TGF beta in prostate cancer: a growth inhibitor that can enhance tumorigenicity.
A common feature of cancer cells is the autocrine production of growth promoters and the loss of function of tumor suppressors. In our search for such features of prostate cancer, we discovered that transforming growth factor beta 1 (TGF beta 1) levels are higher in prostate cancer than in normal prostate, and prostate cancer cells can activate endogenously-produced latent TGF beta to a bioactive form. Because TGF beta 1 is a potent growth inhibitor of epithelial cells, it seems paradoxical that malignant epithelial cells make high levels of a growth inhibitor. Even prostate cancer cells can be growth-inhibited by TGF beta 1, but only under specific conditions in vitro (plating at low cell density in serum-free medium), and this response is readily disrupted by growth factors, serum, and extracellular matrix, to all of which the cells are exposed in vivo. This explains why prostate cancer cells are resistant to the growth-inhibitory effect of TGF beta in vivo. In vivo, TGF beta 1 actually enhances prostate tumor growth and metastasis, but not by affecting tumor cell proliferation directly. One possibility is that TGF beta affects the host to allow increased numbers of tumor cells to survive and produce progeny. In addition, since prostate cancer cells can still respond to TGF beta, e.g., by increased cell motility, even under conditions that prevent growth inhibition, the ability of TGF beta to enhance tumorigenicity in vivo might also occur via direct effects on the tumor cells themselves. I will discuss new developments in our understanding of TGF beta action, which provide a framework for elucidating the mechanism by which prostate cancer cells have devised a way to protect themselves from being growth-inhibited by TGF beta 1 in vivo. Since the cells retain the ability to be growth-inhibited by TGF beta, indicating that the TGF beta receptors and signaling pathways for growth inhibition are intact, albeit inactive, it might be possible to reactivate this pathway to achieve a therapeutic benefit in vivo.
Barrack
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Department of Urology, University School of Medicine, Baltimore, Maryland, USA.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D008297:Male; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011467:Prostate / Q000737:chemistry / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta