The objective of this proposal is to investigate the role of an adhesion molecule, CD44, in human colorectal carcinoma metastasis with the goal of improving detection and treatment of patients with this disease. CD44 is a cell surface adhesion molecule that is normally present in several isoforms and is postulated to facilitate normal lymphocyte recirculation by modulating adhesion of lymphocytes to specialized lymph node endothelium. Experimental data support the notion that tumor cells may gain access to lymph nodes by mimicking lymphocytes in their cell surface expression of a specific CD44 isoform, CD44R1. By developing CD44R1 specific antibodies as well as experimentally manipulating CD44R1 expression in colorectal carcinoma cells, we propose to improve our understanding of colorectal carcinoma metastasis in a manner that 1) increases the clinically useful prognostic information obtained from primary colorectal tumors; 2) provides a model for treatment of colorectal carcinoma metastases; and 3) enhances detection of asymptomatic patients with colorectal carcinoma. First, we will measure CD44R1 transcript and protein expression in clinical specimens representing primary colorectal tumors, metastases, and normal colonic mucosa. CD44R1-specific antisera will be developed using recombinant fusion proteins for the protein measurements. CD44R1 expression levels will be correlated with clinical and pathological parameters of metastatic disease. Second, we will examine the function of CD44R1 in vivo in a human colorectal carcinoma cell line, KM12, implanted into nude mice. We will examine the ability to modulate metastatic potential by experimentally manipulating CD44R1 expression in these cells. We will also assess the ability to block metastasis in this model using CD44-immunoglobulin fusion proteins. Third, we will use the specific CD44 antisera to develop an assay to detect colorectal carcinoma cells shed into the stool by virtue of their abnormal CD44R1 expression. We will use these results to develop a screening test to detect patients with colorectal carcinomas by examining stool smears. The proposed project will shed new light on mechanisms of human colorectal carcinoma metastasis in a manner that will aid in the detection and therapy of patients with this disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Experimental Therapeutics Subcommittee 1 (ET)
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Massachusetts General Hospital
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