TUMOR PROMOTING EFFECTS OF TGF-BETA1

转化生长因子（tgf - β）是一种多功能因子，可诱导多种影响细胞生长和分化的过程。在包括肠上皮在内的正常上皮细胞中，tgf - β具有有效的生长抑制作用和肿瘤抑制作用。另一方面，在特定条件下，tgf - β实际上可能促进肿瘤发生。tgf - β受体和选择的tgf - 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，tgf - β的几种作用，如趋化活性和侵袭性增加，COX-2和前列腺素释放的表达增加以及RhoB表达的增加，导致COX-2和前列腺素释放的上皮到间质表达和RhoB表达的增加导致上皮到间质转化（EMT）。根据最近的观察，该提议的中心假设是：在肠道和其他类型的上皮细胞中，由于tgf - β信号转导的改变，tgf - 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，选择性地靶向tgf - β的肿瘤促进作用，同时保留肿瘤抑制作用。

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.