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Hypoxia, inflammation, and the tumor microenvironment in metastatic disease

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Abstract

Metastasis, the leading cause of cancer deaths, is an intricate process involving many important tumor and stromal proteins that have yet to be fully defined. This review discusses critical components necessary for the metastatic cascade, including hypoxia, inflammation, and the tumor microenvironment. More specifically, this review focuses on tumor cell and stroma interactions, which allow cell detachment from a primary tumor, intravasation to the blood stream, and extravasation at a distant site where cells can seed and tumor metastases can form. Central players involved in this process and discussed in this review include integrins, matrix metalloproteinases, and soluble growth factors/matrix proteins, including the connective tissue growth factor and lysyl oxidase.

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References

  1. Jemal, A., et al. (2009). Cancer statistics, 2009. CA: A Cancer Journal for Clinicians, 59(4), 225–249.

    Article  Google Scholar 

  2. Krug, E. L., Mjaatvedt, C. H., & Markwald, R. R. (1987). Extracellular matrix from embryonic myocardium elicits an early morphogenetic event in cardiac endothelial differentiation. Developmental Biology, 120(2), 348–355.

    Article  PubMed  CAS  Google Scholar 

  3. Hay, E. D. (1995). An overview of epithelio-mesenchymal transformation. Acta Anatomica (Basel), 154(1), 8–20.

    Article  CAS  Google Scholar 

  4. Tarin, D., Thompson, E. W., & Newgreen, D. F. (2005). The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Research, 65(14), 5996–6000. discussion 6000-1.

    Article  PubMed  CAS  Google Scholar 

  5. Birchmeier, W., & Behrens, J. (1994). Cadherin expression in carcinomas: Role in the formation of cell junctions and the prevention of invasiveness. Biochimica et Biophysica Acta, 1198(1), 11–26.

    PubMed  CAS  Google Scholar 

  6. Hotz, B., et al. (2007). Epithelial to mesenchymal transition: Expression of the regulators snail, slug, and twist in pancreatic cancer. Clinical Cancer Research, 13(16), 4769–4776.

    Article  PubMed  CAS  Google Scholar 

  7. Gravdal, K., et al. (2007). A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clinical Cancer Research, 13(23), 7003–7011.

    Article  PubMed  CAS  Google Scholar 

  8. Margulis, A., et al. (2005). E-cadherin suppression accelerates squamous cell carcinoma progression in three-dimensional, human tissue constructs. Cancer Research, 65(5), 1783–1791.

    Article  PubMed  CAS  Google Scholar 

  9. Yilmaz, M., & Christofori, G. (2009). EMT, the cytoskeleton, and cancer cell invasion. Cancer and Metastasis Reviews, 28(1–2), 15–33.

    Article  PubMed  Google Scholar 

  10. Haraguchi, M., et al. (2008). Snail regulates cell-matrix adhesion by regulation of the expression of integrins and basement membrane proteins. Journal of Biological Chemistry, 283(35), 23514–23523.

    Article  PubMed  CAS  Google Scholar 

  11. Gordon, K. J., et al. (2008). Loss of type III transforming growth factor beta receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression. Carcinogenesis, 29(2), 252–262.

    Article  PubMed  CAS  Google Scholar 

  12. Ozdamar, B., et al. (2005). Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science, 307(5715), 1603–1609.

    Article  PubMed  CAS  Google Scholar 

  13. Dumont, N., Bakin, A. V., & Arteaga, C. L. (2003). Autocrine transforming growth factor-beta signaling mediates Smad-independent motility in human cancer cells. Journal of Biological Chemistry, 278(5), 3275–3285.

    Article  PubMed  CAS  Google Scholar 

  14. Kalluri, R. (2003). Basement membranes: Structure, assembly and role in tumour angiogenesis. Nature Reviews Cancer, 3(6), 422–433.

    Article  PubMed  CAS  Google Scholar 

  15. Bhowmick, N. A., Neilson, E. G., & Moses, H. L. (2004). Stromal fibroblasts in cancer initiation and progression. Nature, 432(7015), 332–337.

