Stromal Influences in Prostatic Carcinogenesis

  • Gerald R. Cunha
  • Simon W. Hayward
  • Thea Tlsty
  • Gary D. Grossfeld
Conference paper


It has been estimated that 184,500 new cases of prostate cancer (PRCA) will be diagnosed in the USA during 1998 and that 39,200 deaths will result from this disease. Thus, PRCA is the most commonly diagnosed malignancy, and the second leading cause of cancer-related death amongst American men. Our laboratory has investigated some of the unique biological characteristics of PRCA with the ultimate goal of formulating new, less invasive therapeutic strategies. We have recently hypothesized that epigenetic influences from adjacent stromal cells may be crucial in determining whether a particular prostate tumor remains dormant or becomes invasive (1). This hypothesis (Figure 1) suggests that subsequent to initial genetic damage to prostatic epithelium (PRE), signaling from epithelium to the surrounding stroma/mesenchyme (SM) cells becomes abnormal, resulting in dedifferentiation of SM towards a fibroblastic phenotype. One of the predicted consequences of such a change in differentiation state of SM is that the local microenvironment of the epithelium becomes altered, and thus the influence of stroma on epithelium changes from homeostatic to mitogenic. These changes subsequently lead to increased epithelial proliferation, migration and ultimately, to an increase in invasive potential of genetically altered prostatic epithelial cells.


