MACROPHAGE-STIMULATING PROTEIN AND ITS RECEPTOR IN NON-SMALL-CELL LUNG-TUMORS - INDUCTION OF RECEPTOR TYROSINE PHOSPHORYLATION AND CELL-MIGRATION

Previously, we identified macrophage-stimulating protein (MSP) as bein g expressed during hamster lung injury induced by nitrosamine carcinog ens. Transient, generalized epithelial-cell hyperplasia during the pre neoplastic period, and eventually nonneuroendocrine (non-NE) lung tumo rs, are known to develop in these nitrosamine-treated hamsters. We wis hed to test the hypothesis that MSP and its tyrosine kinase receptor, RON, might represent an autocrine/paracrine system involved in the pat hogenesis of human nonneuroendocrine lung tumors, the non-small-cell c arcinomas (NSCLCs). We found that this occurred in a paracrine fashion in three of eight primary human NSCLCs that expressed messenger RNA ( mRNA) for MSP at high levels in histologically normal lung adjacent to the tumor, but not in the primary tumor, together with mRNA for RON i n both normal and tumor tissue. MSP and RON could also constitute an a utocrine/paracrine system in human NSCLC cell lines: five of 16 cell l ines (squamous and adenosquamous) expressed both MSP and RON; and an a dditional five of 16 cell lines expressed RON without detectable MSP. Although three cases of primary squamous-cell carcinomas expressed MSP (two of three in the tumor and one of three in nonneoplastic lung), m RNA for RON was not detectable in these cases. RON was functional in a ll tested RON mRNA-positive cell lines, with exogenous MSP inducing RO N-mediated tyrosine phosphorylation. Treatment of a RON-positive adeno squamous carcinoma cell line with MSP additionally resulted in increas ed motility in a cell-migration assay, suggesting that MSP might promo te cell migration of some NSCLCs. In conclusion, MSP and RON might rep resent an autocrine/paracrine system involved in the pathogenesis of l ung cancer, although the nature of the biologic responses in different cell types might vary considerably.