    Article  PubMed  CAS  Google Scholar 

  16. Desgrosellier, J. S., & Cheresh, D. A. (2010). Integrins in cancer: Biological implications and therapeutic opportunities. Nataure Reviews Cancer, 10(1), 9–22.

    Article  CAS  Google Scholar 

  17. Takayama, S., et al. (2005). The relationship between bone metastasis from human breast cancer and integrin alpha(v)beta3 expression. Anticancer Research, 25(1A), 79–83.

    PubMed  CAS  Google Scholar 

  18. Liapis, H., Flath, A., & Kitazawa, S. (1996). Integrin alpha V beta 3 expression by bone-residing breast cancer metastases. Diagnostic Molecular Pathology, 5(2), 127–135.

    Article  PubMed  CAS  Google Scholar 

  19. McCabe, N. P., et al. (2007). Prostate cancer specific integrin alphavbeta3 modulates bone metastatic growth and tissue remodeling. Oncogene, 26(42), 6238–6243.

    Article  PubMed  CAS  Google Scholar 

  20. Hosotani, R., et al. (2002). Expression of integrin alphaVbeta3 in pancreatic carcinoma: Relation to MMP-2 activation and lymph node metastasis. Pancreas, 25(2), e30–e35.

    Article  PubMed  Google Scholar 

  21. Gruber, G., et al. (2005). Correlation between the tumoral expression of beta3-integrin and outcome in cervical cancer patients who had undergone radiotherapy. British Journal of Cancer, 92(1), 41–46.

    Article  PubMed  CAS  Google Scholar 

  22. Landen, C. N., et al. (2008). Tumor-selective response to antibody-mediated targeting of alphavbeta3 integrin in ovarian cancer. Neoplasia, 10(11), 1259–1267.

    PubMed  CAS  Google Scholar 

  23. Bello, L., et al. (2001). Alpha(v)beta3 and alpha(v)beta5 integrin expression in glioma periphery. Neurosurgery, 49(2), 380–9. discussion 390.

    Article  PubMed  CAS  Google Scholar 

  24. Mullamitha, S. A., et al. (2007). Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors. Clinincal Cancer Reseach, 13(7), 2128–2135.

    Article  CAS  Google Scholar 

  25. Ricart, A. D., et al. (2008). Volociximab, a chimeric monoclonal antibody that specifically binds alpha5beta1 integrin: A phase I, pharmacokinetic, and biological correlative study. Clinical Cancer Research, 14(23), 7924–7929.

    Article  PubMed  CAS  Google Scholar 

  26. Gross, J., & Lapiere, C. M. (1962). Collagenolytic activity in amphibian tissues: A tissue culture assay. Proceedings of the National Academy of Science of the United States America, 48, 1014–1022.

    Article  CAS  Google Scholar 

  27. Brinckerhoff, C. E., & Matrisian, L. M. (2002). Matrix metalloproteinases: A tail of a frog that became a prince. Nature Reviews Molecular Cell Biology, 3(3), 207–214.

    Article  PubMed  CAS  Google Scholar 

  28. Burrage, P., et al. (2006). Matrix metalloproteinases: Role in arthritis. Frontiers in Bioscience, 11, 529–543.

    Google Scholar 

  29. Zucker, S., et al. (1999). Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications. Annals of the New York Academy of Sciences, 878, 212–227.

    Article  PubMed  CAS  Google Scholar 

  30. Koc, M., et al. (2006). Matrix metalloproteinase-9 (MMP-9) elevated in serum but not in bronchial lavage fluid in patients with lung cancer. Tumori, 92(2), 149–154.

    PubMed  CAS  Google Scholar 

  31. Hilska, M., et al. (2007). Prognostic significance of matrix metalloproteinases-1, -2, -7 and -13 and tissue inhibitors of metalloproteinases-1, -2, -3 and -4 in colorectal cancer. International Journal of Cancer, 121(4), 714–723.

    Article  CAS  Google Scholar 

  32. Lengyel, E., et al. (2001). Expression of latent matrix metalloproteinase 9 (MMP-9) predicts survival in advanced ovarian cancer. Gynecologic Oncology, 82(2), 291–298.

