Stromal LRP1 in lung adenocarcinoma predicts clinical outcome.

PURPOSE LRP1 (low-density lipoprotein receptor-related protein 1) is a broadly expressed receptor that binds multiple extracellular ligands and participates in protein clearance. It is expressed in numerous cancers, but its role in lung cancer has not been characterized. Here, we investigate the relationship between LRP1 and lung cancer. EXPERIMENTAL DESIGN LRP1 mRNA levels were determined in lung tumors from several large, multicenter studies. LRP1 protein localization was determined by immunohistochemical analysis of lung tumor microarrays. Normal fibroblasts, fibroblasts treated with the LRP1 inhibitor RAP (receptor-associated protein), and Lrp1 null fibroblasts were cocultured with 3 independent lung cancer cell lines to investigate the role of LRP1 on tumor cell proliferation. RESULTS LRP1 mRNA levels are significantly decreased in lung tumors relative to nontumorous lung tissue. Lower expression of LRP1 in lung adenocarcinomas correlates with less favorable clinical outcome in a cohort of 439 patients. Immunohistochemical analysis shows that LRP1 is primarily expressed in stromal cells in 94/111 lung cancers, with very little protein found in cancer cells. A growth-suppressive function of mouse embryonic fibroblast (MEF) cells was observed in 3 lung cancer cell lines tested (H460, H2347, and HCC4006 cells); growth suppression was blocked by the LRP1 inhibitor RAP. Lrp1 deletion in fibroblasts reduced the ability of MEF cells to suppress tumor cell mitosis. In a validation set of adenocarcinomas, we confirmed a significant, positive correlation between both LRP1 mRNA and protein levels and favorable clinical outcomes. CONCLUSIONS LRP1 expression is associated with improved lung cancer outcomes. Mechanistically, stromal LRP1 may non-cell autonomously suppress lung tumor cell proliferation.