CDX2 Tumor Suppressor Pathway Defects in Colon Cancer

描述（由申请人提供）：在定义胃肠道癌症发病机制中的关键突变和基因表达变化方面取得了很大进展。在结直肠癌中，腺瘤性结肠息肉病（APC）、K-RAS和p53基因的突变具有决定性作用，其他癌基因和肿瘤抑制基因的缺陷以更多变的方式促进癌症的发展和进展。在人类和/或小鼠中发现易诱发肿瘤发展的特定生殖系（体质）缺陷提供了突出和澄清参与散发性肿瘤发展的基因和机制的可能性。例如，尾部相关Cdx 2同源框转录因子基因失活的杂合小鼠发展结肠息肉，其中上皮细胞失去CDX 2表达，与CDX 2的潜在肿瘤抑制功能一致，并且在人类的一些低分化结肠癌中观察到CDX 2表达的丧失。相反，转基因小鼠胃上皮中的异位CDX 2表达促进肠上皮化生，并且，在人类中，CDX 2表达经常见于胃中产生的肠上皮化生以及胃癌。因此，我们的主要假设是，CDX 2蛋白作为胃肠上皮细胞增殖和分化的关键调节因子发挥作用，并且其功能的缺陷，无论是结肠上皮细胞的功能丧失还是胃上皮细胞的功能获得，都可以促进肿瘤转化。为了更好地理解CDX 2缺陷对胃肠道肿瘤发病机制的贡献，我们提出了以下具体目标。在特定目标1中，我们将定义直接受CDX 2调控的特定细胞基因。在特定目标2中，我们将评估选定的CDX 2调节基因在胃肠道癌细胞增殖、分化和致瘤性生长中的作用。在具体目标3中，我们将使用小鼠癌症模型探索Cdx 2和有限数量的高度感兴趣的CDX 2调节基因在结肠肿瘤发病机制中的作用。除了推进对胃肠道癌症发病机制的认识外，这些结果还可以为改善结直肠癌和其他癌症患者的诊断和治疗提供新的策略。

DESCRIPTION (provided by applicant): Much progress has been made in defining critical mutations and gene expression changes in gastrointestinal cancer pathogenesis. In colorectal cancer, mutations in the adenomatous polyposis coli (APC), K-RAS, and p53 genes have decisive roles, and defects in other oncogenes and tumor suppressor genes contribute in a more variable fashion to cancer development and progression. The discovery of specific germline (constitutional) defects predisposing to tumor development in man and/or the mouse offers the possibility of highlighting and clarifying genes and mechanisms involved in sporadic tumor development. For instance, mice heterozygous for inactivation of the caudal-related Cdx2 homeobox transcription factor gene develop colonic polyps in which the epithelial cells lose CDX2 expression, consistent with a potential tumor suppressor function for CDX2, and loss of CDX2 expression is seen in some poorly differentiated colon carcinomas in man. Conversely, ectopic CDX2 expression in gastric epithelium of transgenic mice promotes intestinal metaplasia, and, in man, CDX2 expression is often seen in intestinal metaplasia arising in the stomach as well as gastric carcinomas. Hence, our primary hypothesis is that the CDX2 protein functions as a critical regulator of proliferation and differentiation in gastrointestinal epithelial cells and defects in its function, either loss-of-function in colonic epithelial cells or gain-of-function in gastric epithelial cells, can promote neoplastic transformation. To better understand the contribution of CDX2 defects to the pathogenesis of gastrointestinal tumors, we propose to pursue the following specific aims. In Specific Aim 1, we will define specific cellular genes that are directly regulated by CDX2. In Specific Aim 2, we will assess the role of selected CDX2-regulated genes in proliferation, differentiation, and tumorigenic growth of gastrointestinal cancer cells. In Specific Aim 3, we will explore the role of Cdx2 and a limited number of high interest CDX2-regulated genes in the pathogenesis of colon tumors, using mouse cancer models. In addition to advancing knowledge of gastrointestinal cancer pathogenesis, the results may offer insights into novel strategies for improving the diagnosis and treatment of patients with colorectal and other cancers.