Mechanisms of TGFbeta Production in Human Cancer Cells

描述：（应用摘要）虽然 TGFb 是一种内源性生长 上皮细胞的抑制剂，这种生长抑制反应经常消失 在实体瘤中。癌细胞显示 TGFb 受体表达改变 属于不再表现出生长抑制敏感性的那些。然而， TGFb 抗性细胞仍然能够产生大量 多肽。由于 TGFb 的旁分泌作用主要是增强肿瘤， 一旦肿瘤上皮细胞变得难以抵抗 TGFb 介导的生长 抑制，关闭肿瘤细胞 TGFb 的产生似乎是有利的。 这种方法应该减少 TGFb 和 TGFb 的旁分泌、促肿瘤作用。 可以为旨在恢复 TGFb 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 揭示了许多介导 TGFb1 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 TGFb1 的产生，并将阐明生产级联 对于 TGFb2 和 TGFb3 亚型。我们假设特定蛋白质 TGFb 产生级联在后期过度表达或过度激活 由于 TGFb 受体而失去自分泌阴性 TGFb 调节的肿瘤 缺陷。我们将检查人类结肠中的相关信号成分 体外以及结肠癌、乳腺癌和前列腺癌中的癌细胞 (HCCC) 来自患者的样本。后者的分子谱研究将进行 通过激光捕获显微切割获得纯细胞群。我们 还将稳定表达相关的反义或野生型版本 HCCC 模型系统中的信号成分以确定对 癌细胞在体外和体内的致瘤潜力。因此，主要 该提案的目标是描述 TGFb 的组成部分 在体外和体内人类癌细胞中发生改变的生产级联 体内，并确定这些特定成分的封锁是否会 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 其体内致瘤潜力。因此，本研究中提出的研究 应用将展示基于 TGFb 的疗法的潜在效用 对抗已进展至 TGFB 生长点的上皮癌 抑制不敏感。

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.