CDX2 TUMOR SUPPRESSOR PATHWAY DEFECTS IN COLON CANCER

结直肠癌发生的病因和暴露是复杂的。尽管如此，在过去的十年中，已经对遗传和体细胞突变在结直肠癌中的作用有了清晰的认识。癌基因（如K-ras）和肿瘤抑制基因（如APC和p53基因）突变的逐步积累被认为是启动腺瘤性息肉形成并随后发展为完全侵袭性和转移性癌症的关键。尽管取得了相当大的进展，但结直肠癌发展背后的其他突变仍有待发现。此外，如果我们希望了解特定突变对癌细胞表型的影响，还有很多工作要做。最近的研究表明，肠道特异性同源盒基因Cdx2的一个等位基因的种系失活，使小鼠在小肠和结肠中容易发生腺瘤性息肉和癌症。我们对确定这一发现与人类结直肠癌的生物学相关性特别感兴趣。我们的初步研究表明，CDX2表达减少或缺失在很大一部分结直肠癌中可见；在一些病例中存在CDX2突变；和CDX2的改变似乎独立于其他基因缺陷而出现。我们已经确定了几个候选的CDX2结合蛋白，这些蛋白可以让我们确定CDX2发挥作用的生长调控途径。本申请所提出的研究将进一步探讨CDX2通路异常在人类结直肠癌中的性质和意义。提出了四个具体目标：1)在结直肠癌细胞系、异种移植物和原发肿瘤中开展全面的CDX2突变分析和表达研究；II)明确肿瘤中CDX2基因表达缺陷的机制；III)确定CDX2是否作为体外生长和/或肿瘤发生的抑制因子，如果是，确定CDX2调节的靶基因；IV)鉴定Cdx-2相互作用蛋白并确定其在癌症发展中的作用。除了进一步加深我们对结直肠癌发病机制的理解外，我们的应用研究可能为改善结直肠癌患者的诊断和治疗提供新的见解。

The etiological factors and exposures that underlie colorectal cancer development are complex. Nevertheless, in the past decade, clearcut insights into the role of inherited and somatic mutations in colorectal cancer have been obtained. The stepwise accumulation of mutations in oncogenes, such as K-ras, and tumor suppressor genes, such as the APC and p53 genes, is believed critical in initiating adenomatous polyp formation and subsequent progression to fully invasive and metastatic cancer. Despite the considerable progress, additional mutations that underlie colorectal cancer development await discovery. Moreover, much work remains if we hope to understand the means by which specific mutations contribute to the cancer cell phenotype. Recent studies indicate that germline inactivation of one allele of an intestinal-specific homeobox gene, known as Cdx2, strongly predisposes mice to the development of adenomatous polyps and cancers in the small intestine and colon. We are particularly interested in determining the biological relevance of this finding with respect to human colorectal cancer. Our preliminary studies indicate that reduced or absent CDX2 expression is seen in a significant fraction of colorectal cancer; CDX2 mutations are present in some cases; and CDX2 alterations appear to arise independently of other gene defects. We have identified several candidate Cdx2-binding proteins that may allow us to define the growth regulatory pathway(s) in which CDX2 functions. The studies proposed in this application will further explore the nature and significance of CDX2 pathway abnormalities in human colorectal cancer. Four specific aims are proposed: I) To carry out comprehensive CDX2 mutational analyses and expression studies in colorectal cancer cell lines, xenografts, and primary tumors; II) To define mechanisms underlying CDX2 gene expression defects in cancer; III) To determine if CDX2 functions as a suppressor of in vitro growth and/or tumorigenesis, and if so, to define CDX2- regulated target genes; and IV) To identify Cdx-2 interacting proteins and address their role in cancer development. In addition to furthering our understanding of colorectal cancer pathogenesis, the studies in our application may offer novel insights for improving the diagnosis and treatment of patients with colorectal cancer.