Skip to main content
SpringerLink
Log in

The Role of the Tumor Microenvironment in Regulating Angiogenesis

  • Chapter
  • First Online:
Biomarkers of the Tumor Microenvironment

Abstract

The tumor microenvironment plays a crucial role in cancer development and progression. Paracrine signaling between tumor cells and the nonneoplastic, genetically normal, cells that make up the microenvironment is a critical component influencing the progression of tumors from the in situ stage to metastatic disease. Despite the importance of these paracrine signaling mechanisms and factors, the vast majority of academic research and development in the pharmaceutical industry is still targeted toward mutations and aberrant signaling pathways within tumor cells. As a result, the intercellular signaling between tumor cells and the microenvironment has not been as extensively studied with regard to the regulation of angiogenesis. In this chapter we define the key players in the regulation of angiogenesis and examine how their expression is regulated in the microenvironment. The resulting analysis presents observations that at first glance may seem paradoxical. However, these nuances serve to underscore the complexity of interactions and the need to better delineate and define the environmental context underlying these mechanisms.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  2. Ronnov-Jessen L, Petersen OW, Bissell MJ. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev. 1996;76(1):69–125.

    Article  CAS  PubMed  Google Scholar 

  3. Chung LW, Davies R. Prostate epithelial differentiation is dictated by its surrounding stroma. Mol Biol Rep. 1996;23(1):13–9.

    Article  CAS  PubMed  Google Scholar 

  4. Tuxhorn JA, Ayala GE, Rowley DR. Reactive stroma in prostate cancer progression. J Urol. 2001;166(6):2472–83.

    Article  CAS  PubMed  Google Scholar 

  5. Henshall SM, et al. Altered expression of androgen receptor in the malignant epithelium and adjacent stroma is associated with early relapse in prostate cancer. Cancer Res. 2001;61(2):423–7.

    CAS  PubMed  Google Scholar 

  6. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86(3):353–64.

    Article  CAS  PubMed  Google Scholar 

  7. Camps JL, et al. Fibroblast-mediated acceleration of human epithelial tumor growth in vivo. Proc Natl Acad Sci U S A. 1990;87(1):75–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Grey AM, et al. Purification of the migration stimulating factor produced by fetal and breast cancer patient fibroblasts. Proc Natl Acad Sci U S A. 1989;86(7):2438–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Picard O, Rolland Y, Poupon MF. Fibroblast-dependent tumorigenicity of cells in nude mice: implication for implantation of metastases. Cancer Res. 1986;46(7):3290–4.

    CAS  PubMed  Google Scholar 

  10. Olumi AF, et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999;59(19):5002–11.

    CAS  PubMed  Google Scholar 

  11. Hom YK, et al. Uterine and vaginal organ growth requires epidermal growth factor receptor signaling from stroma. Endocrinology. 1998;139(3):913–21.

    Article  CAS  PubMed  Google Scholar 

  12. Donjacour AA, Cunha GR. Stromal regulation of epithelial function. Cancer Treat Res. 1991;53:335–64.

    Article  CAS  PubMed  Google Scholar 

  13. Cunha GR, et al. Stromal-epithelial interactions in adult organs. Cell Differ. 1985;17(3):137–48.

    Article  CAS  PubMed  Google Scholar 

  14. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.

    Article  CAS  PubMed  Google Scholar 

  15. Akiyama H, et al. Induction of VEGF gene expression by retinoic acid through Sp1-binding sites in retinoblastoma Y79 cells. Invest Ophthalmol Vis Sci. 2002;43(5):1367–74.

    PubMed  Google Scholar 

  16. Damert A, Ikeda E, Risau W. Activator-protein-1 binding potentiates the hypoxia-induciblefactor-1-mediated hypoxia-induced transcriptional activation of vascular-endothelial growth factor expression in C6 glioma cells. Biochem J. 1997;327(Pt 2):419–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rak J, et al. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res. 1995;55(20):4575–80.

    CAS  PubMed  Google Scholar 

  18. Wojta J, et al. Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells. Lab Investig. 1999;79(4):427–38.

    CAS  PubMed  Google Scholar 

  19. Xiong S, et al. Up-regulation of vascular endothelial growth factor in breast cancer cells by the heregulin-beta1-activated p38 signaling pathway enhances endothelial cell migration. Cancer Res. 2001;61(4):1727–32.