    Article  PubMed  CAS  Google Scholar 

  33. Roy, R., Yang, J., & Moses, M. A. (2009). Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. Journal of Clinical Oncology, 27(31), 5287–5297.

    Article  PubMed  CAS  Google Scholar 

  34. Dublanchet, A. C., et al. (2005). Structure-based design and synthesis of novel non-zinc chelating MMP-12 inhibitors. Bioorganic & Medicinal Chemistry Letters, 15(16), 3787–3790.

    Article  CAS  Google Scholar 

  35. Chan, D. A., & Giaccia, A. J. (2007). Hypoxia, gene expression, and metastasis. Cancer and Metastasis Reviews, 26(2), 333–339.

    Article  PubMed  CAS  Google Scholar 

  36. Masson, N., et al. (2001). Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO Journal, 20(18), 5197–5206.

    Article  PubMed  CAS  Google Scholar 

  37. Chan, D. A., et al. (2002). Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1alpha. Journal Biological Chemistry, 277(42), 40112–40117.

    Article  CAS  Google Scholar 

  38. Bedogni, B., & Powell, M. B. (2009). Hypoxia, melanocytes and melanoma—Survival and tumor development in the permissive microenvironment of the skin. Pigment Cell Melanoma Research, 22(2), 166–174.

    Article  PubMed  CAS  Google Scholar 

  39. Epstein, A. C., et al. (2001). C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell, 107(1), 43–54.

    Article  PubMed  CAS  Google Scholar 

  40. Jaakkola, P., et al. (2001). Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 292(5516), 468–472.

    Article  PubMed  CAS  Google Scholar 

  41. Mole, D. R., et al. (2009). Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts. Journal of Biological Chemistry, 284(25), 16767–16775.

    Article  PubMed  CAS  Google Scholar 

  42. Michieli, P. (2009). Hypoxia, angiogenesis and cancer therapy: To breathe or not to breathe? Cell Cycle, 8(20), 3291–3296.

    PubMed  Google Scholar 

  43. Kim, J. W., et al. (2006). HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metabolism, 3(3), 177–185.

    Article  PubMed  CAS  Google Scholar 

  44. Bindra, R. S., et al. (2005). Alterations in DNA repair gene expression under hypoxia: Elucidating the mechanisms of hypoxia-induced genetic instability. Annals of the New York Academy of Sciences, 1059, 184–195.

    Article  PubMed  CAS  Google Scholar 

  45. Tang, N., et al. (2004). Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell, 6(5), 485–495.

    Article  PubMed  CAS  Google Scholar 

  46. Pennacchietti, S., et al. (2003). Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell, 3(4), 347–361.

    Article  PubMed  Google Scholar 

  47. Canning, M. T., et al. (2001). Oxygen-mediated regulation of gelatinase and tissue inhibitor of metalloproteinases-1 expression by invasive cells. Experimental Cell Research, 267(1), 88–94.

    Article  PubMed  CAS  Google Scholar 

  48. Esteban, M. A., et al. (2006). Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Research, 66(7), 3567–3575.

    Article  PubMed  CAS  Google Scholar 

  49. Imai, T., et al. (2003). Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. American Journal of Pathology, 163(4), 1437–1447.

    PubMed  CAS  Google Scholar 

  50. Jiang, Y. G., et al. (2007). Role of Wnt/beta-catenin signaling pathway in epithelial–mesenchymal transition of human prostate cancer induced by hypoxia-inducible factor-1alpha. International Journal of Urology, 14(11), 1034–1039.

    Article  PubMed  CAS  Google Scholar 

  51. Erler, J. T., et al. (2006). Lysyl oxidase is essential for hypoxia-induced metastasis. Nature, 440(7088), 1222–1226.

    Article  PubMed  CAS  Google Scholar 

  52. Dewhirst, M. W., et al. (1989). Morphologic and hemodynamic comparison of tumor and healing normal tissue microvasculature. International Journal of Radiation Oncology, Biology, Physics, 17(1), 91–99.

