MUCIN GLYCOPROTEINS IN COLON CANCER METASTASIS

结直肠癌是北美第二常见的上皮性癌症，据估计，美国每年的死亡率为55000人。大多数与结肠癌相关的死亡是由于转移，这是一个复杂的多步骤过程，通过这个过程，肿瘤细胞逃离原发肿瘤，并在远处建立次要病灶。粘蛋白是结肠癌的主要分泌糖蛋白，Galectin-3是一种内源性粘蛋白结合蛋白，在结肠癌转移中起重要作用。通过相互作用的配体和结构基序的鉴定，现在出现了支持粘蛋白和Galectin-3的特定功能的直接证据(S)。粘蛋白至少由9个基因编码，虽然MUC2基因在粘液性癌中的作用已经确定，但MUC2和其他粘蛋白的哪些结构域是促进结肠癌细胞转移所必需的仍有待确定。Galectin-3也由不同的结构域组成。该蛋白可能定位于细胞核、细胞质、细胞表面或由结肠癌细胞分泌，因此可能以多种方式促进转移。这项建议的长期目标是确定结肠癌细胞表面和分泌的糖蛋白如何影响其转移能力。根据目前的资助期间的进展，将继续努力阐明结肠癌粘蛋白、粘蛋白结合蛋白和转移之间的结构-功能关系。我们假设，粘蛋白辅基蛋白和谷胶凝集素-3的特定结构域对于它们的转移促进作用是必要的，并且在结肠癌转移的特定阶段，这些分子相互作用促进肿瘤扩散。为了实现这些目标，提出了以下具体目标：1)确定哪些粘蛋白的结构域是促进结肠癌细胞转移所必需的；2)确定MUC2和Galectin-3是否相互作用影响结肠癌细胞的转移潜能；3)确定在肝脏定植的哪个阶段，MUC2和Galectin-3作用于增强粘液性结肠癌细胞的转移潜能。进一步了解粘蛋白和Galectin-3在结肠癌转移中的作用，可能使设计特定的诊断和治疗策略来改变转移疾病的过程成为可能。

Colorectal cancer is the second most common epithelial cancer in North America with an estimated annual mortality of 55,000 in the United States. The majority of colon cancer-related deaths are due to metastasis, a complex multi-step process by which tumor cells escape the primary tumor and establish secondary foci at distant sites. Mucins, the major secreted glycoproteins of the colon and galectin-3 an endogenous mucin binding protein play an important role in colon cancer metastasis. Direct evidence in support of a particular function(s) for mucin and galectin-3 are now emerging through identification of interacting ligands and structural motifs. Mucins are encoded by at least 9 genes and while a role for the MUC2 gene in mucinous carcinomas has been established, it remains to be determined which structural domains of MUC2 and other mucins are necessary to promote metastasis of colon cancer cells. Galectin-3 also consists of distinct structural domains. The protein may be localized in the nucleus, cytoplasm, on the cell surface or be secreted by colon cancer cells, and may therefore act in several ways to promote metastasis. The long-term objective of this proposal is to determine how the cell surface and secreted glycoproteins of colon cancer cells influence their metastatic capacity. Based on progress during the current funding period efforts will continue which are designed to elucidate the structure-function relationships between colon cancer mucins, mucin-binding proteins and metastasis. We hypothesize that specific structural domains of mucin apoproteins and glaectin-3 are necessary for their metastasis-enhancing effects, and that these molecules interact to promote tumor spread during defined stages of colon cancer metastasis. To accomplish these goals the following specific aims are proposed 1) Determine which structural domains of mucins are necessary for promoting the metastasis of colon cancer cells 2) Determine whether MUC2 and galectin-3 interact to affect the metastatic potential of colon cancer cells 3) Determine at which stages of liver colonization MUC2 and galectin-3 act to augment the metastatic potential of mucinous colon cancer cells. Further understanding of the roles of mucins and galectin-3 in colon cancer metastasis may make it possible to design specific diagnostic and therapeutic strategies to alter the course of metastatic disease.