Skip to main content

Advertisement

Log in

Vascular endothelium in cancer

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

The vascular endothelium plays an essential role during organogenesis and in tissue homeostasis. Growing evidence also supports its essential and complex role in tumour biology and cancer progression. In particular, excessive proliferation and transformation or dysfunction of endothelial cells leads to pathological (lymph)angiogenesis or vascular malfunctions, which are hallmarks of neoplastic and malignant disorders. Reciprocal interactions between endothelial cells and the local tumour microenvironment may regulate tumour progression and resistance to anti-cancer therapies in a tumour-type-specific manner.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8:464–478

    Article  PubMed  CAS  Google Scholar 

  • Alajati A, Laib AM, Weber H, Boos AM, Bartol A, Ikenberg K, Korff T, Zentgraf H, Obodozie C, Graeser R, Christian S, Finkenzeller G, Stark GB, Héroult M, Augustin HG (2008) Spheroid-based engineering of a human vasculature in mice. Nat Methods 5:439–445

    Article  PubMed  CAS  Google Scholar 

  • Alitalo K, Carmeliet P (2002) Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1:219–227

    Article  PubMed  CAS  Google Scholar 

  • Alitalo K, Tammela T, Petrova TV (2005) Lymphangiogenesis in development and human disease. Nature 438:946–953

    Article  PubMed  CAS  Google Scholar 

  • Asahara T, Murohara T, Sullivan A, Silver M, Zee R van der, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967

    Article  PubMed  CAS  Google Scholar 

  • Arap W, Kolonin MG, Trepel M, Lahdenranta J, Cardó-Vila M, Giordano RJ, Mintz PJ, Ardelt PU, Yao VJ, Vidal CI, Chen L, Flamm A, Valtanen H, Weavind LM, Hicks ME, Pollock RE, Botz GH, Bucana CD, Koivunen E, Cahill D, Troncoso P, Baggerly KA, Pentz RD, Do KA, Logothetis CJ, Pasqualini R (2002) Steps toward mapping the human vasculature by phage display. Nat Med 8:121–127

    Article  PubMed  CAS  Google Scholar 

  • Bais C, Santomasso B, Coso O, Arvanitakis L, Raaka EG, Gutkind JS, Asch AS, Cesarman E, Gershengorn MC, Mesri EA (1998) G-protein-coupled receptor of Kaposi’s sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391:86–89

    Article  PubMed  CAS  Google Scholar 

  • Bandyopadhyay S, Zhan R, Chaudhuri A, Watabe M, Pai SK, Hirota S, Hosobe S, Tsukada T, Miura K, Takano Y, Saito K, Pauza ME, Hayashi S, Wang Y, Mohinta S, Mashimo T, Iiizumi M, Furuta E, Watabe K (2006) Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nat Med 12:933–938

    Article  PubMed  CAS  Google Scholar 

  • Bianco P, Robey PG, Simmons PJ (2008) Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2:313–319

    Article  PubMed  CAS  Google Scholar 

  • Boshoff C, Weiss R (2002) AIDS-related malignancies. Nat Rev Cancer 2:373–382

    Article  PubMed  CAS  Google Scholar 

  • Boshoff C, Endo Y, Collins PD, Takeuchi Y, Reeves JD, Schweickart VL, Siani MA, Sasaki T, Williams TJ, Gray PW, Moore PS, Chang Y, Weiss RA (1997) Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. Science 278:290–294

    Article  PubMed  CAS  Google Scholar 

  • Brown LF, Dezube BJ, Tognazzi K, Dvorak HF, Yancopoulos GD (2000) Expression of Tie1, Tie2, and angiopoietins 1, 2, and 4 in Kaposi’s sarcoma and cutaneous angiosarcoma. Am J Pathol 156:2179–2183

