Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Paper
  • Published:

Elements regulating angiogenesis and correlative microvessel density in benign hyperplastic and malignant prostate tissue

Abstract

Purpose: To quantify the ex vivo production of proangiogenic proteins (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (tPA)) and angiogenesis inhibitors (plasminogen activator inhibitor type-1 (PAI-1) and angiostatin) from epithelial and stromal components of primary prostate cancer (CaP) and benign prostatic hyperplasia (BPH) cultures. To perform microvessel density (MVD) counts on sections of BPH and CaP from the same prostatectomy specimens.

Scope: Angiogenic cytokine expression was measured by immunoassays and in vitro angiostatin generating capacities assessed using immunoblotting. CaP and BPH tissue was immunostained using factor VIII antibody to determine MVD.

Conclusions: Elements regulating angiogenesis are present in both primary cultures of CaP and BPH, suggesting that angiogenic ability is well established in the absence of carcinoma.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Folkman J, Watson K, Ingber D, Hanahan D . Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 1989; 339: 58–61.

    Article  CAS  PubMed  Google Scholar 

  2. Folkman J, Shing J . Angiogenesis. J Biol Chem 1992; 267: 10931–10934.

    CAS  PubMed  Google Scholar 

  3. Weidner N et al. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 1993; 143: 401–409.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Chung LW, Davies R . Prostate epithelial differentiation is dictated by its surrounding stroma. Mol Biol Rep 1996; 23: 13–19.

    Article  CAS  PubMed  Google Scholar 

  5. Chung LW . The role of stromal–epithelial interaction in normal and malignant growth. Cancer Surv 1995; 23: 33–42.

    CAS  PubMed  Google Scholar 

  6. Chung LW . Implications of stromal–epithelial interaction in human prostate cancer growth, progression and differentiation. Semin Cancer Biol 1993; 4: 183–192.

    CAS  PubMed  Google Scholar 

  7. Cetinkaya MGS et al. Relationship between prostate specific antigen density, microvessel density and prostatic volume in benign prostatic hyperplasia and advanced prostatic carcinoma. Int Urol Nephrol 1998; 30: 581–585.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Ferrer FA et al. Vascular endothelial growth factor (VEGF) expression in human prostate cancer: in situ and in vitro expression of VEGF by human prostate cancer cells. J Urol 1997; 157: 2329–2333.

    Article  CAS  PubMed  Google Scholar 

  10. Jackson M, Bentel J, Tilley W . Vascular endothelial growth factor (VEGF) expression in prostate cancer and benign prostatic hyperplasia. J Urol 1997; 157: 2323–2328.

    Article  CAS  PubMed  Google Scholar 

  11. Pepper MS, Ferrara N, Orci L, Montesano R . Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun 1992; 189: 824–831.

    Article  CAS  PubMed  Google Scholar 

  12. Giri D, Ropiquet F, Ittmann M . Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. Clin Cancer Res 1999; 5: 1063–1071.

    CAS  PubMed  Google Scholar 

  13. Hollas W et al. Expression of Urokinase and its receptor in invasive and non-invasive prostate cancer cell lines. Thrombosis Haemostasis 1992; 68: 662–666.

    Article  CAS  PubMed  Google Scholar 

  14. Van Veldhuizen P, Sadasivan R, Cherian R, Wyatt A . Urokinase-type plasminogen activator expression in human prostate carcinomas. Am J Med Sci 1996; 312: 8–11.

    Article  CAS  PubMed  Google Scholar 

  15. Pepper MS et al. Angiogenesis: a paradigm for balanced extracellular proteolysis during cell migration and morphogenesis. Enzyme Protein 1996; 49: 138–162.

    Article  CAS  PubMed  Google Scholar 

  16. Evans CP et al. Inhibition of prostate cancer neovascularization and growth by urokinase-type plasminogen activator receptor blockade. Cancer Res 1997; 57: 3594–3599.

    CAS  PubMed  Google Scholar 

  17. Parangi S et al. Anti-angiogenic therapy of transgenic mice impairs de novo tumor growth. Proc Natl Acad Sci (Washington) 1996; 93: 2002–2007.