    CAS  PubMed  Google Scholar 

  20. Watnick R, et al. Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell. 2003;3(3):219–31.

    Article  CAS  PubMed  Google Scholar 

  21. Rak J, et al. Oncogenes and tumor angiogenesis: differential modes of vascular endothelial growth factor up-regulation in ras-transformed epithelial cells and fibroblasts. Cancer Res. 2000;60(2):490–8.

    CAS  PubMed  Google Scholar 

  22. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2(8):563–72.

    Article  CAS  PubMed  Google Scholar 

  23. Pettaway CA, et al. Selection of highly metastatic variants of different human prostatic carcinomas using orthotopic implantation in nude mice. Clin Cancer Res. 1996;2(9):1627–36.

    CAS  PubMed  Google Scholar 

  24. Leung DW, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306–9.

    Article  CAS  PubMed  Google Scholar 

  25. Senger DR, et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219(4587):983–5.

    Article  CAS  PubMed  Google Scholar 

  26. Brogi E, et al. Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. Circulation. 1994;90(2):649–52.

    Article  CAS  PubMed  Google Scholar 

  27. Tsai JC, Goldman CK, Gillespie GY. Vascular endothelial growth factor in human glioma cell lines: induced secretion by EGF, PDGF-BB, and bFGF. J Neurosurg. 1995;82(5):864–73.

    Article  CAS  PubMed  Google Scholar 

  28. Fukumura D, et al. Tumor induction of VEGF promoter activity in stromal cells. Cell. 1998;94(6):715–25.

    Article  CAS  PubMed  Google Scholar 

  29. Kim KJ, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362(6423):841–4.

    Article  CAS  PubMed  Google Scholar 

  30. Gerber HP, et al. Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res. 2000;60(22):6253–8.

    CAS  PubMed  Google Scholar 

  31. Folkman J, Klagsbrun M. Angiogenic factors. Science. 1987;235(4787):442–7.

    Article  CAS  PubMed  Google Scholar 

  32. Shing Y, et al. Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor. Science. 1984;223(4642):1296–9.

    Article  CAS  PubMed  Google Scholar 

  33. Klagsbrun M, et al. Human tumor cells synthesize an endothelial cell growth factor that is structurally related to basic fibroblast growth factor. Proc Natl Acad Sci U S A. 1986;83(8):2448–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dionne CA, et al. Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors. EMBO J. 1990;9(9):2685–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Abraham JA, et al. Human basic fibroblast growth factor: nucleotide sequence and genomic organization. EMBO J. 1986;5(10):2523–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Abraham JA, et al. Nucleotide sequence of a bovine clone encoding the angiogenic protein, basic fibroblast growth factor. Science. 1986;233(4763):545–8.

    Article  CAS  PubMed  Google Scholar 

  37. Rogelj S, et al. Characterization of tumors produced by signal peptide-basic fibroblast growth factor-transformed cells. J Cell Biochem. 1989;39(1):13–23.

    Article  CAS  PubMed  Google Scholar 

  38. Rogelj S, et al. Basic fibroblast growth factor fused to a signal peptide transforms cells. Nature. 1988;331(6152):173–5.

    Article  CAS  PubMed  Google Scholar 

  39. Gleave M, et al. Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts. Cancer Res. 1991;51(14):3753–61.

    CAS  PubMed  Google Scholar 

  40. Guddo F, et al. The expression of basic fibroblast growth factor (bFGF) in tumor-associated stromal cells and vessels is inversely correlated with non-small cell lung cancer progression. Hum Pathol. 1999;30(7):788–94.

    Article  CAS  PubMed  Google Scholar 

  41. Qu Z, et al. Synthesis of basic fibroblast growth factor by murine mast cells. Regulation by transforming growth factor beta, tumor necrosis factor alpha, and stem cell factor. Int Arch Allergy Immunol. 1998;115(1):47–54.

