CD44, a cell hyaluronate receptor, and its splice variant forms, has been implicated as a causal factor in the phenotype of certain cancer cells and may have diagnostic, prognostic and therapeutic application. In preliminary studies, CD44 in found in all colorectal carcinomas and a majority of adenomas, but not in corresponding normal mucosa. The goal of this research is to implement the translation of these research findings to clinical utility with colorectal and pancreatic cancer. Better markers to predict which patients have cells committed to malignant transformation or occult metastasis would lead to improved clinical management and utilization of medical care resources. Specific aims are the following: 1. Characterize CD44 protein and mRNA in human colorectal and pancreatic cancer: In the initial studies, CD44 in non-neoplastic colonic mucosa will be compared to that in primary colorectal cancers, metastatic lesions, adenoma, epithelial hyperplasia, and precursor lesions. The timing of expression of will be correlated to the adenoma-carcinoma sequence in the large bowel. Protocols and insight developed with the more adaptable colorectal cancer system will then also be applied to the analysis of pancreatic cancer. CD44 expression will be elucidated by immunohistochemistry for tissue localization. Western blots with domain specific antisera probes for protein structure, and polymerase chain reaction and Northern blots with domain specific oligonucleotide primers and probes for mRNA expression and structure. 2. Evaluate CD44 expression as a diagnostic and prognostic marker of colorectal and pancreatic cancer. CD44 as a diagnostic and prognostic marker will be directly compared to other molecular, biochemical and pathological markers, utilizing a well organized program for clinical, pathological, molecular and statistical analysis that is active at this institution. 3. Apply a novel procedure for targeting CD 44 splice variant protein sequences to the MHC class II helper T cell pathway in an analysis of the immunoreactivity of these sequences and their possible use for immunotherapy of colorectal cancer. Splice variant protein sequences will be targeted to the MHC class II pathway for presentation to helper T cells as chimeric molecules containing the endosomal/lysosomal targeting sequence of lysosomal membrane glycoproteins. This procedure will test the presence of antigenic peptide sequences in the CD44 variant domains, the recognition of these sequences by helper T cells, and the function of these activated T cells on effector B cell and cytotoxic T cell function against cancer cells expressing the CD44 variant protein.
NIH ExPorter
NIH ExPorter