Genes & Nutrition

, Volume 3, Issue 1, pp 29–34

The role of microenvironment in tumor angiogenesis



Tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion and metastasis through its provision of survival signals, secretion of growth and pro-angiogenic factors, and direct adhesion molecule interactions. This review examines its importance in the induction of an angiogenic response in tumors and in multiple myeloma. The encouraging results of pre-clinical and clinical trials in which tumors have been treated by targeting the tumor microenvironment are also discussed.


Angiogenesis Anti-angiogenesis Metastasis Microenvironment Multiple myeloma Tumor growth 


  1. 1.
    Ribatti D, Vacca A, Dammacco F (1999) The role of vascular phase in solid tumor growth: a historical review. Neoplasia 1:293–302PubMedCrossRefGoogle Scholar
  2. 2.
    Folkman J (1984) What is the role of endothelial cells in angiogenesis? Lab Invest 51:601–604PubMedGoogle Scholar
  3. 3.
    Ribatti D, Nico B, Crivellato E, Roccaro AM, Vacca A (2007) The history of angiogenic switch concept. Leukemia 21:44–52PubMedCrossRefGoogle Scholar
  4. 4.
    Leek RD, Lander RJ, Harris AL, Lewis CE (1999) Necrosis correlates with high vascular density and focal macrophages infiltration in invasive carcinoma of the breast. Br J Cancer 79:991–995PubMedCrossRefGoogle Scholar
  5. 5.
    Bingle L, Brown NJ, Lewis CE (2002) The role of tumor associated macrophages in tumor progression: implications for new anticancer therapies. J Pathol 196:254–265PubMedCrossRefGoogle Scholar
  6. 6.
    Jenkins DC, Charles IG, Thompson LL, Moss DW, Holmes LS, Baylis SA, Rhodes P, Westmore K, Emson PC, Moncada S (1995) Role of nitric oxide in tumor growth. Proc Natl Acad Sci USA 92:4392–4396PubMedCrossRefGoogle Scholar
  7. 7.
    Chambers AF, Groom AC, Mac Donald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–572PubMedCrossRefGoogle Scholar
  8. 8.
    Reading CL, Hutchins JF (1985) Carbohydrate structure in tumor immunity. Cancer Metastasis Rev 4:221–260PubMedCrossRefGoogle Scholar
  9. 9.
    Turner GA (1982) Surface properties of the metastatic cell. Invasion Metastasis 2:197–216PubMedGoogle Scholar
  10. 10.
    Hujanen ES, Terranova VP (1985) Migration of tumor cells to organ-derived chemoattractants. Cancer Res 45:3517–3521PubMedGoogle Scholar
  11. 11.
    Nicolson GL (1988a) Cancer metastasis: tumor cell and host organ properties important in metastasis to specific secondary sites. Biochim Biophys Acta 948:175–224PubMedGoogle Scholar
  12. 12.
    Nicolson GL (1988b) Organ specificity of tumor metastasis: role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites. Cancer Metastasis Rev 7:143–188PubMedCrossRefGoogle Scholar
  13. 13.
    Nicolson GL, Dulski KM (1986) Organ specificity of metastatic tumor colonization is related to organ-selective growth properties of malignant cells. Int J Cancer 38:289–294PubMedCrossRefGoogle Scholar
  14. 14.
    Fidler IJ (1986) Rationale and methods for the use of nude mice to study the biology and therapy of human cancer metastasis. Cancer Metastasis Rev 5:29–49PubMedCrossRefGoogle Scholar
  15. 15.
    Talmadge JE, Fidler IJ (1982) Cancer metastasis is selective or random depending on the parent tumour population. Nature 297:593–594PubMedCrossRefGoogle Scholar
  16. 16.
    Weiss L (1979) Dynamic aspects of cancer cell populations in metastasis. Am J Pathol 97:601–608PubMedGoogle Scholar
  17. 17.
    Greene HS, Harvey EK (1964) The relationship between the dissemination of tumor cells and the distribution of metastases. Cancer Res 24:799–811PubMedGoogle Scholar
  18. 18.
    Auerbach R, Alby L, Morrissey LW, Tu M, Joseph J (1985) Expression of organ-specific antigens on capillary endothelial cells. Microvasc Res 29:401–411PubMedCrossRefGoogle Scholar
  19. 19.