Androgen Receptor Prostatic Epithelial Cell Epithelial Proliferation Prostatic Carcinogenesis Prostatic Stroma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hayward S W, Rosen MA, Cunha GR (1997) Stromal-epithelial interactions in normal and neoplastic prostate. Br J Urology 79 (Suppl. 2): 18–26.Google Scholar
  2. 2.
    Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87:159–170.PubMedCrossRefGoogle Scholar
  3. 3.
    Vogelstein B, Fearon ER, Hamilton SR etal. (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532.PubMedCrossRefGoogle Scholar
  4. 4.
    Cunha GR, Donjacour A A, Cooke PS etal. (1987) The endocrinology and developmental biology of the prostate. Endocrine Rev 8:338–362.CrossRefGoogle Scholar
  5. 5.
    Cunha GR, Battle E, Young P etal. (1992) Role of epithelial-mesenchymal interactions in the differentiation and spatial organization of visceral smooth muscle. Epithelial Cell Biol 1:76–83.PubMedGoogle Scholar
  6. 6.
    Hayward SW, Cunha GR, Dahiya R (1996) Normal development and carcinogenesis of the prostate: A unifying hypothesis. Ann N Y Acad Sei 784:50–62.CrossRefGoogle Scholar
  7. 7.
    Cunha GR, Young P (1991) Inability of Tfm (testicular feminization) epithelial cells to express androgen-dependent seminal vesicle secretory proteins in chimeric tissue recombinants. Endocrinology 128:3293–3298.PubMedCrossRefGoogle Scholar
  8. 8.
    Donjacour AA, Cunha GR (1993) Assessment of prostatic protein secretion in tissue recombinants made of urogenital sinus mesenchyme and urothelium from normal or androgen-insensitive mice. Endocrinology 131:2342–2350.CrossRefGoogle Scholar
  9. 9.
    Hayward S W, Baskin LS, Haughney PC etal. (1996) Stromal development in the ventral prostate, anterior prostate and seminal vesicle of the rat. Acta Anatomica 155:94–103.PubMedCrossRefGoogle Scholar
  10. 10.
    Nemeth JA, Lee C (1996) Prostatic ductal system in rats: Regional variation in stromal organization. Prostate 28:124–128.PubMedCrossRefGoogle Scholar
  11. 11.
    Ronnov-Jessen L, Peterson O, Bisseil M (1996) Cellular changes involved in conversion of normal to malignant breast: Importance of the stromal reaction. Physiological Rev 76:69–125.Google Scholar
  12. 12.
    Basset P, Wolf C, Chambon P (1993) Expression of the stromelysin-3 gene in fibroblastic cells of invasive carcinomas of the breast and other human tissues: a review. Breast Cancer Res Treat 24:185–193.PubMedCrossRefGoogle Scholar
  13. 13.
    Masson R, Lefebvre O, Noel A etal. (1998) In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy. J Cell Biol 140:1535–1541.PubMedCrossRefGoogle Scholar
  14. 14.
    Oishi K, Romijn JC, Schroeder FH (1981) The surface character of separated prostatic cells and cultured fibroblasts of prostatic tissue as determined by concanavalin-a hemadsorption. Prostate 2:11–21.PubMedCrossRefGoogle Scholar
  15. 15.
    Bosman FT, de Bruine A, Flohil C etal. (1993) Epithelial-stromal interactions in colon cancer. Int J Dev Biol 37:203–211.PubMedGoogle Scholar
  16. 16.
    Adam L, Crepin M, Lelong JC etal. (1994) Selective interactions between mammary epithelial cells and fibroblasts in co-culture. Int J Cancer 59:262–268.PubMedCrossRefGoogle Scholar
  17. 17.
    Hayward SW, Dahiya R, Cunha GR etal. (1995) Establishment and characterization of an immortalized but non-tumorigenic human prostate epithelial cell Line: BPH-1. In Vitro 31 A: 14–24.Google Scholar
  18. 18.
    Olumi AF, Grossfeld GD, Hayward SW etal. (1997) Human prostatic carcinoma-associated fibroblasts promote tumorigenesis, enhance proliferation and inhibit death of prostatic epithelial cells. Nature Medicine Submitted.Google Scholar
  19. 19.
    Thompson TC, Timme TL, Kadmon D etal. (1993) Genetic predisposition and mesenchymal-epithelial interactions in ras+myc-induced carcinogenesis in reconstituted mouse prostate. Molec Carcinogenesis 7:165–179.CrossRefGoogle Scholar
  20. 20.
    Camps JL, Chang S-M, Hsu TC etal. (1990) Fibroblast-mediated acceleration of human epithelial tumor growth in vivo. Proc Natl Acad Sei USA 87:75–79.CrossRefGoogle Scholar
  21. 21.
    Gleave ME, Hsieh JT, von Eschenbach AC etal. (1992) Prostate and bone fibroblasts induce human prostate cancer growth in vivo: implications for bidirectional tumor-stromal cell interaction in prostate carcinoma growth and metastasis. J Urol 147:1151–1159.PubMedGoogle Scholar
  22. 22.
    Wu HC, Hsieh JT, Gleave ME etal. (1994) Derivation of androgen- independent human LNCaP prostatic cancer cell sublines: role of bone stromal cells. Int J Cancer 57:406–412.PubMedCrossRefGoogle Scholar
  23. 23.
    Chung LWK, Chang S, Bell C etal. (1989) Co-inoculation of tumorigenetic rat prostate mesenchymal cells with non-tumorigenic epithelial cells results in the development of carcinosarcoma in syngeneic and athymic animals. Int J Cancer 43:1179–1187.PubMedCrossRefGoogle Scholar
  24. 24.
    Hayashi N, Tsuji M, Sugimura Y etal. (1996) Change in the morphological and functional cytodifferentiation induced by seminal vesicle mesenchyme in cell suspensions of rat Dunning prostatic adenocarcinoma cells. Int J Cancer 68:788–794.PubMedCrossRefGoogle Scholar
  25. 25.
    Hayashi N, Cunha GR (1991) Mesenchyme-induced changes in neoplastic characteristics of the Dunning prostatic adenocarcinoma. Cancer Res 51:4924–4930.PubMedGoogle Scholar

Copyright information

© Springer-Verlag New York, Inc. 2001

Authors and Affiliations

  • Gerald R. Cunha
  • Simon W. Hayward
  • Thea Tlsty
  • Gary D. Grossfeld

There are no affiliations available

Personalised recommendations