TGF-Beta Regulation of Intestinal Epithelial Cells

描述(由申请人提供)：结直肠肿瘤是美国癌症发病率和死亡率的主要原因。尽管基因组学革命在癌症治疗方面取得了令人瞩目的进展，但这些进展并未转化为晚期疾病患者存活率的绝对改善。因此，继续研究结肠癌的分子发病机制，以提高结肠癌的诊断和治疗水平是至关重要的。在过去的十年里，我们研究了自分泌生长抑制因子，转化生长因子β(TGFβ)，在正常和异常的肠上皮生长中。在此期间，其受体TGFbet和Smad信号通路被决定性地认为是肠上皮细胞肿瘤抑制的关键轴。然而，在某些情况下，TGFbeta信号可能有助于促进肿瘤，这是一种在肿瘤疾病中日益被认识到的二元性功能。我们建议在体内和体外的肠道肿瘤模型中探索TGFbeta的这种双重活性，特别是在致癌RAS的背景下，我们将其定义为生长抑制Smad依赖的TGFbeta信号的关键抑制因子。最重要的假设是，在肿瘤发生的早期，TGFbeta是一种肿瘤抑制因子，通过Smad依赖的信号转导。在疾病的后期阶段，部分受致癌RAS的影响，TGFbeta信号转换为促进肿瘤的信号。具体目的是1)验证组蛋白脱乙酰酶是Smad结合伙伴和Smad依赖的信号调节器的假设；2)使用微阵列分析测试TGFbeta在RAS转化的细胞中诱导独特的转录组的假设，然后利用结果进一步鉴定TGFbeta是肿瘤促进剂；3)使用TGFbeta信号增强的基因工程小鼠来测试TGFbeta将在TGFbeta信号和结直肠癌的动物模型中同时具有肿瘤抑制和促进肿瘤功能的假设。对肿瘤抑制和TGFβ促肿瘤作用途径的剖析将使我们有机会在不影响其肿瘤抑制功能的情况下选择性地抑制其不良作用。

DESCRIPTION (provided by applicant): Colorectal neoplasia is a leading cause of cancer morbidity and mortality in the United States. Although the genomics revolution has resulted in high profile advances in cancer therapeutics, these have not translated into a definitive improvement in the survival of patients with advanced disease. Thus, it is critical to continue the study of the molecular pathogenesis of colon cancer with the goal of improved diagnosis and treatment. Over the past decade, we have studied the autocrine growth inhibitory factor, transforming growth factor beta(TGFbeta), in normal and aberrant intestinal epithelial growth. During this interval, TGFbet, its receptor, and the Smad signaling pathway have been decisively recognized as a critical axis of tumor suppression in the intestinal epithelium. In certain contexts however, TGFbeta signaling may contribute to tumor promotion, a duality of function that is increasingly recognized in neoplastic disorders. We propose to explore this dual activity of TGFbeta in in vivo and in vitro models of intestinal neoplasia, especially in the context of oncogenic Ras, which we have defined as a key repressor of growth inhibitory Smad-dependent TGFbeta signaling. The overarching hypothesis is that TGFbeta is a tumor suppressor via Smad-dependent signaling early in tumorigenesis. At later stages of disease TGFbeta signaling switches, in part under the influence of oncogenic Ras, to tumor promotion. The specific aims are to 1) test the hypothesis that histone deacetylases are Smad-binding partners and modulators of Smad-dependent signaling; 2) test the hypothesis, using microarray analysis, that TGFbeta induces a unique transcriptome in Ras-transformed cells and then use the results to further characterize TGFbeta as a tumor promoter; 3) test the hypothesis that TGFbeta will have both tumor suppressing and tumor promoting functions in animal models of TGFbeta signaling and colorectal cancer using genetically engineered mice in which TGFbeta signaling is enhanced. Dissection of the pathways involved in the tumor suppressive versus the tumor promoting effects of TGFbeta will lead to opportunities to selectively inhibit its undesirable effects without compromising its tumor suppressive functions.