TUMOR PROMOTING EFFECTS OF TGF-BETA1

转化生长因子是一种多功能因子，可诱导多种细胞过程影响生长和分化。在包括肠上皮在内的正常上皮细胞中，转化生长因子-β具有很强的生长抑制作用和肿瘤抑制作用。另一方面，在选定的条件下，转化生长因子-β实际上可能促进肿瘤的发生。转化生长因子-β受体和特定的转化生长因子-β信号转导蛋白(Smad蛋白家族)的突变与很大一部分人类结直肠癌和胰腺癌有关。有证据表明，转化生长因子-β的多种作用，如增加趋化活性和侵袭力，增加COX-2的表达和前列腺素释放，以及增加RhoB的表达，导致上皮细胞向间充质细胞的表达，前列腺素释放和RhoB的增加，导致上皮细胞向间充质细胞的转变(EMT)。根据最近的观察，这一建议的中心假设是：由于转化生长因子-β信号转导的改变，在肠道和其他类型的上皮细胞中，转化生长因子-β的促肿瘤作用超过了肿瘤抑制作用。这项研究的长期目标是确定新的治疗策略，在保留肿瘤抑制作用的同时，选择性地针对转化生长因子-β的促肿瘤作用。

Transforming growth factor (TGF-beta) is a multi-functional factor that induces a wide variety of cellular processes affecting growth and differentiation. In normal epithelial cells, including intestinal epithelium, TGF-beta has a potent growth inhibitory effect and serves a tumor suppressor role. On the other hand, under selected conditions TGF-beta may actually promote tumorigenesis. Mutations in the TGF-beta receptors and selected TGF-beta signal transduction proteins (Smad family of proteins) have been associated with a significant fraction of human colorectal and pancreatic cancers. Evidence suggests that several effects of TGF-beta such as increased chemotactic activity and invasiveness, increased expression of COX-2 and prostaglandin release and increased expression of RhoB cause a epithelial to mesenchymal expression of COX-2 and prostaglandin release and increased expression of RhoB cause a epithelial to mesenchymal transition (EMT). Based on recent observations, the central hypothesis of this proposal is: tumor promoting effects of TGF-beta over-ride tumor suppressor effects during of intestinal and other types of epithelial cells, due to a witch in TGF-beta signal transduction. A long term of this investigation is to identify novel therapeutic strategies that selectively target the tumor promoting effects of TGF-beta, while preserving the tumor suppressive actions.