Targeting TGF-beta in prostate cancer: therapeutic possibilities during tumor progression.
BACKGROUND
TGF-beta regulates prostate growth by inhibiting epithelial cell proliferation and inducing apoptosis through eliciting a dynamic signaling pathway. In metastatic prostate cancer, however, TGF-beta serves as a tumor promoter. TGF-beta engages Smad-dependent and Smad-independent mechanisms to exert its action. During prostate tumorigenesis, prostate cells exhibit loss or mutation of TGF-beta transmembrane receptors. Increased production of TGF-beta causes immunosuppression, extracellular matrix degradation, epithelia to mesenchymal transition and angiogenesis that promotes tumor cell invasion and metastasis.


OBJECTIVE
The molecular basis for effective therapeutic targeting of TGF-beta must be directed towards the double-edge-sword nature of the cytokine: inhibiting the TGF-beta tumor promoter capabilities in advanced metastatic prostate cancer, although retaining the growth-inhibitory abilities exhibited in early stages of prostate tumorigenesis.


CONCLUSIONS
The current understanding of the therapeutic possibilities of targeting TGF-beta signaling during prostate tumor progression is built on preclinical studies. Studies targeting TGF-beta signaling pathway for the treatment of several human malignancies include the use of neutralizing antibodies, antisense oligonucelotides and small molecule inhibitors of kinase activity of the receptor complex. This review focuses on exploiting the therapeutic potential of targeting TGF-beta signaling in the context of its contribution to prostate cancer initiation and progression to metastasis.
Jones
Elisabeth
E
University of Kentucky, Surgery/Urology and Markey Cancer Center, 306 Combs Building, 800 Rose Street, Lexington, KY 40536, USA.
Pu
Hong
H
Kyprianou
Natasha
N
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D018450:Disease Progression; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D016212:Transforming Growth Factor beta