Skip to main content

Advertisement

SpringerLink
Log in

The merits of vascular targeting for gynecologic malignancies

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Neovascularization is an early and critical step in tumor development and progression. Tumor vessels are distinct from their normal counterparts morphologically as well as at a molecular level. Recent studies on factors involved in tumor vascular development have identified new therapeutic targets for inhibiting tumor neovascularization and thus tumor progression. However, the process of tumor blood vessel formation is complex, and each tumor exhibits unique features in its vasculature. An understanding of the relative contribution of various pathways in the development of tumor vasculature is critical for developing effective and selective therapeutic approaches. Several such agents are currently in clinical trials, and many others are under development. In this review, the mechanisms and factors involved in tumor blood vessel formation are discussed. In addition, selected novel classes of antivascular therapies, including those targeting tumor endothelial cells and other components of the tumor vasculature, are summarized.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990, 82:4–6.

    Article  PubMed  CAS  Google Scholar 

  2. Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cancer Res 1996, 86:353–364.

    CAS  Google Scholar 

  3. Bergers G, Banjamin LE: Tumorigenesis and the angiogenic switch. Nat Rev, Cancer 2003, 3:401–410. This article provides a review of the process of angiogenesis.

    Article  CAS  Google Scholar 

  4. Hobson B, Denekamp J: Endothelial proliferation in tumors and normal tissues: continuous labeling studies. Br J Cancer 1984, 49:405–413.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  6. Hellstrom M, Gerhardt H, Kalen M, et al.: Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 2001, 153:543–553.

    Article  PubMed  CAS  Google Scholar 

  7. St. Croix B, Rago C, Velculescu V, et al.: Genes expressed in human tumor endothelium. Science 2000, 289:1197–1202.

    Article  PubMed  CAS  Google Scholar 

  8. Hida K, Hida Y, Amin DN, et al.: Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res 2004, 64:8249–8255.

    Article  PubMed  CAS  Google Scholar 

  9. Risau W: Mechanisms of angiogenesis. Nature 1997, 386:671–674.

    Article  PubMed  CAS  Google Scholar 

  10. Rafii S: Circulating endothelial precursors: mystery, reality and promise. J Clin Invest 2000, 105:17–19.

    PubMed  CAS  Google Scholar 

  11. Sood AK, Fletcher MS, Zahn CM, et al.: The clinical significance of tumor cell-lined vasculature in ovarian carcinoma: implications for anti-vasculogenic therapy. Cancer Biol Therapy 2002, 1:661–664.

    Google Scholar 

  12. Sood AK, Seftor EA, Fletcher M, et al.: Molecular determinants of ovarian cancer plasticity. Am J Pathol 2001, 158:1279–1288.

    PubMed  CAS  Google Scholar 

  13. Holash J, Wiegand SJ, Yancopoulos GD: New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 1999, 18:5356–5362.

    Article  PubMed  CAS  Google Scholar 

  14. Carmeliet P, Ferreira V, Breier G, et al.: Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996, 380:435–439.

    Article  PubMed  CAS  Google Scholar 

  15. Ferrara N, Carver-Moore K, Chen H, et al.: Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996, 380:439–442.

    Article  PubMed  CAS  Google Scholar 

  16. Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors. Nat Med 2003, 9:669–676.

    Article  PubMed  CAS  Google Scholar 

  17. Gerber HP, McMurtry A, Kowalski J, et al.: Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway: requirement for Flk-1/KDR activation. J Biol Chem 1998, 273:30336–30343.

    Article  PubMed  CAS  Google Scholar 

  18. Cooper BC, Ritchie JM, Broghammer CL, et al.: Preoperative serum vascular endothelial growth factor levels: significance in ovarian cancer. Clin Cancer Res 2002, 8:3193–3197.

    PubMed  CAS  Google Scholar 

  19. Claffey KP, Brown LF, del Aguila LF, et al.: Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastases. Cancer Res 1996, 56:172–181.

    PubMed  CAS  Google Scholar 

  20. Oku T, Tjuvajev JG, Migyagawa T, et al.: Tumor growth modulation by sense and antisense vascular endothelial growth factor gene expression: effects on angiogenesis, vascular permeability, blood volume, blood flow, fluorodeoxglucose uptake, and proliferation of human melanoma intracerebral xenografts. Cancer Res 1998, 58:4185–4192.

    PubMed  CAS  Google Scholar 

  21. Dvorak HF, Brown LF, Detmar M, Dvorak AM: Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 1995, 146:1029–1039.

    PubMed  CAS  Google Scholar 

  22. Zeng H, Dvorak HF, Mukhopadhyay D: Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) receptor-1 down-modulates VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent pathways. J Biol Chem 2001, 276:26969–26979.