    PubMed  CAS  Google Scholar 

  • Bruyère F, Melen-Lamalle L, Blacher S, Roland G, Thiry M, Moons L, Frankenne F, Carmeliet P, Alitalo K, Libert C, Sleeman JP, Foidart JM, Noël A (2008) Modeling lymphangiogenesis in a three-dimensional culture system. Nat Methods 5:431–437

    Article  PubMed  Google Scholar 

  • Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, Allen M, Frank A, Bayazitov IT, Zakharenko SS, Gajjar A, Davidoff A, Gilbertson RJ (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11:69–82

    Article  PubMed  CAS  Google Scholar 

  • Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660

    Article  PubMed  CAS  Google Scholar 

  • Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438:932–936

    Article  PubMed  CAS  Google Scholar 

  • Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257

    Article  PubMed  CAS  Google Scholar 

  • Chi JT, Chang HY, Haraldsen G, Jahnsen FL, Troyanskaya OG, Chang DS, Wang Z, Rockson SG, Rijn M van de, Botstein D, Brown PO (2003) Endothelial cell diversity revealed by global expression profiling. Proc Natl Acad Sci USA 100:10623–10628

    Article  PubMed  CAS  Google Scholar 

  • Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:262–266

    Article  Google Scholar 

  • Conejo-Garcia JR, Benencia F, Courreges MC, Kang E, Mohamed-Hadley A, Buckanovich RJ, Holtz DO, Jenkins A, Na H, Zhang L, Wagner DS, Katsaros D, Caroll R, Coukos G (2004) Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of VEGF-A. Nat Med 10:950–958

    Article  PubMed  CAS  Google Scholar 

  • Della Bella S, Taddeo A, Calabrò ML, Brambilla L, Bellinvia M, Bergamo E, Clerici M, Villa ML (2008) Peripheral blood endothelial progenitors as potential reservoirs of Kaposi’s sarcoma-associated herpesvirus. PLoS ONE 3:e1520

    Article  PubMed  Google Scholar 

  • De Palma M, Venneri MA, Roca C, Naldini L (2003) Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat Med 9:789–795

    Article  PubMed  Google Scholar 

  • Engels EA, Pfeiffer RM, Goedert JJ, Virgo P, McNeel TS, Scoppa SM, Biggar RJ, for the HIV/AIDS Cancer Match Study (2006) Trends in cancer risk among people with AIDS in the United States 1980–2002. AIDS 20:1645–1654

    Article  PubMed  Google Scholar 

  • Euvrard S, Kanitakis J, Claudy A (2003) Skin cancers after organ transplantation. N Engl J Med 348:1681–1691

    Article  PubMed  Google Scholar 

  • Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438:967–974

    Article  PubMed  CAS  Google Scholar 

  • Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS (2007) Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67:3560–3564

    Article  PubMed  CAS  Google Scholar 

  • Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186

    PubMed  CAS  Google Scholar 

  • Folkman J (2000) Tumour angiogenesis. In: Holland JF, Frei E, Bast RC, Kufe DW, Morton DL, Weichselbaum RR (eds) Cancer medicine. Decker, Ontario, pp 132–152

    Google Scholar 

  • Gale NW, Thurston G, Davis S, Wiegand SJ, Holash J, Rudge JS, Yancopoulos GD (2002) Complementary and coordinated roles of the VEGFs and angiopoietins during normal and pathologic vascular formation. Cold Spring Harb Symp Quant Biol 67:267–273

    Article  PubMed  CAS  Google Scholar 

  • Galli D, Innocenzi A, Staszewsky L, Zanetta L, Sampaolesi M, Bai A, Martinoli E, Carlo E, Balconi G, Fiordaliso F, Chimenti S, Cusella G, Dejana E, Cossu G, Latini R (2005) Mesoangioblasts, vessel-associated multipotent stem cells, repair the infarcted heart by multiple cellular mechanisms: a comparison with bone marrow progenitors, fibroblasts, and endothelial cells. Arterioscler Thromb Vasc Biol 25:692–697