    Article  CAS  Google Scholar 

  18. O'Reilly MS, Hmolmgren L, Chen C, Folkman J . Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 1996; 2: 689–692.

    Article  CAS  PubMed  Google Scholar 

  19. Westphal JR et al. Angiostatin generation by human tumor cell lines: involvement of plasminogen activators. Int J Cancer 2000; 86: 760–767.

    Article  CAS  PubMed  Google Scholar 

  20. O'Mahony CA et al. Angiostatin generation by human pancreatic cancer. J Surg Res 1998; 77: 55–58.

    Article  CAS  PubMed  Google Scholar 

  21. Dong Z, Kumar R, Yang X, Fidler IJ . Macrophage-derived metallo-elastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 1997; 88: 801–810.

    Article  CAS  PubMed  Google Scholar 

  22. Falcon DJ, Khan KMF, Layne T, Fernandes L . Macrophage formation of angiostatin during inflammation. J Biol Chem 1998; 273: 31480–31485.

    Article  Google Scholar 

  23. O'Reilly MS et al. Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance. J Biol Chem 1999; 274: 29568–29571.

    Article  CAS  PubMed  Google Scholar 

  24. Heidtmann HH et al. Generation of angiostatin-like fragments from plasminogen by prostate- specific antigen. Br J Cancer 1999; 81: 1269–1273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Peehl DM, Sellers RG, Wong ST . Defined medium for normal adult human prostatic stromal cells. In Vitro Cell Dev Biol Anim 1998; 34: 555–560.

    Article  CAS  PubMed  Google Scholar 

  26. Dall'Era MA et al. Differential expression of angiogenic cytokines by cell lines and primary cultures of human prostate cancer. Prostate Cancer prostatic Dis 2001; 4: 106–111.

    Article  CAS  PubMed  Google Scholar 

  27. Shyh S-J et al. Comparative regulation of angiogenesis in benign hyperplastic and malignant prostate tissue. Proc Am Assoc Cancer Res 2001; 42: 106.

    Google Scholar 

  28. Sugamoto T et al. The expression of basic fibroblast growth factor and vascular endothelial growth factor in prostatic adenocarcinoma: correlation with neovascularization. Anticancer Res 2001; 21: 77–88.

    CAS  PubMed  Google Scholar 

  29. Kirchheimer JC et al. Plasminogen activator activity in bone metastases of prostatic carcinomas as compared to primary tumors. Invasion Metastasis 1985; 5: 344–355.

    CAS  PubMed  Google Scholar 

  30. Miyake H et al. Elevation of serum levels of urokinase-type plasminogen activator and its receptor is associated with disease progression and prognosis in patients with prostate cancer. Prostate 1999; 39: 123–129.

    Article  CAS  PubMed  Google Scholar 

  31. Silberman M, Partin A, Veltri R, Epstein J . Tumor angiogenesis correlates with progression after radical prostatectormy but not with pathologic stage in gleason sum 5 to 7 adenocarcinoma of the prostate. Cancer 1997; 79: 772–779.

    Article  CAS  PubMed  Google Scholar 

  32. Rubin M et al. Microvessel density in prostate cancer: lack of correlation with tumor grade, pathologic stage, and clinical outcome. Urology 1999; 53: 542–547.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors appreciate the assistance of Dr Donna Peehl, Stanford University, in the technique of establishing primary prostate cultures. CPE was supported by University of California, Davis Health System Research Award, American Cancer Society Institutional Research Award #205, The New York Academy of Medicine Edwin Beer Fellowship.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C P Evans.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shih, SJ., Dall'Era, M., Westphal, J. et al. Elements regulating angiogenesis and correlative microvessel density in benign hyperplastic and malignant prostate tissue. Prostate Cancer Prostatic Dis 6, 131–137 (2003). https://doi.org/10.1038/sj.pcan.4500637

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.pcan.4500637

Keywords

This article is cited by

Search

Quick links