cancer Cell 2005, 7, 513-520.
141. Faivre, S. J.; Santoro, A.; Delly, R. K.; Merle, P.; Gane, E.; Douillard, J.; Waldschmidt, D.; Mulcahy, M. F.; Costentin, C.; Minguez, B.; Papappicco, P; Gueorguieva, I.; Cleverly, A.; Desaiah, D.; Lahn, M. M. F.; Murray, N.; Benhadji, K. A.; Rayond, E.; Giannelli, G. Randomized dose comparison phase II study of the oral transforming growth factor-beta (TGF-α) receptor I kinase inhibitor LY2157299 monohydrate (LY) in patients with advanced hepatocellular carcinoma (HCC). J. Clin. Oncol. 2013, 31 (Suppl; abstr 4118).
142. Biggar, R. J.; Andersen, E. W.; Kroman, N.; Wohlfahrt, J; Melbye, M. Breast cancer in women using digoxin: tumor characteristics and relapse risk. Breast Cancer Res. 2013, 15, R13.
143. Joensuu, H.; Eriksson, M.; Sundby, H. K.; Hartmann, J. T.; Pink, D.; Schütte, J.; Ramadori, G.; Hohenberger, P.; Duyster, J.; Al-Batran, S. E.; Schlemmer, M.; Bauer, S.; Wardelmann, E.; Sarlomo-Rikala, M.; Nilsson, B.; Sihto, H.; Monge, O. R.; Bono, P.; Kallio, R.; Vehtari, A.; Leinonen, M.; Alvegard, T.; Reichardt, P. One vs. three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA 2012, 307, 1265-1272.
144. Hoff, P. M.; Hoff, A. O.; Phan, A. T.; Sherman, S. I.; Yao, J.; White, N.; Phan, L.; Abbruzzese, J. L.; Gagel, R. F. Phase I/II trial of capecitabine (C), dacarbazine (D) and imatinib (I) (CDI) for patients (pts) metastatic medullary thyroid carcinomas (MTC). J. Clin. Oncol. 2006, 24 (18 Suppl), 13048.
145. Wenham, R. M.; Leach, J. W.; Scudder, S. A.; Amin, B. R.; Pippitt, C. H.; Gordon, A. N.; Nanayakkara, N.; Hurh, E.; Stepan, D. E.; Schilder, R. J.; Lee, H. Phase Ib study of AMG 386 combined with either pegylated liposomal doxorubicin (PLD) or topotecan (T) inpatients with advanced ovarian cancer. J. Clin. Oncol. 2010, 28 (Suppl; abstr 5049).
146. Dieras, V.; Jassem, J.; Dirix, L. Y.; Guastalla, J. P.; Bono, P.; Hurvitz, S. A.; Goncalves, A.; Romieu, G.; Limentani, S. A.; Jerusalem, G. H. M.; Lakshmaiah, K.; Roche, H. H.; Sanchez-Rovira, P.; Pienkowski, T.; Segui-Palmer, M. A.; Li, A.; Sun, Y.; Pickett-Gies, C. A.; Wildiers, H. A randomized, placebo-controlled phase II study of AMG 386 plus bevacizumab (Bev) and paclitaxel (P) or AMG 386 plus P as first-line therapy in patients (pts) with HER2-negative, locally recurrent or metastatic breast cancer (LR/MBC). J. Clin. Oncol. 2011, 29 (Suppl; abstr 544).
147. Vahdat, L. T.; Miller, K.; Sparano, J. A.; Youssoufian, H.; Schwartz, J. D.; Nanda, S.; Wang, W.; Abad, L.; Dontabhaktuni, A.; Rutstein, M. D. Randomized phase II study of capecitabine with or without ramucirumab (IMC-1121B) or IMC-18F1 in patients with unresectable, locally advanced or metastatic breast cancer (mBC) previously treated with anthracycline and taxane therapy (CP20-0903/NCT01234402). J. Clin. Oncol. 2011, 29 (Suppl; abstr TPS151).