    Auerbach R, Lu WC, Pardon E, Gumkowski F, Kaminska G, Kaminski M (1987) Specificity of adhesion between murine tumor cells and capillary endothelium: an in vitro correlate of preferential metastasis in vivo. Cancer Res 47:1492–1496PubMedGoogle Scholar
  20. 20.
    Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 1:571–573CrossRefGoogle Scholar
  21. 21.
    Ribatti D, Vacca A, Dammacco F, English D (2003) Angiogenesis and anti-angiogenesis in hematological malignancies. J Hematother Stem Cell Res 12:11–22PubMedCrossRefGoogle Scholar
  22. 22.
    Vacca A, Ribatti D, Roncali L, Ranieri G, Serio G, Silvestris F, Dammacco F (1994) Bone marrow angiogenesis and progression in multiple myeloma. Br J Haematol 87:503–508PubMedCrossRefGoogle Scholar
  23. 23.
    Vacca A, Ribatti D (2006) Bone marrow angiogenesis in multiple myeloma. Leukemia 20:193–199PubMedCrossRefGoogle Scholar
  24. 24.
    Vacca A, Ria R, Ribatti D, Semeraro F, Djonov V, Di Raimondo F, Dammacco F (2003b) A paracrine loop in the vascular endothelial growth factor pathway triggers tumor angiogenesis and growth in multiple myeloma. Haematologica 88:176–185PubMedGoogle Scholar
  25. 25.
    Asosingh K, De Raeve H, Menu E, Van Riet I, Van Mark E, Van Camp B, Vanderkerken K (2004) Angiogenic swithc during 512MM murine myeloma tumorigenesis: role of CD45 heterogeneity. Blood 103:3131–3177PubMedCrossRefGoogle Scholar
  26. 26.
    Kumar S, Rajkumar SV, Kimlinger T, Greipp PR, Witzig TE (2005) CD45 expression by bone marrow plasma cells in multiple myeloma: clinical and biological correlations. Leukemia 19:1466–1470PubMedCrossRefGoogle Scholar
  27. 27.
    Kumar S, Witzig TE, Timm M, Huagg J, Welik L, Kimlinger TK, Greipp PR, Rajkumar SV (2004) Bone marrow angiogenic ability and expression of angiogenic cytokines in myeloma: evidence favoring loss of marrow angiogenesis inhibitory activity with disease progression. Blood 104:1559–1165CrossRefGoogle Scholar
  28. 28.
    Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, Porter D, Hu M, Chin L, Richardson A, Schnitt S, Sellers WR, Polyak K (2004) Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6:17–32PubMedCrossRefGoogle Scholar
  29. 29.
    Kuehl WM, Bersagel PL (2002) Multiple myeloma: evolving genetic events and host interactions. Nature Rev Cancer 2:175–187CrossRefGoogle Scholar
  30. 30.
    Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS (1999) Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 93:1658–1667PubMedGoogle Scholar
  31. 31.
    Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ, Dalton WS (2000) Adhesion to fibronectin via beta 1 integrin regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene 19:4319–4327PubMedCrossRefGoogle Scholar
  32. 32.
    Hazlehurst LA, Enkemann SA, Beam CA, Argilagos RF, Painter J, Shain KH, Saporta S, Boulware D, Moscinski L, Alsina M, Dalton WS (2003) Genotypic and phenotypic comparisons of de novo and acquired melphalan resistance in an isogenic multiple myeloma cell line model. Cancer Res 63:7900–7906PubMedGoogle Scholar
  33. 33.
    Vacca A, Ria R, Presta M, Ribatti D, Iurlaro M, Merchionne F, Tanghetti E, Dammacco F (2001) Alpha (v) beta (3) integrin engagement modulates cell adhesion, proliferation, and protease secretion in human lymphoid tumor cells. Exp Hematol 29:993–1003PubMedCrossRefGoogle Scholar
  34. 34.
    Hideshima T, Podar K, Chauhan D, Anderson KC (2005) Cytokines and signal transduction. Best Pract Res Clin Haematol 18:509–524PubMedCrossRefGoogle Scholar
  35. 35.
    Hideshima T, Nakamura N, Chauhan D, Anderson HC (2001) The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene 20:5991–6000PubMedCrossRefGoogle Scholar
  36. 36.
    Vacca A, Ribatti D, Presta M, Minischetti M, Iurlaro M, Ria R, Albini A, Bussolino F, Dammacco F (1999) Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 93:3064–3073PubMedGoogle Scholar
  37. 37.
