Induction of transforming growth factor beta in hormonally treated human prostate cancer

Abstract

Summary Transforming growth factor beta-i (TGF-P1) has been proposed as a mediator of tumour growth in a number of tumours and cell lines including prostate, and in a recent study was shown to be up-regulated in the stroma of breast cancer tissue following treatment with the anti-oestrogen tamoxifen. Immunolocalisation of the intracellular form of TGF-P1 confirmed that the source of the stromal TGF-Pf was the peritumoral fibroblasts. We present here the results of a study in which five patients with hormonally unresponsive prostatic carcinoma and seven patients responding to a luteinising hormone-releasing hormone analogue had prostate biopsies taken before and during treatment. These were stained for TGF-P expression prior to treatment and at either relapse or 3 months later respectively. Six of seven clinically responding tumours and three of five relapsed tumours showed up-regulation of extracellular TGF-p1, again primarily in the stroma, with no apparent up-regulation of intracellular TGF-p1, TGF-P2 or TGF-P3. These data illustrate that the epithelial growth inhibitor TGF-P1 can be induced by hormonal manipulation in prostate cancer in vivo, and may continue to be up-regulated even after relapse. This suggests that relapse of hormonally treated prostate cancer may be associated with a failure of the epithelium to respond to stromal TGF-p1.

A Phase I/II Study of High-Dose Tamoxifen in Combination with Vinblastine in Patients with Androgen-Independent Prostate Cancer

“…Loss of responsiveness to TGF-b has been associated with clinical progression of prostate cancer (11), and there is also some speculation that it might be responsible for androgenindependent disease. Tamoxifen (1-[p dimethylaminoethoxyphenyl]-1,2-diphenyl-1-butene) has been shown to upregulate TGF-b production and activation by many cell types including human prostate cancer cell lines (29) and human breast cancer cell lines (30). Tamoxifen has also been shown to inhibit prostate cancer cell growth by its PKC inhibitory activity (31) and induction of p21 wafl/cip 1 (12).…”

“…Hence, Tamoxifen has been shown to reverse the early molecular and cellular events leading to prostate carcinogenesis (32). This clinical trial was designed to expand on the preclinical observation that high-dose tamoxifen increases the sensitivity of prostate cancer cells to growth inhibition by TGF-b, induces stromal cell production of TGF-b and induces cell-cycle blockade at the G 1 /S-phase interphase (12,29). Vinblastine, is known to bind directly to tubulin, causing disruption of microtubules composing the mitotic spindle (33) and thus blocking the cell in the G 2 /M-phase interphase.…”

Synthesis and secretion of transforming growth factor beta isoforms by primary cultures of human breast tumour fibroblasts in vitro and their modulation by tamoxifen

“…However, such induction of TGF-3,1 may not be a property unique to tamoxifen. Recently, up-regulation of extracellular TGF-,B has been observed in prostate cancer patients following various forms of ablative androgen therapy (Muir et al, 1994). Therefore, TGF-# induction may be a common step in several therapeutic interventions which may not involve classical hormone receptors.…”

Clinical Approaches to Osseous Metastases in Prostate Cancer

“…Factors such as transforming growth factor beta (TGF-β) form a component of the proposed basis of such linkage. TGF-β, which is produced by prostate cancer cell lines [34] and is elevated in prostate cancer pathology specimens [35,36], activates both osteoblast bone deposition and osteoclastic bone resorption [37]. Furthermore, suppressing osteoclast activity results in a decrease in osteoblastic lesions.…”