    PubMed  CAS  Google Scholar 

  53. Jain, R. K. (2005). Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science, 307(5706), 58–62.

    Article  PubMed  CAS  Google Scholar 

  54. Hanahan, D., & Folkman, J. (1996). Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 86(3), 353–364.

    Article  PubMed  CAS  Google Scholar 

  55. Shweiki, D., et al. (1992). Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature, 359(6398), 843–845.

    Article  PubMed  CAS  Google Scholar 

  56. Holash, J., et al. (1999). Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science, 284(5422), 1994–1998.

    Article  PubMed  CAS  Google Scholar 

  57. Ruan, K., Song, G., & Ouyang, G. (2009). Role of hypoxia in the hallmarks of human cancer. Journal Cell Biochemistry, 107(6), 1053–1062.

    Article  CAS  Google Scholar 

  58. Laderoute, K. R., et al. (2000). Opposing effects of hypoxia on expression of the angiogenic inhibitor thrombospondin 1 and the angiogenic inducer vascular endothelial growth factor. Clinincal Cancer Research, 6(7), 2941–2950.

    CAS  Google Scholar 

  59. Talks, K. L., et al. (2000). The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. American Journal of Pathology, 157(2), 411–421.

    PubMed  CAS  Google Scholar 

  60. Kallman, R. F., & Dorie, M. J. (1986). Tumor oxygenation and reoxygenation during radiation therapy: Their importance in predicting tumor response. International Journal of Radiation Oncology, Biology, Physics, 12(4), 681–685.

    PubMed  CAS  Google Scholar 

  61. Daruwalla, J., & Christophi, C. (2006). Hyperbaric oxygen therapy for malignancy: A review. World Journal of Surgery, 30(12), 2112–2131.

    Article  PubMed  Google Scholar 

  62. Engert, A. (2005). Recombinant human erythropoietin in oncology: Current status and further developments. Annals of Oncology, 16(10), 1584–1595.

    Article  PubMed  CAS  Google Scholar 

  63. Galluzzo, M., et al. (2009). Prevention of hypoxia by myoglobin expression in human tumor cells promotes differentiation and inhibits metastasis. Journal of Clinical Investigative, 119(4), 865–875.

    Article  CAS  Google Scholar 

  64. Csiszar, K. (2001). Lysyl oxidases: A novel multifunctional amine oxidase family. Progress in Nucleic Acid Research and Molecular Biology, 70, 1–32.

    Article  PubMed  CAS  Google Scholar 

  65. Pinnell, S. R., & Martin, G. R. (1968). The cross-linking of collagen and elastin: Enzymatic conversion of lysine in peptide linkage to alpha-aminoadipic-delta-semialdehyde (allysine) by an extract from bone. Proceedings of the National Academy of Science of the United States of America, 61(2), 708–716.

    Article  CAS  Google Scholar 

  66. Trackman, P. C., et al. (1992). Post-translational glycosylation and proteolytic processing of a lysyl oxidase precursor. Journal of Biological Chemistry, 267(12), 8666–8671.

    PubMed  CAS  Google Scholar 

  67. Cronshaw, A. D., Fothergill-Gilmore, L. A., & Hulmes, D. J. (1995). The proteolytic processing site of the precursor of lysyl oxidase. Biochemical Journal, 306(Pt 1), 279–284.

    PubMed  CAS  Google Scholar 

  68. Panchenko, M. V., et al. (1996). Metalloproteinase activity secreted by fibrogenic cells in the processing of prolysyl oxidase. Potential role of procollagen C-proteinase. Journal of Biological Chemistry, 271(12), 7113–7119.

    Article  PubMed  CAS  Google Scholar 

  69. Nellaiappan, K., et al. (2000). Fully processed lysyl oxidase catalyst translocates from the extracellular space into nuclei of aortic smooth-muscle cells. Journal of Cell Biochemistry, 79(4), 576–582.

    Article  CAS  Google Scholar 

  70. Kagan, H. M., & Li, W. (2003). Lysyl oxidase: Properties, specificity, and biological roles inside and outside of the cell. Journal of Cell Biochemistry, 88(4), 660–672.

    Article  CAS  Google Scholar 

  71. Kagan, H. M., et al. (1983). Histone H1 is a substrate for lysyl oxidase and contains endogenous sodium borotritide-reducible residues. Biochemical and Biophysical Research Communications, 115(1), 186–192.

