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Evaluation of Altered Stromal/Epithelial Tissue Arrangement of the c-Kit Messaging System in the Control of Breast Cancer
Final rept. 1 Jul 2006-30 Jun 2008
ALBANY MEDICAL COLL NY
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Previous studies have shown that there is a progressive loss of c-Kit expression in breast epithelial tissue as this tissue changes from normal to benign to cancerous, while simultaneously there is a gain in c-Kit expression in the surrounding stromal tissue. We have studied this inversion in c-Kit expression in an organotypic environment in vivo and in culture to determine its influence on tumor growth and tumor chemosensitivity. Human breast cancer cells Hs578T and autologous surrounding fibroblasts Hs578Bst were admixed and grown as xenografts in the mammary fat pad of immune deficient mice and in culture on a layer of collagen I in Mat Tek dishes. Overexpression of c-Kit in fibroblasts was carried out using Lipofectamine-mediated transfection of pcDNA3c-Kit. Chemosensitivity to the c-Kit modulating drugs, imatinib and alpha-fetoprotein-derived peptide AFPep, was evaluated. Xenografted tumor cells grew only when injected in admixture with fibroblasts. Growth was accentuated when fibroblasts overexpressed c-Kit. Both imatinib and AFPep inhibited tumor growth when tumor was inoculated with its normal fibroblasts. However, within the context of c-Kit-overexpressing fibroblasts, tumor lost sensitivity to growth inhibition by imatinib but not to AFPep. In culture, tumor became more rounded when grown in the context of fibroblasts. In the presence of imatinib tumor growth and migration was inhibited and fibroblasts were induced into a dendritic morphology. Overexpression of c-Kit in fibroblasts prevented the imatinib-induced changes in morphology and migration. In the presence of AFPep, tumor growth was inhibited, migration was partially inhibited, but there were no changes in tumor or fibroblast morphology andoverexpression of c-Kit in fibroblasts did not significantly impact response of tumor to AFPep.
APPROVED FOR PUBLIC RELEASE