    Borset M, Hjorth-Hansen H, Seidel C, Sundan A, Waage A (1996a) Hepatocyte growth factor and its receptor c-met in multiple myeloma. Blood 88:3998–4004PubMedGoogle Scholar
  38. 38.
    Barillé S, Aknhoundi C, Colette M, Mellerin MP, Rapp MJ, Harousseau JL, Bataille R, Amiot M (1997) Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of proMMP-2, and induction of MMP-1 by myeloma cells. Blood 90:1649–1655PubMedGoogle Scholar
  39. 39.
    Dankbar B, Padro T, Leo R, Feldmann B, Koropff M, Mesters RM, Serve H, Berdel WE, Kienast J (2000) Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood 95:2630–2636PubMedGoogle Scholar
  40. 40.
    Ferlin M, Noraz N, Hertogh C, Brochier J, Taylor N, Klein B (2000) Insulin-like growth factor induces the survival and proliferation of myeloma cells through an interleukin-6 independent transduction pathway. Br J Haematol 111:626–634PubMedCrossRefGoogle Scholar
  41. 41.
    Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT, Lin B, Lentzsch S, Davies FE, Chauhan D, Schlossman RL, Richardson P, Ralph P, Wu L, Payvandi F, Muller G, Stirling DI, Anderson KC (2001) Adherence of multiple myeloma cells to bone marrow stromal cells up-regulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 15:1950–1961PubMedGoogle Scholar
  42. 42.
    Pellegrino A, Ria R, Di Pietro G, Cirulli T, Surico G, Pennisi A, Morabito F, Ribatti D, Vacca A (2005) Bone marrow endothelial cells in multiple myeloma secrete CXC-chemokines that mediates interactions with plasma cells. Br J Haematol 129:248–256PubMedCrossRefGoogle Scholar
  43. 43.
    Vacca A, Ria R, Semeraro F, Merchionne F, Coluccia M, Boccarelli A, Scavelli C, Nico B, Gernone A, Battelli F, Tablio A, Guidolin D, Petrucci MT, Ribatti D, Dammacco F (2003) Endothelial cells in the bone marrow of patients with multiple myeloma. Blood 102:3340–3348PubMedCrossRefGoogle Scholar
  44. 44.
    Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V, Adams J, Anderson KC (2002) NF-kappa B as a therapeutic target in mutiple myeloma. J Biol Chem 277:16639–16647PubMedCrossRefGoogle Scholar
  45. 45.
    Hayashi T, Hideshima T, Nguyen AN, Munoz O, Podar K, Hamasaki M, Ishitsuka K, Yasui H, Richardson P, Chakravarty S, Murphy A, Chauhan D, Higgins LS, Anderson KC (2004) Transforming growth factor beta receptor I kinase inhibitor down-regulates cytokine secretion and multiple myeloma cell growth in the bone marrow microenvironment. Clin Cancer Res 10:7540–7546PubMedCrossRefGoogle Scholar
  46. 46.
    Hideshima T, Podar K, Chauhan D, Ishitsuka K, Mitsiades C, Tai YT, Hamasaki M, Raje N, Hideshima H, Schreiner G, Nguyen AN, Navas T, Munshi NC, Richardson PG, Higgins LS, Anderson KC (2004) p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. Oncogene 23:8766–8776PubMedCrossRefGoogle Scholar
  47. 47.
    Ochiai N, Uchida R, Fuchida S, Okano A, Okamoto M, Ashihara E, Inaba T, Fujita N, Matsubara H. Shimazaki C (2003) Effects of farnesyl transferase inhibitor R115777 on the growth of fresh and cloned myeloma cells in vitro. Blood 102:3349–3353PubMedCrossRefGoogle Scholar
  48. 48.
    Hideshima T, Richardson P, Chauhan D, Palombella WJ, Elliott PJ, Adams J, Anderson KC (2001b) The proteasome inhibitor PS-341 inhibits growth, induces apotosis, and overcomes drug resistance in multiple myeloma cells. Cancer Res 61:3071–3073PubMedGoogle Scholar
  49. 49.
    Hideshima T, Chauhan D, Hayashi T, Akiyama M, Mitsiades N, Mitsiades C, Podar K, Munsji N, Richardson PG, Anderson KC (2003) Proteasome inhibitor PS-341 abrogates IL-6 triggering signaling cascade via caspase-dependent down-regulation of gp130 in multiple myeloma. Oncogene 22:8386–8393PubMedCrossRefGoogle Scholar
  50. 50.
    Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M, Hideshima T, Chauhan D, Joseph M, Libermann TA, Garcia-Echeverria C, Pearson MA, Hofmann F, Anderson KC. Kung AL (2004) Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell 5:221–230PubMedCrossRefGoogle Scholar
  51. 51.
    Ribatti D, Vacca A (2005) Therapeutic renaissance of thalidomide in the treatment of hematological malignancies. Leukemia 18:1525–1531CrossRefGoogle Scholar
  52. 52.
    Podar K, Anderson KC (2005) The pathophysiological role of VEGF in hematologic malignancies: therapeutic implications. Blood 105:1383–1395PubMedCrossRefGoogle Scholar
  53. 53.
    Bruno B Giaccone L, Rotta M, Anderson K, Boccadoro M (2005) Novel targeted drugs for the treatment of multiple myeloma: from bench to bedside. Leukemia 19:1729–1738CrossRefGoogle Scholar
  54. 54.
    Podar K, Catley LP, Tai YT, Shringarpure R, Carvalho P, Hayashi T, Burger R, Schlossman RL, Richardson PG, Pandite LN, Kumar R, Hideshima T, Chauhan D, Anderson KC (2004) GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment. Blood 103:3474–3479PubMedCrossRefGoogle Scholar
  55. 55.
    Le Blanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, Neuberg D, Goloubeva O, Pien CS, Adams J, Gupta D, Richardson PG, Munshi NC, Anderson KC (2002) Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 62:4996–5000Google Scholar
  56. 56.
    Roccaro AM, Hideshima T, Raje N, Kumar S, Ishitsuka K, Yasui H, Shiraishi N, Ribatti D, Nico B, Vacca A, Dammacco F, Richardson PG, Anderson KC (2006) Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells. Cancer Res 66:184–191PubMedCrossRefGoogle Scholar
  57. 57.
    Tran J, Master Z, Yu JL, Rak J, Dumont DJ, Kerbel RS (2002) A role of survivin in chemoresistance of endothelial cells mediated by VEGF. Proc Natl Acad Sci USA 99:4349–4354PubMedCrossRefGoogle Scholar
  58. 58.
    Grand EK, Chase AJ, Heath C, Rahemtulla A, Cross NC (2004) Targeting FGFR3 in mutiple myeloma: inhibition of t (4; 14)-positive cells by SU5402 and PD173074. Leukemia 18:962–966PubMedCrossRefGoogle Scholar
  59. 59.
    Trudel S, Ely S, Farooqi Y, Affer M, Robbiani DF, Chesi M, Bergsagel PL (2004) Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t (4; 14) myeloma. Blood 103:3521–3528PubMedCrossRefGoogle Scholar
  60. 60.
    Trudel S, Li ZH, Wei E, Weismann M, Chang H, Chen C, Reece D, Heise C, Stewart AK (2005) CHIR-258, a novel multitargeted tyrosine kinase inhibitor for the potential treatment of t (4; 14) multiple myeloma. Blood 105:2941–2948PubMedCrossRefGoogle Scholar
  61. 61.
    Akiyama M, Hideshima T,Hayashi T, Tai YT, Mitsiades CS, Mitsiades N, Chauhan D, Richardson P, Munschi NC, Anderson KC (2002) Cytokines modulate telomerase activity in human multiple myeloma cell line. Cancer Res 62:3876–3882PubMedGoogle Scholar
  62. 62.
    Ge NI, Rudikoff S (2000) Insulin-like growth factor I as a dual effector of multiple myeloma cell growth. Blood 96:2856–2861PubMedGoogle Scholar
  63. 63.
    Mitsiades CS, Mitsiades N, Poulaki V, Schlossman R, Akiyama M, Chauhan D, Hideshima T, Treon SP, Munshi NC, Richardson PG, Anderson KC (2002) Activation of NF-kappa B and up-regulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene 21:5673–5683PubMedCrossRefGoogle Scholar
  64. 64.
    Quiang YW, Kopantzev E, Rudikoff S (2002) Insulinlike growth factor I signaling in multiple myeloma: downstream elements, functional correlate, and pathway cross-talk. Blood 99:4138–4146CrossRefGoogle Scholar
  65. 65.
    Tu Y, Gardner A, Lichtenstein A (2000) The phosphatidylinostol 3 kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses. Cancer Res 60:6763–6770PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Department of Human Anatomy and HistologyUniversity of Bari Medical SchoolBariItaly
  2. 2.Department of Biomedical Sciences and Human OncologyUniversity of Bari Medical SchoolBariItaly

Personalised recommendations