Mechanisms of TGFbeta Production in Human Cancer Cells

人类癌细胞中 TGFbeta 产生的机制

• 批准号: 6732111
• 负责人: Kathleen M Mulder
• 金额: $ 31.93万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6732111
• 关键词: AP1 protein; JUN kinase; antisense nucleic acid; athymic mouse; breast neoplasms; colon neoplasms; enzyme activity; genetic promoter element; growth factor receptors; human tissue; mitogen activated protein kinase; mixed tissue /cell culture; neoplasm /cancer genetics; paracrine; prostate neoplasms; protein isoforms; transforming growth factors

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.

描述：（应用摘要）尽管TGFB是内源性生长 上皮细胞的抑制剂，这种生长抑制反应常常丢失 在实体瘤中。显示TGFB受体表达改变的癌细胞 是不再表现出生长抑制敏感性的人之一。然而， TGFB耐药细胞仍然能够产生大量 多肽。由于TGFB的旁分泌作用在很大程度上是肿瘤的增强作用 一旦肿瘤上皮细胞已对TGFB介导的生长难治 抑制作用，关闭肿瘤细胞TGFB产生似乎是有利的。 这种方法应减少TGFB和 可以提供旨在恢复TGFB增长的策略的新颖替代品 对抗性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。 拟议研究的结果将定义更微妙的机制 为TGFB1的生产做出贡献，并将阐明生产级联 对于TGFB2和TGFB3同工型。我们假设在 TGFB生产级联反表达或过度激活 由于TGFB受体而导致的自分泌阴性TGFB调节的肿瘤 缺陷。我们将检查人类结肠中相关的信号传导成分 体外和结肠，乳腺癌和前列腺癌的癌细胞（HCCC）细胞（HCCC） 来自患者的样本。将进行后一种分子分析研究 通过激光捕获微分解的纯细胞种群。我们 还将稳定表达相关的反义或野生型版本 HCCC模型系统中的信号传导组件，以确定对 癌细胞在体外和体内的致瘤潜力。因此，专业 该提案的目标是描述TGFB的组件 生产级联反应在人类癌细胞中在体外和 体内，并确定这些特定组件的封锁是否会 减少肿瘤细胞TGFB产生，旁分泌对基质细胞的影响，以及 它在体内的致瘤潜力。因此，提出的研究 应用将证明基于TGFB的治疗剂的潜在实用性 反对已经发展到TGFB增长点的上皮癌 抑制性不敏感。