Mechanisms of TGFbeta Production in Human Cancer Cells

描述：（应用摘要）虽然TGF β是一种内源性生长因子， 上皮细胞的生长抑制剂，这种生长抑制反应通常会丢失 in solid实体tumors肿瘤.显示TGF β受体表达改变的癌细胞 是那些不再显示生长抑制敏感性的细胞之一。然而，在这方面， 抗TGF β细胞仍然能够产生大量的 多肽。由于TGF β的旁分泌作用在很大程度上是肿瘤增强的， 一旦肿瘤上皮细胞变得对TGF β介导的生长不敏感 因此，在抑制肿瘤生长的情况下，关闭肿瘤细胞TGF β的产生似乎是有利的。 这种方法应该减少TGF β的旁分泌，肿瘤促进作用， 可以为旨在恢复TGF β生长的策略提供一种新的替代方案 对耐药肿瘤细胞的抑制敏感性。我们的初步研究 已经揭示了许多介导TGF β 1产生的信号成分。 拟议研究的结果将定义更微妙的机制， 有助于生产的TGF β 1，并将阐明生产级联 TGFb2和TGFb3同种型。我们假设，在细胞中的特定蛋白质， TGF β产生级联在晚期过度表达或过度激活 由于TGF β受体而失去自分泌负性TGF β调节的肿瘤 缺陷我们将研究人类结肠中的相关信号成分 体外和结肠癌、乳腺癌和前列腺癌中的癌细胞（HCC细胞） 患者的样本。将进行后面的分子谱研究 用激光捕获显微切割获得的纯细胞群。我们 也将稳定表达相关的反义或野生型形式 HCCC模型系统中的信号组件，以确定对 癌细胞在体外和体内的致瘤潜力。因此，少校 本提案的目标是描述TGF b的组成部分 在体外人癌细胞中和在体外人癌细胞中改变的生产级联， 体内，并确定这些特定成分的阻断是否会 减少肿瘤细胞TGFb的产生，其对基质细胞的旁分泌作用，和 其在体内的致瘤潜力。因此，本报告中提出的研究 应用将证明基于TGF β的治疗剂的潜在效用 针对已经发展到TGFB生长点的上皮癌 抑制性不敏感

DESCRIPTION: (Application Abstract) Although TGFb is an endogenous growth inhibitor for epithelial cells, this growth inhibitory response is often lost in solid tumors. Cancer cells displaying altered expression of TGFb receptors are among those that no longer display growth inhibitory sensitivity. However, the TGFb-resistant cells are still able to produce large quantities of the polypeptide. Since the paracrine effects of TGFb are largely tumor-enhancing, once the tumor epithelial cells have become refractory to TGFb-mediated growth inhibition, it would seem advantageous to shut off tumor cell TGFb production. This approach should reduce the paracrine, tumor-promoting effects of TGFb and could provide a novel alternative to strategies designed to restore TGFb growth inhibitory sensitivity to the resistant tumor cells. Our preliminary studies have revealed many of the signaling components which mediate TGFb1 production. The results of the proposed studies will define more subtle mechanisms which contribute to production of TGFb1, and will elucidate the production cascades for the TGFb2 and TGFb3 isoforms. We hypothesize that specific proteins in the TGFb production cascades are over-expressed or over-activated in late-stage tumors that have lost autocrine negative TGFb regulation due to TGFb receptor defects. We will examine the relevant signaling components in human colon carcinoma cells (HCCCs) in vitro and in colon, breast, and prostate cancer samples from patients. The latter molecular profiling studies will be performed with pure populations of cells procured by laser capture microdissection. We will also stably express antisense or wild-type versions of the relevant signaling components in HCCC model systems to determine the effect on the tumorigenic potential of the cancer cells in vitro and in vivo. Thus, the major objectives of this proposal are to delineate the components of the TGFb production cascades which are altered in human cancer cells in vitro and in vivo, and to determine whether blockade of these specific components will reduce tumor cell TGFb production, its paracrine effects on stromal cells, and its tumorigenic potential in vivo. Accordingly, the studies proposed in this application will demonstrate the potential utility of TGFb-based therapeutics against epithelial cancers which have progressed to the point of TGFB growth inhibitory insensitivity.