    Article  CAS  PubMed  Google Scholar 

  42. Roberts AB, et al. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986;83(12):4167–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Baird A, Durkin T. Inhibition of endothelial cell proliferation by type beta-transforming growth factor: interactions with acidic and basic fibroblast growth factors. Biochem Biophys Res Commun. 1986;138(1):476–82.

    Article  CAS  PubMed  Google Scholar 

  44. Frater-Schroder M, et al. Transforming growth factor-beta inhibits endothelial cell proliferation. Biochem Biophys Res Commun. 1986;137(1):295–302.

    Article  CAS  PubMed  Google Scholar 

  45. Pertovaara L, et al. Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem. 1994;269(9):6271–4.

    CAS  PubMed  Google Scholar 

  46. Goldsmith KT, Gammon RB, Garver RI Jr. Modulation of bFGF in lung fibroblasts by TGF-beta and PDGF. Am J Phys. 1991;261(6 Pt 1):L378–85.

    CAS  Google Scholar 

  47. Murphy-Ullrich JE, Schultz-Cherry S, Hook M. Transforming growth factor-beta complexes with thrombospondin. Mol Biol Cell. 1992;3(2):181–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Penttinen RP, Kobayashi S, Bornstein P. Transforming growth factor beta increases mRNA for matrix proteins both in the presence and in the absence of changes in mRNA stability. Proc Natl Acad Sci U S A. 1988;85(4):1105–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Schultz-Cherry S, Lawler J, Murphy-Ullrich JE. The type 1 repeats of thrombospondin 1 activate latent transforming growth factor-beta. J Biol Chem. 1994;269(43):26783–8.

    CAS  PubMed  Google Scholar 

  50. Schultz_Cherry S, Murphy_Ullrich JE. Thrombospondin causes activation of latent transforming growth factor-beta secreted by endothelial cells by a novel mechanism. J Cell Biol. 1993;122(4):923–32.

    Article  CAS  PubMed  Google Scholar 

  51. Schultz_Cherry S, et al. Thrombospondin binds and activates the small and large forms of latent transforming growth factor-beta in a chemically defined system. J Biol Chem. 1994;269(43):26775–82.

    CAS  PubMed  Google Scholar 

  52. Falanga V, et al. Hypoxia upregulates the synthesis of TGF-beta 1 by human dermal fibroblasts. J Invest Dermatol. 1991;97(4):634–7.

    Article  CAS  PubMed  Google Scholar 

  53. Dong J, et al. VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis. EMBO J. 2004;23(14):2800–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Majack RA, Mildbrandt J, Dixit VM. Induction of thrombospondin messenger RNA levels occurs as an immediate primary response to platelet-derived growth factor. J Biol Chem. 1987;262(18):8821–5.

    CAS  PubMed  Google Scholar 

  55. Majack RA, Cook SC, Bornstein P. Platelet-derived growth factor and heparin-like glycosaminoglycans regulate thrombospondin synthesis and deposition in the matrix by smooth muscle cells. J Cell Biol. 1985;101(3):1059–70.

    Article  CAS  PubMed  Google Scholar 

  56. Chang HJ, et al. Extracellular signal-regulated kinases and AP-1 mediate the up-regulation of vascular endothelial growth factor by PDGF in human vascular smooth muscle cells. Int J Oncol. 2006;28(1):135–41.

    CAS  PubMed  Google Scholar 

  57. Sengupta K, et al. Thombospondin-1 disrupts estrogen-induced endothelial cell proliferation and migration and its expression is suppressed by estradiol. Mol Cancer Res. 2004;2(3):150–8.

    CAS  PubMed  Google Scholar 

  58. Colombel M, et al. Androgens repress the expression of the angiogenesis inhibitor thrombospondin-1 in normal and neoplastic prostate. Cancer Res. 2005;65(1):300–8.

    CAS  PubMed  Google Scholar 

  59. Gupta PB, et al. Systemic stromal effects of estrogen promote the growth of estrogen receptor-negative cancers. Cancer Res. 2007;67(5):2062–71.

