Mechanisms of TGFbeta Production in Human Cancer Cells

描述：(应用摘要)尽管TGFb是一种内生增长 上皮细胞的抑制剂，这种生长抑制反应通常会丢失 在实体瘤中。肿瘤细胞表达TGFb受体的改变 属于不再表现出生长抑制敏感性的那些。然而， 抗TGFb的细胞仍然能够产生大量的 多肽。由于TGFb的旁分泌作用主要是增强肿瘤， 一旦肿瘤上皮细胞对TGFb介导的生长产生抵抗力 抑制，似乎有利于阻断肿瘤细胞TGFb的产生。 这种方法应该会减少TGFb和TGFb的旁分泌、促肿瘤作用 可以为旨在恢复TGFb增长的战略提供新的替代方案 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TGFb1产生的信号成分。 拟议的研究结果将定义更微妙的机制， 有助于TGFb1的生产，并将阐明生产级联 对于TGFb2和TGFB3亚型。我们假设细胞内的特定蛋白质 TGFb生产级联在后期过度表达或过度激活 由于TGFb受体而失去自分泌负TGFb调节的肿瘤 缺陷。我们将研究人类结肠中的相关信号成分。 体外及结肠癌、乳腺癌和前列腺癌中的癌细胞 病人的样本。将进行后一项分子图谱研究。 通过激光捕获显微切割获得纯净的细胞群。我们 也会稳定地表达相关的反义或野生型版本 HCCC模型系统中的信令组件以确定对 癌细胞在体内和体外的致瘤潜能。因此，少校 这项提案的目标是勾勒出政府融资平台的组成部分。 人类癌细胞在体外和体内发生变化的产生级联反应 体内，并确定阻断这些特定成分是否会 减少肿瘤细胞TGFb的产生及其对基质细胞的旁分泌作用，以及 它在体内的致瘤潜力。因此，本报告中提出的研究 应用将展示基于肿瘤生长因子b的治疗的潜在效用 抗上皮癌，已经发展到TGFb生长的地步 抑制性麻木不仁。

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.