    Article  PubMed  CAS  Google Scholar 

  72. Giampuzzi, M., Oleggini, R., & Di Donato, A. (2003). Demonstration of in vitro interaction between tumor suppressor lysyl oxidase and histones H1 and H2: Definition of the regions involved. Biochimica et Biophysica Acta, 1647(1–2), 245–251.

    PubMed  CAS  Google Scholar 

  73. Warburton, D., & Shi, W. (2005). Lo, and the niche is knit: Lysyl oxidase activity and maintenance of lung, aorta, and skin integrity. American Journal of Pathology, 167(4), 921–922.

    PubMed  CAS  Google Scholar 

  74. Maki, J. M., et al. (2005). Lysyl oxidase is essential for normal development and function of the respiratory system and for the integrity of elastic and collagen fibers in various tissues. American Journal of Pathology, 167(4), 927–936.

    PubMed  CAS  Google Scholar 

  75. Maki, J. M., et al. (2002). Inactivation of the lysyl oxidase gene Lox leads to aortic aneurysms, cardiovascular dysfunction, and perinatal death in mice. Circulation, 106(19), 2503–2509.

    Article  PubMed  CAS  Google Scholar 

  76. Hornstra, I. K., et al. (2003). Lysyl oxidase is required for vascular and diaphragmatic development in mice. Journal of Biology Chemistry, 278(16), 14387–14393.

    Article  CAS  Google Scholar 

  77. Hayashi, K., et al. (2004). Comparative immunocytochemical localization of lysyl oxidase (LOX) and the lysyl oxidase-like (LOXL) proteins: Changes in the expression of LOXL during development and growth of mouse tissues. Journal of Molecular Histology, 35(8–9), 845–855.

    Article  PubMed  CAS  Google Scholar 

  78. Kagan, H. M., et al. (1986). Ultrastructural immunolocalization of lysyl oxidase in vascular connective tissue. Journal of Cell Biology, 103(3), 1121–1128.

    Article  PubMed  CAS  Google Scholar 

  79. Sakai, M., et al. (2009). Expression of lysyl oxidase is correlated with lymph node metastasis and poor prognosis in esophageal squamous cell carcinoma. Annals of Surgical Oncology, 16(9), 2494–2501.

    Article  PubMed  Google Scholar 

  80. Albinger-Hegyi, A., et al. (2009). Lysyl oxidase expression is an independent marker of prognosis and a predictor of lymph node metastasis in oral and oropharyngeal squamous cell carcinoma (OSCC). International Journal of Cancer, 126(11), 2653–2662.

    Google Scholar 

  81. Le, Q. T., et al. (2009). Validation of lysyl oxidase as a prognostic marker for metastasis and survival in head and neck squamous cell carcinoma: Radiation Therapy Oncology Group trial 90-03. Journal of Clinical Oncology, 27(26), 4281–4286.

    Article  PubMed  CAS  Google Scholar 

  82. Erler, J. T., & Giaccia, A. J. (2006). Lysyl oxidase mediates hypoxic control of metastasis. Cancer Research, 66(21), 10238–10241.

    Article  PubMed  CAS  Google Scholar 

  83. Kirschmann, D. A., et al. (2002). A molecular role for lysyl oxidase in breast cancer invasion. Cancer Research, 62(15), 4478–4483.

    PubMed  CAS  Google Scholar 

  84. Giampuzzi, M., et al. (2005). Beta-catenin signaling and regulation of cyclin D1 promoter in NRK-49F cells transformed by down-regulation of the tumor suppressor lysyl oxidase. Biochimica et Biophysica Acta, 1745(3), 370–381.

    PubMed  CAS  Google Scholar 

  85. Peinado, H., et al. (2005). A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO Journal, 24(19), 3446–3458.

    Article  PubMed  CAS  Google Scholar 

  86. Higgins, D. F., et al. (2004). Hypoxic induction of Ctgf is directly mediated by Hif-1. American Journal of Physiology. Renal Physiology, 287(6), F1223–F1232.

