Role of Tumor Collagenase Stimulating Factor in Breast Cancer Invasion and Metastasis.
Annual rept. 1 Dec 94-30 Nov 95,
STATE UNIV OF NEW YORK AT STONY BROOK RESEARCH FOUNDATION
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Tumor Collagenase Stimulating Factor TCSF is a 58 kDa glycoprotein identified in the plasma membrane of cancer cells which induces fibroblasts to produce Matrix Metalloproteinases MMPs. Using immunohistochemical techniques, we have characterized the cellular localization of TCSF as compared to gelatinase A in human breast tumor tissue. Antibodies to TCSF reacted strongly with noninvasive and invasive cancer cells with intense staining of the plasma membrane. Normal appearing breast ducts also stained positively with anti-TCSF antibody. To distinguish between cells producing TCSF and gelatinase A, we performed in situ hybridization ISH using specific radiolabeled RNA antisense probes. TCSF mRNAs were detected in both noninvasive and invasive ductal cancer cells and in premalignant breast lesions, but not in normal mammary ducts. Gelatinase A mRNA was expressed by peritumoral fibroblasts, but not by cancer cells. The discrepancy between immunolocalization and ISH data suggests a long half-life for TCSF protein in cells. Human TCSF has been expressed as a fusion protein with glutathione-S-transferase in the prokaryotic pGEX vector. The 28 kDa noglycosylated fusion protein was biologically inactive. In contrast, CHO cells transfected with human TCSF cDNA produced TCSF that was post-translationally processed to a 58 kDa biologically active protein which stimulated fibroblast production of MMPs, but not TIMP-1.
- Medicine and Medical Research