    Article  PubMed  CAS  Google Scholar 

  23. Gille H, Kowalski J, Li B, et al.: Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2): a reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem 2001, 276:3222–3230.

    Article  PubMed  CAS  Google Scholar 

  24. Fan F, Wey JS, McCarty MF, et al.: Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene 2005, 24:2647–2653.

    Article  PubMed  CAS  Google Scholar 

  25. Thaker PH, Yazici S, Nilsson MB, et al.: Antivascular therapy for orthotopic human ovarian carcinoma through blockade of the vascular endothelial growth factor and epidermal growth factor receptors. Clin Cancer Res, 2005, 11:4923–4933. This article highlights the importance of dual targeting of VEGFR and EGFR for antivascular therapy.

    Article  PubMed  CAS  Google Scholar 

  26. Kuo CJ, Farnebo F, Yu EY, et al.: Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer. Proc Natl Acad Sci U S A 2001, 98:4605–4610.

    Article  PubMed  CAS  Google Scholar 

  27. Ferrara N, Hillan KJ, Gerber HP, Novotny W: Case history: Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004, 3:391–400.

    Article  PubMed  CAS  Google Scholar 

  28. Yang JC, Haworth L, Sherry RM, et al.: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003, 349:427–434.

    Article  PubMed  CAS  Google Scholar 

  29. Ramaswamy B, Shapiro CL: Phase II trial of bevacizumab in combination with docetaxel in women with advanced breast cancer. Clin Breast Cancer 2003, 4:292–294.

    Article  PubMed  CAS  Google Scholar 

  30. Hu L, Hofmann J, Zaloudek C, et al.: Vascular endothelial growth factor immunoneutralization plus Paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer. Am J Pathol 2002, 161:1917–1924.

    PubMed  CAS  Google Scholar 

  31. Burger RA, Sill M, Monk BJ, et al.: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): a Gynecologic Oncology Group (GOG) study [abstract]. Proc ASCO 2005, 23(16S):457.

    Google Scholar 

  32. Holash J, Davis S, Papadopoulos N, et al.: VEGF-Trap: A VEGF blocker with potent anti-tumor effects. Proc Natl Acad Sci U S A 2002, 99:11393–11398.

    Article  PubMed  CAS  Google Scholar 

  33. Byrne AT, Ross L, Holash J, et al.: Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res 2003, 9:5721–5728.

    PubMed  CAS  Google Scholar 

  34. Dupont J, et al.: Phase 1 and pharmacokinetic study of VEGF Trap administered subcutaneously (sc) to patients with advanced solid malignancies. J Clin Oncol 2004, 22:14S (July 15 supplement).

    Google Scholar 

  35. Xu L, Yoneda J, Herrara C, et al.: Inhibition of malignant ascites and growth of human ovarian carcinoma by oral administration of a potent inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. Int J Oncol 2000, 16:445–454.

    PubMed  CAS  Google Scholar 

  36. Traxler P, Allegrini PR, Brandt R, et al.: AEE787: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res 2004, 64:4931–4941.

    Article  PubMed  CAS  Google Scholar 

  37. Apte SM, Fan D, Killion JJ, Fidler IJ: Targeting the plateletderived growth factor receptor in antivascular therapy for human ovarian carcinoma. Clin Cancer Res 2004, 10:897–908.

    Article  PubMed  CAS  Google Scholar 

  38. Nehls V, Drenckhahn D: The versatility of microvascular pericytes: from mesenchyme to smooth muscle? Histochemistry 1993, 99:1–12.

    Article  PubMed  CAS  Google Scholar 

  39. Allt G, Lawrenson JG: Pericytes: cell biology and pathology. Cells Tissues Organs 2001, 169:1–11.

    Article  PubMed  CAS  Google Scholar 

  40. Wesseling P, Schlingemann RO, Rietveld FJ, et al.: Early and extensive contribution of pericytes/vascular smooth muscle cells to microvascular proliferation in glioblastoma multiforme: an immuno-light and immuno-electron microscopic study. J Neuropathol Exp Neurol 1995, 54:304–310.

    PubMed  CAS  Google Scholar 

  41. Lindahl P, Johansson BR, Leveen P, Betsholtz C: Pericyte loss and microaneursym formation in PDGF-B-deficient mice. Science 1997, 277:242–245.

    Article  PubMed  CAS  Google Scholar 

  42. Fukumura D, Xavier R, Sugiura T, et al.: Tumor induction of VEGF promoter activity in stromal cells. Cell 1998, 94:715–725.

    Article  PubMed  CAS  Google Scholar 

  43. Lindblom P, Gerhardt H, Liebner S, et al.: Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev 2003, 17:1835–1840.