    Article  CAS  PubMed  Google Scholar 

  60. Kaipainen A, et al. PPARalpha deficiency in inflammatory cells suppresses tumor growth. PLoS One. 2007;2(2):e260.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Panigrahy D, et al. PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition. Proc Natl Acad Sci U S A. 2008;105(3):985–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Han J, et al. Transforming growth factor-beta1 (TGF-beta1) and TGF-beta2 decrease expression of CD36, the type B scavenger receptor, through mitogen-activated protein kinase phosphorylation of peroxisome proliferator-activated receptor-gamma. J Biol Chem. 2000;275(2):1241–6.

    Article  CAS  PubMed  Google Scholar 

  63. Aljada A, et al. PPAR gamma ligands, rosiglitazone and pioglitazone, inhibit bFGF- and VEGF-mediated angiogenesis. Angiogenesis. 2008;11(4):361–7.

    Article  CAS  PubMed  Google Scholar 

  64. Noel A, et al. Enhancement of tumorigenicity of human breast adenocarcinoma cells in nude mice by matrigel and fibroblasts. Br J Cancer. 1993;68(5):909–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Noel A, et al. Inhibition of stromal matrix metalloproteases: effects on breast-tumor promotion by fibroblasts. Int J Cancer. 1998;76(2):267–73.

    Article  CAS  PubMed  Google Scholar 

  66. Bergers G, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol. 2000;2(10):737–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14(2):163–76.

    PubMed  PubMed Central  Google Scholar 

  68. Dawson DW, et al. CD36 mediates the in vitro inhibitory effects of thrombospondin-1 on endothelial cells. J Cell Biol. 1997;138(3):707–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Saumet A, et al. Type 3 repeat/C-terminal domain of thrombospondin-1 triggers caspase-independent cell death through CD47/alphavbeta3 in promyelocytic leukemia NB4 cells. Blood. 2005;106(2):658–67.

    Article  CAS  PubMed  Google Scholar 

  70. Lamy L, et al. Interactions between CD47 and thrombospondin reduce inflammation. J Immunol. 2007;178(9):5930–9.

    Article  CAS  PubMed  Google Scholar 

  71. Henkin J, Volpert OV. Therapies using anti-angiogenic peptide mimetics of thrombospondin-1. Expert Opin Ther Targets. 2011;15(12):1369–86.

    Article  CAS  PubMed  Google Scholar 

  72. Rodriguez_Manzaneque JC, et al. Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci U S A. 2001;98(22):12485–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Watnick RS, et al. Thrombospondin-1 repression is mediated via distinct mechanisms in fibroblasts and epithelial cells. Oncogene. 2015;34(22):2823–35.

    Article  CAS  PubMed  Google Scholar 

  74. Li W, et al. GRK3 is essential for metastatic cells and promotes prostate tumor progression. Proc Natl Acad Sci U S A. 2014;111(4):1521–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Brown LF, et al. Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast. Clin Cancer Res. 1999;5(5):1041–56.

    CAS  PubMed  Google Scholar 

  76. Mueller MM, Fusenig NE. Tumor-stroma interactions directing phenotype and progression of epithelial skin tumor cells. Differentiation. 2002;70(9–10):486–97.

    Article  PubMed  Google Scholar 

  77. Streit M, et al. Overexpression of thrombospondin-1 decreases angiogenesis and inhibits the growth of human cutaneous squamous cell carcinomas. Am J Pathol. 1999;155(2):441–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wong SY, Purdie AT, Han P. Thrombospondin and other possible related matrix proteins in malignant and benign breast disease. An immunohistochemical study. Am J Pathol. 1992;140(6):1473–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Bertin N, et al. Thrombospondin-1 and -2 messenger RNA expression in normal, benign, and neoplastic human breast tissues: correlation with prognostic factors, tumor angiogenesis, and fibroblastic desmoplasia. Cancer Res. 1997;57(3):396–9.

    CAS  PubMed  Google Scholar 

  80. Clezardin P, et al. Expression of thrombospondin (TSP1) and its receptors (CD36 and CD51) in normal, hyperplastic, and neoplastic human breast. Cancer Res. 1993;53(6):1421–30.

    CAS  PubMed  Google Scholar 

  81. Filleur S, et al. In vivo mechanisms by which tumors producing thrombospondin 1 bypass its inhibitory effects. Genes Dev. 2001;15(11):1373–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kalas W, Klement P, Rak J. Downregulation of the angiogenesis inhibitor thrombospondin 1 in fibroblasts exposed to platelets and their related phospholipids. Biochem Biophys Res Commun. 2005;334(2):549–54.

