Loss of responsiveness to transforming growth factor β induces malignant transformation of nontumorigenic rat prostate epithelial cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 1999-10, Vol.59 (19), p.4834-4842
• Main Authors: BINWU TANG, DE CASTRO, K, BARNES, H. E, PARKS, W. T, STEWART, L, BÖTTINGER, E. P, DANIELPOUR, D, WAKEFIELD, L. M
• Format: Article
• Language: English
• Subjects: Animal tumors. Experimental tumors; Animals; Apoptosis - drug effects; Biological and medical sciences; Cell Differentiation - drug effects; Cell Division - drug effects; Cell Line; Cell Transformation, Neoplastic; Epithelial Cells; Experimental renal and urinary tract tumors; Extracellular Matrix Proteins - genetics; Gene Expression Regulation - drug effects; Humans; Male; Medical sciences; Mice; Mice, Nude; Prostate; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Protein-Serine-Threonine Kinases; Rats; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - physiology; Recombinant Proteins - metabolism; Transfection; Transforming Growth Factor beta - pharmacology; Transplantation, Heterologous; Tumors
• ISSN: 0008-5472; 1538-7445

Transforming growth factor (TGF)-betas are multifunctional growth factors, the properties of which include the potent inhibition of epithelial cell growth. Expression patterns of TGF-betas and TGF-beta receptors in the normal prostate indicate that these growth regulators play key roles in prostatic development and proliferative homeostasis. Importantly, TGF-beta receptor levels are frequently diminished in malignant human prostate tissue. To test the hypothesis that loss of TGF-beta responsiveness is causally involved in the tumorigenic process, we have used retroviral transduction to introduce a dominant-negative mutant type II TGF-beta receptor (DNR) into the premalignant rat prostatic epithelial cell line, NRP-152. High-level expression of the DNR abolished the ability of TGF-beta to inhibit cell growth, to promote cell differentiation, and to induce apoptosis, and it partially blocked the induction of extracellular matrix gene expression. When injected into nude mice, NRP-152-DNR cells formed carcinomas at 13 of 34 sites, compared with 0 of 30 sites for parental and control cells (P = 0.0001). We conclude that the type II TGF-beta receptor is an important tumor suppressor in the prostate, and furthermore, that loss of TGF-beta responsiveness can contribute early in the tumorigenic process by causing the malignant transformation of preneoplastic cells.