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

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.

转化生长因子-β（TGF - β）是多功能生长因子，其特性包括对上皮细胞生长的强效抑制。TGF - β及其受体在正常前列腺中的表达模式表明，这些生长调节剂在前列腺发育和增殖稳态中起关键作用。重要的是，在人类前列腺恶性组织中，TGF - β受体水平常常降低。为了验证TGF - β反应性丧失在肿瘤发生过程中起因果作用这一假设，我们利用逆转录病毒转导将一种显性负性Ⅱ型TGF - β受体突变体（DNR）导入癌前大鼠前列腺上皮细胞系NRP - 152。DNR的高水平表达消除了TGF - β抑制细胞生长、促进细胞分化和诱导细胞凋亡的能力，并部分阻断了细胞外基质基因表达的诱导。当注射到裸鼠体内时，NRP - 152 - DNR细胞在34个位点中的13个形成了癌，而亲本细胞和对照细胞在30个位点中均无癌形成（P = 0.0001）。我们得出结论，Ⅱ型TGF - β受体是前列腺中一种重要的肿瘤抑制因子，而且，TGF - β反应性的丧失可通过导致癌前细胞的恶性转化在肿瘤发生过程的早期起作用。