Here we report the characterization of an SV40 large-T antigen-immortalized stromal cell line, WPMY-1, derived from the same prostate as our previously described epithelial cell lines. The WPMY-1 cells were determined to be myofibroblasts on the basis of co-expression of smooth muscle alpha-actin and vimentin. They also show positive staining for androgen receptor, large-T antigen, and positive but heterogeneous staining for p53 and pRb. Their growth is stimulated by the synthetic androgen mibolerone to 145% of control (100%). Platelet-derived growth factor BB, epidermal growth factor and basic fibroblast growth factor, at 10 ng/ml, stimulated growth to 138, 143 and 146% of control, respectively. Transforming growth factor-beta, at 10 ng/ml, inhibited serum-induced growth to 65% of control in the presence of 1% serum, and bFGF-induced growth to 30% of control. A serum-free medium was developed for optimal growth of WPMY-1 cells. They show anchorage-independent growth in soft agar. Studies on paracrine interactions show that myofibroblast-conditioned medium causes a marked inhibition of growth in WPE1-10 cells, while conditioned medium from WPE1-10 prostatic epithelial cells caused only a small increase in the growth of WPMY-1 cells. WPMY-1 cells secrete very low levels of MMP-9 but high levels of MMP-2, markedly higher than the epithelial cells. These epithelial and myofibroblast cell lines, derived from the same prostate, provide novel and useful models for studies on paracrine stromal-epithelial interactions in carcinogenesis, tumor progression, prevention and treatment of prostate cancer and benign prostatic hyperplasia.

Adenocarcinoma of the prostate is the most common type of cancer, excluding skin cancer, and the second leading cause of cancer death in adult men in the United States. The lifetime risk for developing symptomatic prostate cancer is one in five for an American man. A pivotal step in carcinogenesis is a shift in the balance between proliferation, differentiation, and apoptosis that favors cell proliferation. Transforming growth factor-beta (TGF-beta) is a key negative growth regulator in the normal prostate. Although TGF-beta) inhibits the proliferation of normal prostate cells and functions as a tumor suppressor in early tumorigenesis, it acts as a tumor promoter in later stages of tumor progression. Elevated expression of TGF-beta in prostate cancer cells is associated with poor clinical outcome. Over-expression of TGF-beta aids tumorigenesis by not only stimulating angiogenesis and suppressing the immune system, but also by acting directly on the prostate tumor cells. While prostate cancer cells become resistant to TGF-beta-induced growth inhibition and apoptosis, they retain other TGF-beta-induced responses that enhance tumorgenicity. such as induction of extracellular matrix proteins, cell adhesion proteins and proteases. These direct tumor effects are mediated primarily through Smad signaling. This review addresses the mechanisms by which prostate cancer cells may acquire TGF-beta resistance and promote tumorgenicity. Understanding the mechanisms underlying TGF-beta resistance is important for the identification and development of better diagnostic markers and more effective strategies for treating prostate cancer.

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