    Article  CAS  PubMed  Google Scholar 

  83. Kalas W, et al. Oncogenes and Angiogenesis: down-regulation of thrombospondin-1 in normal fibroblasts exposed to factors from cancer cells harboring mutant ras. Cancer Res. 2005;65(19):8878–86.

    Article  CAS  PubMed  Google Scholar 

  84. Elenbaas B, Weinberg RA. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res. 2001;264(1):169–84.

    Article  CAS  PubMed  Google Scholar 

  85. Durning P, Schor SL, Sellwood RA. Fibroblasts from patients with breast cancer show abnormal migratory behaviour in vitro. Lancet. 1984;2(8408):890–2.

    Article  CAS  PubMed  Google Scholar 

  86. Schor SL, et al. Foetal and cancer patient fibroblasts produce an autocrine migration-stimulating factor not made by normal adult cells. J Cell Sci. 1988;90(Pt 3):391–9.

    CAS  PubMed  Google Scholar 

  87. Schor SL, Schor AM, Rushton G. Fibroblasts from cancer patients display a mixture of both foetal and adult-like phenotypic characteristics. J Cell Sci. 1988;90(Pt 3):401–7.

    PubMed  Google Scholar 

  88. Tsukada T, et al. HHF35, a muscle actin-specific monoclonal antibody. II. Reactivity in normal, reactive, and neoplastic human tissues. Am J Pathol. 1987;127(2):389–402.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Normanno N, et al. Expression of messenger RNA for amphiregulin, heregulin, and cripto-1, three new members of the epidermal growth factor family, in human breast carcinomas. Breast Cancer Res Treat. 1995;35(3):293–7.

    Article  CAS  PubMed  Google Scholar 

  90. Panico L, et al. Differential immunohistochemical detection of transforming growth factor alpha, amphiregulin and CRIPTO in human normal and malignant breast tissues. Int J Cancer. 1996;65(1):51–6.

    Article  CAS  PubMed  Google Scholar 

  91. Jin L, et al. Expression of scatter factor and c-met receptor in benign and malignant breast tissue. Cancer. 1997;79(4):749–60.

    Article  CAS  PubMed  Google Scholar 

  92. Montesano R, Schaller G, Orci L. Induction of epithelial tubular morphogenesis in vitro by fibroblast-derived soluble factors. Cell. 1991;66(4):697–711.

    Article  CAS  PubMed  Google Scholar 

  93. Seslar SP, Nakamura T, Byers SW. Regulation of fibroblast hepatocyte growth factor/scatter factor expression by human breast carcinoma cell lines and peptide growth factors. Cancer Res. 1993;53(6):1233–8.

    CAS  PubMed  Google Scholar 

  94. To CT, Tsao MS. The roles of hepatocyte growth factor/scatter factor and met receptor in human cancers (Review). Oncol Rep. 1998;5(5):1013–24.

    CAS  PubMed  Google Scholar 

  95. Vande Woude GF, et al. Met-HGF/SF: tumorigenesis, invasion and metastasis. In: Ciba foundation symposium, vol. 212; 1997. p. 119–30. discussion 130–2, 148–54.

    Google Scholar 

  96. Cullen KJ, et al. Insulin-like growth factor expression in breast cancer epithelium and stroma. Breast Cancer Res Treat. 1992;22(1):21–9.

    Article  CAS  PubMed  Google Scholar 

  97. Ellis MJ, et al. Insulin-like growth factor mediated stromal-epithelial interactions in human breast cancer. Breast Cancer Res Treat. 1994;31(2–3):249–61.

    Article  CAS  PubMed  Google Scholar 

  98. Yee D, et al. Analysis of insulin-like growth factor I gene expression in malignancy: evidence for a paracrine role in human breast cancer. Mol Endocrinol. 1989;3(3):509–17.

    Article  CAS  PubMed  Google Scholar 

  99. Basset P, et al. A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature. 1990;348(6303):699–704.

    Article  CAS  PubMed  Google Scholar 

  100. Basset P, et al. Stromelysin-3 in stromal tissue as a control factor in breast cancer behavior. Cancer. 1994;74(3 Suppl):1045–9.