    Article  PubMed  CAS  Google Scholar 

  • Gessain A, Duprez R (2005) Spindle cells and their role in Kaposi’s sarcoma. Int J Biochem Cell Biol 37:2457–2465

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Hansen A, Boshoff C, Lagos D (2007) Kaposi sarcoma as a model of oncogenesis and cancer treatment. Expert Rev Anticancer Ther 7:211–220

    Article  PubMed  Google Scholar 

  • Hong YK, Foreman K, Shin JW, Hirakawa S, Curry CL, Sage DR, Libermann T, Dezube BJ, Fingeroth JD, Detmar M (2004) Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet 36:683–685

    Article  PubMed  CAS  Google Scholar 

  • Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New Engl J Med 350:2335–2342

    Article  PubMed  CAS  Google Scholar 

  • Jain RK (1996) Delivery of molecular medicine to solid tumors. Science 271:1079–1080

    Article  PubMed  CAS  Google Scholar 

  • Jain RK (2008) Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer. Nat Rev Cancer 8:309–316

    Article  PubMed  CAS  Google Scholar 

  • Jain RK, Koenig GC, Dellian M, Fukumura D, Munn LL, Melder RJ (1996) Leukocyte-endothelial adhesion and angiogenesis in tumors. Cancer Metastasis Rev 15:195–204

    Article  PubMed  CAS  Google Scholar 

  • Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449:557–563

    Article  PubMed  CAS  Google Scholar 

  • Kerbel RS, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727–739

    Article  PubMed  CAS  Google Scholar 

  • Kerjaschki D, Huttary N, Raab I, Regele H, Bojarski-Nagy K, Bartel G, Krober SM, Greinix H, Rosenmaier A, Karlhofer F, Wick N, Mazal PR (2006) Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nat Med 12:230–234

    Article  PubMed  CAS  Google Scholar 

  • Koon HB, Bubley GJ, Pantanowitz L, Masiello D, Smith B, Crosby K, Proper J, Weeden W, Miller TE, Chatis P, Egorin MJ, Tahan SR, Dezube BJ (2005) Imatinib-induced regression of AIDS-related Kaposi’s sarcoma. J Clin Oncol 23:982–989

    Article  PubMed  CAS  Google Scholar 

  • Langley RR, Fidler IJ (2007) Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr Rev 28:297–321

    Article  PubMed  CAS  Google Scholar 

  • LeCouter J, Lin R, Ferrara N (2002) Endocrine gland-derived VEGF and the emerging hypothesis of organ-specific regulation of angiogenesis. Nat Med 8:913–917

    Article  PubMed  CAS  Google Scholar 

  • Lawson ND, Scheer N, Pham VN, Kim CH, Chitnis AB, Campos-Ortega JA, Weinstein BM (2001) Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128:3675–3683

    PubMed  CAS  Google Scholar 

  • Lawson ND, Vogel AM, Weinstein BM (2002) Sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev Cell 3:127–136

    Article  PubMed  CAS  Google Scholar 

  • Masood R, Cai J, Zheng T, Smith DL, Naidu Y, Gill PS (1997) Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma. Proc Natl Acad Sci USA 94:979–984

    Article  PubMed  CAS  Google Scholar 

  • Moncada S (2006) Nitric oxide and the vascular endothelium. In: Moncada S, Higgs A (eds) Handbook of Experimental Pharmacology, vol 176. The vascular endothelium. Springer, Berlin Heidelberg New York, pp 213–254

    Google Scholar 

  • Mutlu AD, Cavallin LE, Vincent L, Chiozzini C, Eroles P, Duran EM, Asgari Z, Hooper AT, La Perle KM, Hilsher C, Gao SJ, Dittmer DP, Rafii S, Mesri EA (2007) In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced Kaposi’s sarcoma. Cancer Cell 11:245–258

