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The expression and clinical applications of Wnt-signaling molecules in breast and colorectal cancers

Authors Wong, Cesar Sze Chuen
Issue Date 2002
Summary Cancer is a heterogeneous disease of an array of etiology. In the last two decades, wide range of evidence has converged to a common theme of neoplasia that normal cell proliferation controls are lost at the level of cell signaling, cell-cycle arrest, differentiation or apoptosis. The diagnosis, prognosis and management of cancer patients must be based on a thorough understanding of its molecular constitutes of the disease. Therefore, analysis of proteins involved in any of these deregulated processes is essential for us to elucidate the cause and progression of individual tumors. In the present thesis study, the expressions of various cell cycle regulators and their relationships to cell proliferation, apoptosis and tumor progression were investigated in invasive breast cancer using immunohistochemical methods. The study reported the identification of apoptotic index, Ki-67, c-myc, cyclin D3 and p21 were positively correlated, while p16, p27 and cyclin D1 were negatively correlated to tumor progression. Moreover, a clear decoupling between p21, p27 and p16 as well as between cyclin D1 and cyclin D3 to tumor progression was found, indicating their differential roles in tumor progression. We furthered our investigation by studying the expression of the frizzled related protein (Frp) and its Wnt-signaling molecules in the same tumor system, as Frp is a new family of secreted proteins involved both in apoptosis and Wnt-signaling pathway. Using in-situ hybridization and immunohistochemical methods, we demonstrated that Frp mRNA was down-regulated in tumor areas in most of the cases examined and negatively correlated to both Wnt-1 and β-catenin. β-catenin, a key transcriptional factor responsible for the activation of both c-myc and cyclin D1 in colorectal cancer, was found in the cytoplasm, but not in the nuclei of breast tumor masses, despite the fact that both c-myc and cyclin D1 were elevated in all tumor tissues. The role of β-catenin in the progression of colorectal cancer is a well recognized, but unsettled issue. To re-evaluate the prognostic and diagnostic significance of β-catenin in colorectal cancer, we examined β-catenin expression in more than 300 cases of specimens of polyps, adenomas, and adenocarcinomas using immunohistochemical method by using colorectal tumor specimens. The results showed that β-catenin nuclear signal was statistically correlated not only with the purported sequential stages in colorectal carcinogenesis, but also positively correlated with lymph node metastasis and survival of colorectal cancer patients. Moreover, adenomas associated with synchronous carcinomas showed significantly higher levels of nuclear β-catenin than adenomas without associated carcinomas. In our study, β-catenin nuclear expression was rather unique to colorectal adenocarcinomas, but rare or absent in other gastric-intestinal adenocarcinomas. In this regard, nuclear β-catenin may serve as an additional parameter to aid the distinction of colorectal adenocarcinomas from adenocarcinomas of other sites. To explore the potential of β-catenin as a suitable marker for colorectal cancer screening, we then investigated the possibility of detecting β-catenin DNA & RNA in sera/plasma of colorectal carcinoma and adenoma patients. The results were striking. In both β-catenin DNA & RNA were detected in the blood of 100% of patients with colorectal carcinomas, 79 to 90% of patients with adenomas, but none in normal volunteer controls using PCR and RT-PCR analysis. Finally, in order to have a global understanding of genes that participate in colorectal tumor progression, we analyzed the gene profiles of a benign polyp, adenoma and carcinoma compared to normal colonic tissues using 2,400 genes cDNA microarray. The study provides valuable new information on genes whose expressions were found altered in the process of colorectal cancer carcinogenesis. Among the deregulated genes, three genes, Wnt-5a, cyclin D1, and c-myc showed significant correlation with tumor progression. This finding provides a strong independent evidence that Wnt-signaling pathway plays a crucial role in colon carcinogenesis.
Note Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2002
Language English
Format Thesis
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