    Article  CAS  PubMed  Google Scholar 

  101. Chambers AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst. 1997;89(17):1260–70.

    Article  CAS  PubMed  Google Scholar 

  102. Engel G, et al. Correlation between stromelysin-3 mRNA level and outcome of human breast cancer. Int J Cancer. 1994;58(6):830–5.

    Article  CAS  PubMed  Google Scholar 

  103. Heppner KJ, et al. Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol. 1996;149(1):273–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Lochter A, et al. The significance of matrix metalloproteinases during early stages of tumor progression. Ann N Y Acad Sci. 1998;857:180–93.

    Article  CAS  PubMed  Google Scholar 

  105. Masson R, et al. In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy. J Cell Biol. 1998;140(6):1535–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. McCawley LJ, Matrisian LM. Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today. 2000;6(4):149–56.

    Article  CAS  PubMed  Google Scholar 

  107. Newell KJ, et al. Expression and localization of matrix-degrading metalloproteinases during colorectal tumorigenesis. Mol Carcinog. 1994;10(4):199–206.

    Article  CAS  PubMed  Google Scholar 

  108. Wolf C, et al. Stromelysin 3 belongs to a subgroup of proteinases expressed in breast carcinoma fibroblastic cells and possibly implicated in tumor progression. Proc Natl Acad Sci U S A. 1993;90(5):1843–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sappino AP, et al. Smooth-muscle differentiation in stromal cells of malignant and non-malignant breast tissues. Int J Cancer. 1988;41(5):707–12.

    Article  CAS  PubMed  Google Scholar 

  110. Ronnov-Jessen L, Petersen OW. Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab Investig. 1993;68(6):696–707.

    CAS  PubMed  Google Scholar 

  111. Orimo A, Weinberg RA. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle. 2006;5(15):1597–601.

    Article  CAS  PubMed  Google Scholar 

  112. Orimo A, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121(3):335–48.

    Article  CAS  PubMed  Google Scholar 

  113. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    Article  CAS  PubMed  Google Scholar 

  114. Chiquet-Ehrismann R, et al. Tenascin: an extracellular matrix protein involved in tissue interactions during fetal development and oncogenesis. Cell. 1986;47(1):131–9.

    Article  CAS  PubMed  Google Scholar 

  115. Inaguma Y, et al. Epithelial induction of stromal tenascin in the mouse mammary gland: from embryogenesis to carcinogenesis. Dev Biol. 1988;128(2):245–55.

    Article  CAS  PubMed  Google Scholar 

  116. Brunner A, et al. Prognostic significance of tenascin-C expression in superficial and invasive bladder cancer. J Clin Pathol. 2004;57(9):927–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Mackie EJ, et al. Tenascin is a stromal marker for epithelial malignancy in the mammary gland. Proc Natl Acad Sci U S A. 1987;84(13):4621–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Brown EB, et al. Measurement of macromolecular diffusion coefficients in human tumors. Microvasc Res. 2004;67(3):231–6.

    Article  CAS  PubMed  Google Scholar 

  119. Netti PA, et al. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 2000;60(9):2497–503.

    CAS  PubMed  Google Scholar 

  120. Grum-Schwensen B, et al. Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene. Cancer Res. 2005;65(9):3772–80.

    Article  CAS  PubMed  Google Scholar 

  121. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539–45.

    Article  CAS  PubMed  Google Scholar 

  122. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell. 2005;7(3):211–7.

    Article  CAS  PubMed  Google Scholar 

  123. Mantovani A, et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677–86.

    Article  CAS  PubMed  Google Scholar 

  124. Sher A, Pearce E, Kaye P. Shaping the immune response to parasites: role of dendritic cells. Curr Opin Immunol. 2003;15(4):421–9.

    Article  CAS  PubMed  Google Scholar 

  125. Goerdt S, Orfanos CE. Other functions, other genes: alternative activation of antigen-presenting cells. Immunity. 1999;10(2):137–42.

    Article  CAS  PubMed  Google Scholar 

  126. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23–35.