    Article  PubMed  CAS  Google Scholar 

  44. McCarty MF, Wey J, Stoeltzing O, et al.: ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor tyrosine kinase, inhibits orthotopic growth and angiogenesis of gastric cancer. Mol Cancer Ther 2004, 3:1041–1048.

    PubMed  CAS  Google Scholar 

  45. Kelly JD, Haldeman BA, Grant FJ, et al.: Platelet-derived growth factor (PDGF) stimulates PDGF receptor subunit dimerization and intersubunit trans-phosphorylation. J Biol Chem 1991, 266:8987–8992.

    PubMed  CAS  Google Scholar 

  46. Apte SM, Bucana CD, Killion JJ, et al.: Expression of plateletderived growth factor and activated receptor in clinical specimens of epithelial ovarian cancer and ovarian carcinoma cell lines. Gynecol Oncol 2004, 93:78–86.

    Article  PubMed  CAS  Google Scholar 

  47. Abrammsson A, Lindblom P, Betsholtz: Endothelial and nonendothelial sources of PDGFB regulate pericyte recruitment ad influence vascular pattern formation in tumors. J Clin Invest 2003, 112:1142–1151.

    Article  CAS  Google Scholar 

  48. Bergers G, Song S, Meyer-Morse N, et al.: Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003, 111:1287–1295.

    Article  PubMed  CAS  Google Scholar 

  49. Jayson GC, Parker GJ, Mullamitha S, et al.: Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized, PEGylated di-Fab’, leads to fluid accumulation and is associated with increased tumor vascularized volume. J Clin Oncol 2005, 23:973–981.

    Article  PubMed  CAS  Google Scholar 

  50. Shaheen RM, Tseng WW, Davis DW, et al.: Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms. Cancer Res 2001, 61:1464–1468.

    PubMed  CAS  Google Scholar 

  51. Hanahan D, Bergers G, Bergsland E: Less is more, regularly: metronomic dosing of cytotoxic agents can target tumor angiogenesis in mice. J Clin Invest 2000, 105:1045–1047.

    Article  PubMed  CAS  Google Scholar 

  52. Kerbel RS, Kamen BA: The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 2004, 4:423–436. This articles provides a review of the anti-angiogenic basis of metronomic chemotherapy.

    Article  PubMed  CAS  Google Scholar 

  53. Browder T, Butterfield CE, Kraling BM, et al.: Anti-angiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000, 60:1878–1886.

    PubMed  CAS  Google Scholar 

  54. Markman M, Hall J, Spitz D, et al.: Phase II trial of weekly single-agent paclitaxel in platinum/paclitaxel-refractory ovarian cancer. J Clin Oncol 2002, 20:2365–2369.

    Article  PubMed  CAS  Google Scholar 

  55. Tran J, Master Z, Yu JL, et al.: A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc Natl Acad Sci U S A 2002, 99:4349–4354.

    Article  PubMed  CAS  Google Scholar 

  56. Denekamp J: Review article: Angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy. Br J Radiol 1993, 66:181–196.

    Article  PubMed  CAS  Google Scholar 

  57. Thorpe PE: Vascular targeting agents as cancer therapeutics. Clin Cancer Res 2004, 10:415–427.

    Article  PubMed  Google Scholar 

  58. van der Schaft DWJ, Seftor REB, Seftor EA, et al.: Effects of angiogenesis inhibitors in vascular network formation by human endothelial and melanoma cells. J Natl Cancer Inst 2004, 96:1473–1477. This article provides evidence for therapeutic targeting of vasculogenic mimicry.

    Article  PubMed  Google Scholar 

  59. Rybak SM, Sanovich E, Hollingshead MG, et al.: Vasocrine formation of tumor cell-lined vascular spaces: implications for rational design of antiangiogenic therapies. Cancer Res 2003, 63:2812–2819.

    PubMed  CAS  Google Scholar 

  60. Shaked Y, Bertolini F, Man S, et al.: Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis: Implications for cellular surrogate marker analysis of angiogenesis. Cancer Cell 2005, 7:101–111.

    PubMed  CAS  Google Scholar 

  61. Kamat AA, Sood AK, Simpson JL, et al.: Elevated levels of plasma cell-free DNA in patients with ovarian cancer [abstract]. Proceedings of the 96th annual meeting of the American Association for Cancer Research 2005, 46:845.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Gynecologic Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Unit 1362, PO Box 301439, 77230-1439, Houston, TX, USA

    Anil K. Sood MD

Authors
  1. Aparna A. Kamat MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anil K. Sood MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kamat, A.A., Sood, A.K. The merits of vascular targeting for gynecologic malignancies. Curr Oncol Rep 7, 444–450 (2005). https://doi.org/10.1007/s11912-005-0009-x

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-005-0009-x

Keywords

Search

Navigation