    Article  PubMed  CAS  Google Scholar 

  • Oliner J, Min H, Leal J, Yu D, Rao S, You E, Tang X, Kim H, Meyer S, Han SJ, Hawkins N, Rosenfeld R, Davy E, Graham K, Jacobsen F, Stevenson S, Ho J, Chen Q, Hartmann T, Michaels M, Kelley M, Li L, Sitney K, Martin F, Sun JR, Zhang N, Lu J, Estrada J, Kumar R, Coxon A, Kaufman S, Pretorius J, Scully S, Cattley R, Payton M, Coats S, Nguyen L, Desilva B, Ndifor A, Hayward I, Radinsky R, Boone T, Kendall R (2004) Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6:507–516

    Article  PubMed  CAS  Google Scholar 

  • Nikitenko LL, Boshoff C (2006) Endothelial cells and cancer. In: Moncada S, Higgs A (eds) Handbook of Experimental Pharmacology, vol 176. The vascular endothelium. Springer, Berlin Heidelberg New York, pp 637–664

    Google Scholar 

  • Nikitenko LL, Fox SB, Kehoe S, Rees MCP, Bicknell R (2006) Adrenomedullin and tumor angiogenesis. Br J Cancer 94:1–7

    Article  PubMed  CAS  Google Scholar 

  • Ny A, Koch M, Schneider M, Neven E, Tong RT, Maity S, Fischer C, Plaisance S, Lambrechts D, Héligon C, Terclavers S, Ciesiolka M, Kälin R, Man WY, Senn I, Wyns S, Lupu F, Brändli A, Vleminckx K, Collen D, Dewerchin M, Conway EM, Moons L, Jain RK, Carmeliet P (2005) A genetic Xenopus laevis tadpole model to study lymphangiogenesis. Nat Med 11(9):998–1004

    PubMed  CAS  Google Scholar 

  • Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348

    Article  PubMed  CAS  Google Scholar 

  • Padera TP, Kadambi A, Tomaso E di, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathisen D, Wain J, Mark EJ, Munn LL, Jain RK (2002) Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296:1883–1886

    Article  PubMed  CAS  Google Scholar 

  • Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, Massagué J (2008) TGF-beta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133:66–77

    Article  PubMed  CAS  Google Scholar 

  • Pati S, Pelser CB, Dufraine J, Bryant JL, Reitz MS Jr, Weichold FF (2002) Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma. Blood 99:3771–3779

    Article  PubMed  CAS  Google Scholar 

  • Perry BN, Govindarajan B, Bhandarkar SS, Knaus UG, Valo M, Sturk C, Carrillo CO, Sohn A, Cerimele F, Dumont D, Losken A, Williams J, Brown LF, Tan X, Ioffe E, Yancopoulos GD, Arbiser JL (2006) Pharmacologic blockade of angiopoietin-2 is efficacious against model hemangiomas in mice. J Invest Dermatol 126:2316–2322

    Article  PubMed  CAS  Google Scholar 

  • Peters BA, Diaz LA, Polyak K, Meszler L, Romans K, Guinan EC, Antin JH, Myerson D, Hamilton SR, Vogelstein B, Kinzler KW, Lengauer C (2005) Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nat Med 11:261–262

    Article  PubMed  CAS  Google Scholar 

  • Rafii DC, Psaila B, Butler J, Jin DK, Lyden D (2008) Regulation of vasculogenesis by platelet-mediated recruitment of bone marrow-derived cells. Arterioscler Thromb Vasc Biol 28:217–222

    Article  PubMed  CAS  Google Scholar 

  • Red-Horse K, Crawford Y, Shojaei F, Ferrara N (2007) Endothelium-microenvironment interactions in the developing embryo and in the adult. Dev Cell 12:181–194

    Article  PubMed  CAS  Google Scholar 

  • Ritter MR, Dorrell MI, Edmonds J, Friedlander SF, Friedlander M (2002) Insulin-like growth factor 2 and potential regulators of hemangioma growth and involution identified by large-scale expression analysis. Proc Natl Acad Sci USA 99:7455–7460