    Article  CAS  PubMed  Google Scholar 

  127. Mantovani A, et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549–55.

    Article  CAS  PubMed  Google Scholar 

  128. Mosser DM. The many faces of macrophage activation. J Leukoc Biol. 2003;73(2):209–12.

    Article  CAS  PubMed  Google Scholar 

  129. Crowther M, et al. Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors. J Leukoc Biol. 2001;70(4):478–90.

    CAS  PubMed  Google Scholar 

  130. Dong Z, et al. Angiostatin-mediated suppression of cancer metastases by primary neoplasms engineered to produce granulocyte/macrophage colony-stimulating factor. J Exp Med. 1998;188(4):755–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Dong Z, et al. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell. 1997;88(6):801–10.

    Article  CAS  PubMed  Google Scholar 

  132. O’Reilly MS, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994;79(2):315–28.

    Article  PubMed  Google Scholar 

  133. Norrby K. Mast cells and angiogenesis. APMIS. 2002;110(5):355–71.

    Article  CAS  PubMed  Google Scholar 

  134. Kirshenbaum AS, et al. Demonstration that human mast cells arise from a progenitor cell population that is CD34(+), c-kit(+), and expresses aminopeptidase N (CD13). Blood. 1999;94(7):2333–42.

    CAS  PubMed  Google Scholar 

  135. Matrisian LM. Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet. 1990;6(4):121–5.

    Article  CAS  PubMed  Google Scholar 

  136. Tazzyman S, Lewis CE, Murdoch C. Neutrophils: key mediators of tumour angiogenesis. Int J Exp Pathol. 2009;90(3):222–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Coussens LM, et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 1999;13(11):1382–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Coussens LM, et al. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell. 2000;103(3):481–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Gruber BL, Marchese MJ, Kew R. Angiogenic factors stimulate mast-cell migration. Blood. 1995;86(7):2488–93.

    CAS  PubMed  Google Scholar 

  140. Gruber BL, Marchese MJ, Kew RR. Transforming growth factor-beta 1 mediates mast cell chemotaxis. J Immunol. 1994;152(12):5860–7.

    CAS  PubMed  Google Scholar 

  141. Soucek L, et al. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med. 2007;13(10):1211–8.

    Article  CAS  PubMed  Google Scholar 

  142. Pittenger MF, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7.

    Article  CAS  PubMed  Google Scholar 

  143. Civin CI, et al. Highly purified CD34-positive cells reconstitute hematopoiesis. J Clin Oncol. 1996;14(8):2224–33.

    Article  CAS  PubMed  Google Scholar 

  144. Dennis JE, Charbord P. Origin and differentiation of human and murine stroma. Stem Cells. 2002;20(3):205–14.

    Article  CAS  PubMed  Google Scholar 

  145. Hall B, Andreeff M, Marini F. The participation of mesenchymal stem cells in tumor stroma formation and their application as targeted-gene delivery vehicles. Handb Exp Pharmacol. 2007;180:263–83.

    Article  CAS  Google Scholar 

  146. Schichor C, et al. Vascular endothelial growth factor A contributes to glioma-induced migration of human marrow stromal cells (hMSC). Exp Neurol. 2006;199(2):301–10.

    Article  CAS  PubMed  Google Scholar 

  147. Birnbaum T, et al. Malignant gliomas actively recruit bone marrow stromal cells by secreting angiogenic cytokines. J Neuro-Oncol. 2007;83(3):241–7.

    Article  CAS  Google Scholar 

  148. Kidd S, et al. The (in) auspicious role of mesenchymal stromal cells in cancer: be it friend or foe. Cytotherapy. 2008;10(7):657–67.

    Article  CAS  PubMed  Google Scholar 

  149. Spaeth E, et al. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther. 2008;15(10):730–8.

    Article  CAS  PubMed  Google Scholar 

  150. Dwyer RM, et al. Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin Cancer Res. 2007;13(17):5020–7.

    Article  CAS  PubMed  Google Scholar 

  151. Coffelt SB, et al. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells. Proc Natl Acad Sci U S A. 2009;106(10):3806–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Sun B, et al. Correlation between melanoma angiogenesis and the mesenchymal stem cells and endothelial progenitor cells derived from bone marrow. Stem Cells Dev. 2005;14(3):292–8.