    Article  PubMed  CAS  Google Scholar 

  87. Bork, P. (1993). The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Letters, 327(2), 125–130.

    Article  PubMed  CAS  Google Scholar 

  88. Wenger, C., et al. (1999). Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells. Oncogene, 18(4), 1073–1080.

    Article  PubMed  CAS  Google Scholar 

  89. Xie, D., et al. (2004). Levels of expression of CYR61 and CTGF are prognostic for tumor progression and survival of individuals with gliomas. Clinical Cancer Research, 10(6), 2072–2081.

    Article  PubMed  CAS  Google Scholar 

  90. Kubo, M., et al. (1998). Expression of fibrogenic cytokines in desmoplastic malignant melanoma. British Journal of Dermatology, 139(2), 192–197.

    Article  PubMed  CAS  Google Scholar 

  91. Shimo, T., et al. (2001). Connective tissue growth factor as a major angiogenic agent that is induced by hypoxia in a human breast cancer cell line. Cancer Letters, 174(1), 57–64.

    Article  PubMed  CAS  Google Scholar 

  92. Hartel, M., et al. (2004). Desmoplastic reaction influences pancreatic cancer growth behavior. World Journal of Surgery, 28(8), 818–825.

    Article  PubMed  Google Scholar 

  93. Bennewith, K. L., et al. (2009). The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth. Cancer Research, 69(3), 775–784.

    Article  PubMed  CAS  Google Scholar 

  94. Dornhofer, N., et al. (2006). Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis. Cancer Research, 66(11), 5816–5827.

    Article  PubMed  Google Scholar 

  95. Dammeier, J., et al. (1998). Connective tissue growth factor: A novel regulator of mucosal repair and fibrosis in inflammatory bowel disease? International Journal of Biochemistry and Cell Biology, 30(8), 909–922.

    Article  PubMed  CAS  Google Scholar 

  96. Igarashi, A., et al. (1996). Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders. Journal of Investigative Dermatology, 106(4), 729–733.

    Article  PubMed  CAS  Google Scholar 

  97. Ito, Y., et al. (1998). Expression of connective tissue growth factor in human renal fibrosis. Kidney International, 53(4), 853–861.

    Article  PubMed  CAS  Google Scholar 

  98. Kondo, S., et al. (2002). Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases. Carcinogenesis, 23(5), 769–776.

    Article  PubMed  CAS  Google Scholar 

  99. Koliopanos, A., et al. (2002). Connective tissue growth factor gene expression alters tumor progression in esophageal cancer. World Journal of Surgery, 26(4), 420–427.

    Article  PubMed  Google Scholar 

  100. Shakunaga, T., et al. (2000). Expression of connective tissue growth factor in cartilaginous tumors. Cancer, 89(7), 1466–1473.

    Article  PubMed  CAS  Google Scholar 

  101. Kuper, H., Adami, H. O., & Trichopoulos, D. (2000). Infections as a major preventable cause of human cancer. Journal of Internal Medicine, 248(3), 171–183.

    Article  PubMed  CAS  Google Scholar 

  102. Pisani, P., et al. (1997). Cancer and infection: Estimates of the attributable fraction in 1990. Cancer Epidemiology, Biomarkers and Prevention, 6(6), 387–400.

    PubMed  CAS  Google Scholar 

  103. Coussens, L. M., & Werb, Z. (2002). Inflammation and cancer. Nature, 420(6917), 860–867.

    Article  PubMed  CAS  Google Scholar 

  104. Wu, Y., & Zhou, B. P. (2010). TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion. British Journal of Cancer, 102(4), 639–644.

    Article  PubMed  CAS  Google Scholar 

  105. Schoppmann, S. F., et al. (2002). Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. American Journal of Pathology, 161(3), 947–956.

    PubMed  CAS  Google Scholar 

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Acknowledgments

Due to the broad scope of this review, we apologize to anyone we failed to cite. This work was supported by the National Institutes of Health (RO1 CA-116685, PO1 CA-67166, and T32 CA121940 to E.C.F and to A.J.G.).

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  1. Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA, USA

    Elizabeth C. Finger & Amato J. Giaccia

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Finger, E.C., Giaccia, A.J. Hypoxia, inflammation, and the tumor microenvironment in metastatic disease. Cancer Metastasis Rev 29, 285–293 (2010). https://doi.org/10.1007/s10555-010-9224-5

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