Clinical and Translational Oncology

, Volume 11, Issue 3, pp 138–142 | Cite as

Tumoral angiogenesis and breast cancer

  • Parham Khosravi ShahiEmail author
  • Alicia Soria Lovelle
  • Gumersindo Pérez Manga
Educational Series Molecular Tragets in Oncology


Breast cancer (BC) is the most common neoplasm in women in Western countries. Tumoral angiogenesis (TA) is essential for the growth and spread of BC cells. There are at least 6 different angiogenic growth factors associated with TA in BC. The major mediator of TA is vascular endothelial growth factor (VEGF), a homodimeric heparin-binding glycoprotein. VEGF signals through VEGF receptor-2 (VEGFR-2), the major VEGF signalling receptor that mediates sprouting angiogenesis. Recently, different antiangiogenic agents have shown efficacy in the treatment of advanced BC. Bevacizumab, a humanised monoclonal antibody against VEGF, in combination with taxanes improves progression-free survival and overall response rate in first-line therapy. Other new antiangiogenic agents, called multi-kinase inhibitors (sunitinib and pazopanib), are under investigation. Finally, a schedule of treatment called metronomic chemotherapy, with antiangiogenic activity, has also demonstrated efficacy in the treatment of advanced BC.


VEGF Sunitinib Bevacizumab Metronomic chemotherapy Pazopanib 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kerbel RS (2006) Antiangiogenic therapy: a universal chemosensitization strategy for cancer. Science 312:1171–1175PubMedCrossRefGoogle Scholar
  2. 2.
    Khosravi P (2006) Angiogenesis y neoplasias. An Med Interna 23:355–356Google Scholar
  3. 3.
    Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674PubMedCrossRefGoogle Scholar
  4. 4.
    Veikkola T, Karkkainen M, Claesson-Welsh L et al (2000) Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 60:203–212PubMedGoogle Scholar
  5. 5.
    Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676PubMedCrossRefGoogle Scholar
  6. 6.
    Khosravi P, Fernandez I (2008) Tumoral angiogenesis: review of the literature. Cancer Invest 26:104–108CrossRefGoogle Scholar
  7. 7.
    Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358:2039–2049PubMedCrossRefGoogle Scholar
  8. 8.
    Foekens JA, Peters HA, Grebenchtchikov N et al (2001) High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res 61:5407–5414PubMedGoogle Scholar
  9. 9.
    Linderholm B, Grankvist K, Wilking N et al (2000) Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. J Clin Oncol 18:1423–1431PubMedGoogle Scholar
  10. 10.
    Kumar R, Yoneda J, Bucana CD et al (1998) Regulation of distinct steps of angiogenesis by different angiogenic molecules. Int J Oncol 12:749–757PubMedGoogle Scholar
  11. 11.
    Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9:677–684PubMedCrossRefGoogle Scholar
  12. 12.
    Harris AL (2002) Hypoxia — a key regulatory factor in tumor growth. Nat Rev Cancer 2:38–47PubMedCrossRefGoogle Scholar
  13. 13.
    Hewitson KS, McNeill LA, Riordan MV et al (2002) Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J Biol Chem 277:26351–26355PubMedCrossRefGoogle Scholar
  14. 14.
    Fox SB, Bragança J, Turley H et al (2004) CITED4 inhibits hypoxia-activated transcription in cancer cells, and its cytoplasmic location in breast cancer is associated with elevated expression of tumor cell hypoxia-inducible factor 1α. Cancer Res 64:6075–6081PubMedCrossRefGoogle Scholar
  15. 15.
    Willett CG, Boucher Y, di Tomaso E et al (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145–147PubMedCrossRefGoogle Scholar
  16. 16.
    Cobleigh M, Langmuir V, Sledge GW et al (2003) A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 30:117–124PubMedCrossRefGoogle Scholar
  17. 17.
    Miller K, Chap LI, Holmes FA et al (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792–799PubMedCrossRefGoogle Scholar
  18. 18.
    Miller K, Wang M, Gralow J et al (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676PubMedCrossRefGoogle Scholar
  19. 19.
    Schneider BP, Wang M, Radovich M et al (2008) Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 26:4672–4678PubMedCrossRefGoogle Scholar
  20. 20.
    Cristofanilli M, Valero V, Mangalik A et al (2008) A phase II multicenter, double-blind, randomized trial to compare anastrozole plus gefinitib with anastrozole plus placebo in postmenopausal women with hormone receptor-positive (HR+) metastatic breast cancer (MBC). J Clin Oncol 26:abstr 1012Google Scholar
  21. 21.
    Abrams TJ, Lee LB, Murray LJ et al (2003) SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2:471–478PubMedGoogle Scholar
  22. 22.
    Mendel DB, Laird AD, Xin X et al (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9:327–337PubMedGoogle Scholar
  23. 23.
    O’Farrell AM, Abrams TJ, Yuen HA et al (2003) SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101:3597–3605PubMedCrossRefGoogle Scholar
  24. 24.
    Murray LJ, Abrams TJ, Long KR et al (2003) SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis 20:757–766PubMedCrossRefGoogle Scholar
  25. 25.
    Burstein HJ, Elias AD, Rugo HS et al (2008) Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 26:1810–1816PubMedCrossRefGoogle Scholar
  26. 26.
    Slamon D, Gomez HL, Kabbinavar F et al (2008) Randomized study of pazopanib + lapatinib vs. lapatinib alone in patients with HER2- positive advanced or metastatic breast cancer. J Clin Oncol 26:abstr 1016Google Scholar
  27. 27.
    Laquente B, Vinals F, Germa JR (2007) Metronomic chemotherapy: an antiangiogenic scheduling. Clin Transl Oncol 9:93–98PubMedCrossRefGoogle Scholar
  28. 28.
    Khosravi P, Pérez-Manga G (2007) Una nueva estrategia terapéutica en el cáncer de mama: quimioterapia metronómica. An Med Interna 24:261–262Google Scholar
  29. 29.
    Gasparini G (2001) Metronomic scheduling: the future of chemotherapy? Lancet Oncol 2:733–740PubMedCrossRefGoogle Scholar
  30. 30.
    Orlando L, Cardillo A, Rocca A et al (2006) Prolonged clinical benefit with metronomic chemotherapy in patients with metastatic breast cancer. Anticancer Drugs 17:961–967PubMedCrossRefGoogle Scholar
  31. 31.
    Orlando L, Cardillo A, Ghisini R et al (2006) Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with Her-2 positive metastatic breast cancer. BMC Cancer 6:225–233PubMedCrossRefGoogle Scholar
  32. 32.
    Dellapasqua S, Bertolini F, Bagnardi V et al (2008) Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol 26:4899–4905PubMedCrossRefGoogle Scholar

Copyright information

© Feseo 2009

Authors and Affiliations

  • Parham Khosravi Shahi
    • 1
    Email author
  • Alicia Soria Lovelle
    • 1
  • Gumersindo Pérez Manga
    • 1
  1. 1.Servicio de Oncología MédicaHospital General Universitario Gregorio MarañónMadridSpain

Personalised recommendations