    Article  CAS  PubMed  Google Scholar 

  153. Beckermann BM, et al. VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma. Br J Cancer. 2008;99(4):622–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Suratt BT, et al. Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis. Blood. 2004;104(2):565–71.

    Article  CAS  PubMed  Google Scholar 

  155. Friedman AD. Transcriptional regulation of granulocyte and monocyte development. Oncogene. 2002;21(21):3377–90.

    Article  CAS  PubMed  Google Scholar 

  156. Kanwar VS, Cairo MS. Neonatal neutrophil maturation, kinetics, and function. In: Abramson JS, Wheeler JG, editors. The Neutrophil. New York: Oxford University Press; 1993. p. 1–16.

    Google Scholar 

  157. Steele RW, et al. Functional capacity of marginated and bone marrow reserve granulocytes. Infect Immun. 1987;55(10):2359–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Suwa T, et al. Interleukin-6 induces demargination of intravascular neutrophils and shortens their transit in marrow. Am J Physiol Heart Circ Physiol. 2000;279(6):H2954–60.

    Article  CAS  PubMed  Google Scholar 

  159. Bellocq A, et al. Neutrophil alveolitis in bronchioloalveolar carcinoma: induction by tumor-derived interleukin-8 and relation to clinical outcome. Am J Pathol. 1998;152(1):83–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Mentzel T, et al. The association between tumour progression and vascularity in myxofibrosarcoma and myxoid/round cell liposarcoma. Virchows Arch. 2001;438(1):13–22.

    Article  CAS  PubMed  Google Scholar 

  161. Mhawech-Fauceglia P, et al. The source of APRIL up-regulation in human solid tumor lesions. J Leukoc Biol. 2006;80(4):697–704.

    Article  CAS  PubMed  Google Scholar 

  162. Nielsen BS, 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. 1996;65(1):57–62.

    Article  CAS  PubMed  Google Scholar 

  163. Xie K. Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev. 2001;12(4):375–91.

    Article  CAS  PubMed  Google Scholar 

  164. Coussens LM, Werb Z. Matrix metalloproteinases and the development of cancer. Chem Biol. 1996;3(11):895–904.

    Article  CAS  PubMed  Google Scholar 

  165. Gaudry M, et al. Intracellular pool of vascular endothelial growth factor in human neutrophils. Blood. 1997;90(10):4153–61.

    CAS  PubMed  Google Scholar 

  166. Huang S, et al. Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. J Natl Cancer Inst. 2002;94(15):1134–42.

    Article  CAS  PubMed  Google Scholar 

  167. Nozawa H, Chiu C, Hanahan D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci U S A. 2006;103(33):12493–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Clark RA, Klebanoff SJ. Neutrophil-mediated tumor cell cytotoxicity: role of the peroxidase system. J Exp Med. 1975;141(6):1442–7.

    Article  CAS  PubMed  Google Scholar 

  169. Di Carlo E, et al. The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood. 2001;97(2):339–45.

    Article  PubMed  Google Scholar 

  170. Ai S, et al. Angiogenic activity of bFGF and VEGF suppressed by proteolytic cleavage by neutrophil elastase. Biochem Biophys Res Commun. 2007;364(2):395–401.

    Article  CAS  PubMed  Google Scholar 

  171. Scapini P, et al. Generation of biologically active angiostatin kringle 1-3 by activated human neutrophils. J Immunol. 2002;168(11):5798–804.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery Vascular Biology Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Randolph S. Watnick

Authors
  1. Randolph S. Watnick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Randolph S. Watnick .

Editor information

Editors and Affiliations

  1. Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway

    Lars A. Akslen

  2. Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Randolph S. Watnick

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Watnick, R.S. (2017). The Role of the Tumor Microenvironment in Regulating Angiogenesis. In: Akslen, L., Watnick, R. (eds) Biomarkers of the Tumor Microenvironment. Springer, Cham. https://doi.org/10.1007/978-3-319-39147-2_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-39147-2_1

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-39145-8

  • Online ISBN: 978-3-319-39147-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation