MUCIN GLYCOPROTEINS IN COLON CANCER METASTASIS

结直肠癌是北美第二常见的上皮癌，在美国估计年死亡率为55，000。 大多数结肠癌相关死亡是由于转移，这是一个复杂的多步骤过程，肿瘤细胞通过该过程逃离原发肿瘤并在远处部位建立继发病灶。 粘蛋白是结肠分泌的主要糖蛋白，半乳糖凝集素3是结肠癌的内源性粘蛋白结合蛋白，在结肠癌转移中起重要作用。 支持粘蛋白和半乳糖凝集素-3的特定功能的直接证据现在通过相互作用配体和结构基序的鉴定而出现。 粘蛋白由至少9种基因编码，虽然已经确定了MUC 2基因在粘液癌中的作用，但仍然需要确定MUC 2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。 半乳糖凝集素-3也由不同的结构域组成。 该蛋白质可以定位于细胞核、细胞质、细胞表面或由结肠癌细胞分泌，因此可以以几种方式起作用以促进转移。 这项提案的长期目标是确定结肠癌细胞的细胞表面和分泌的糖蛋白如何影响其转移能力。 基于目前资助期间的进展，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。 我们假设粘蛋白脱辅基蛋白和glaectin-3的特定结构域是其转移增强效应所必需的，并且这些分子在结肠癌转移的确定阶段相互作用以促进肿瘤扩散。 为了实现这些目标，提出了以下具体目标：1）确定粘蛋白的哪些结构域对于促进结肠癌细胞的转移是必需的; 2）确定MUC 2和半乳糖凝集素-3是否相互作用以影响结肠癌细胞的转移潜力; 3）确定MUC 2和半乳糖凝集素-3在肝定植的哪个阶段起作用以增强粘液性结肠癌细胞的转移潜力。 进一步了解粘蛋白和半乳糖凝集素-3在结肠癌转移中的作用，可能会设计特定的诊断和治疗策略来改变转移性疾病的进程。

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.