    Article  PubMed  CAS  Google Scholar 

  • Seaman S, Stevens J, Yang MY, Logsdon D, Graff-Cherry C, St Croix B (2007) Genes that distinguish physiological and pathological angiogenesis. Cancer Cell 11:539–554

    Article  PubMed  CAS  Google Scholar 

  • Sgadari C, Barillari G, Toschi E, Carlei D, Bacigalupo I, Baccarini S, Palladino C, Leone P, Bugarini R, Malavasi L, Cafaro A, Falchi M, Valdembri D, Rezza G, Bussolino F, Monini P, Ensoli B (2002) HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma. Nat Med 8:225–232

    Article  PubMed  CAS  Google Scholar 

  • Sodhi A, Chaisuparat R, Hu J, Ramsdell AK, Manning BD, Sausville EA, Sawai ET, Molinolo A, Gutkind JS, Montaner S (2006) The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor. Cancer Cell 10:133–143

    Article  PubMed  CAS  Google Scholar 

  • Spring H, Schüler T, Arnold B, Hämmerling GJ, Ganss R (2005) Chemokines direct endothelial progenitors into tumor neovessels. Proc Natl Acad Sci USA 102:18111–18116

    Article  PubMed  CAS  Google Scholar 

  • Stallone G, Schena A, Infante B, Di Paolo S, Loverre A, Maggio G, Ranieri E, Gesualdo L, Schena FP, Grandaliano G (2005) Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med 352:1317–1323

    Article  PubMed  CAS  Google Scholar 

  • Taddeo A, Presicce P, Brambilla L, Bellinvia M, Villa ML, Della Bella S (2008) Circulating endothelial progenitor cells are increased in patients with classic Kaposi’s sarcoma. J Invest Dermatol 128:2125–2128

    Article  PubMed  CAS  Google Scholar 

  • Vart RJ, Nikitenko LL, Lagos D, Trotter MW, Cannon M, Bourboulia D, Gratrix F, Takeuchi Y, Boshoff C (2007) Kaposi’s sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoietin-2 expression in lymphatic endothelial cells. Cancer Res 67:4042–4051

    Article  PubMed  CAS  Google Scholar 

  • Wang HW, Trotter MW, Lagos D, Bourboulia D, Henderson S, Makinen T, Elliman S, Flanagan AM, Alitalo K, Boshoff C (2004) Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet 36:687–693

    Article  PubMed  CAS  Google Scholar 

  • Wilting J, Aref Y, Huang R, Tomarev SI, Schweigerer L, Christ B, Valasek P, Papoutsi M (2006) Dual origin of avian lymphatics. Dev Biol 292:165–173

    Article  PubMed  CAS  Google Scholar 

  • Yaniv K, Isogai S, Castranova D, Dye L, Hitomi J, Weinstein BM (2006) Live imaging of lymphatic development in the zebrafish. Nat Med 12:711–716

    Article  PubMed  CAS  Google Scholar 

  • Zhong TP, Childs S, Leu JP, Fishman MC (2001) Gridlock signalling pathway fashions the first embryonic artery. Nature 414:216–220

    Article  PubMed  CAS  Google Scholar 

  • Zlotnik A (2004) Chemokines in neoplastic progression. Semin Cancer Biol 14:181–185

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The author is grateful to Chris Boshoff, Juan Funes, Dimitrios Lagos, Vicky Emuss and Amy Hansen for useful discussions.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Leonid L. Nikitenko.

Additional information

This work was supported by Cancer Research UK.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nikitenko, L.L. Vascular endothelium in cancer. Cell Tissue Res 335, 223–240 (2009). https://doi.org/10.1007/s00441-008-0707-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-008-0707-4

Keywords

Navigation