Randolph Hastings, M.D., Ph.D., Veterans Medical Research Foundation: Determinants of Lepidic Growth in Bronchioloalveolar Carcinoma

Bronchioloalveolar carcinoma (BAC) is a form of lung adenocarcinoma characterized by lepidic growth; i.e., expansion of the tumors within the confines of the existing bronchial and alveolar airways. The carcinomas are minimally invasive, have a low risk of metastasis and carry a better prognosis than other lung adenocarcinomas. The difference in growth pattern and disparity in outcomes may relate, in part, to a divergence between BAC and adenocarcinomas in the expression of integrins, the membrane proteins that mediate cell attachment to the extracellular matrix. BACs tend to produce integrins, including ɑ11 and ɑ31, which recognize proteins in the basement membrane of normal airways, such as collagen and laminin. Thus, growing along the airways is a natural pattern for BAC. On the other hand, invasive adenocarcinomas express ɑ51 and recognize fibronectin, a stromal protein in the lung. Our pilot data suggest that parathyroid hormone-related protein (PTHrP) may decrease the expression of ɑ51 in BAC compared to invasive lung adenocarcinomas and alter growth on fibronectin. The goal of this project is to determine whether PTHrP contributes to an integrin-dependent switch from non-lepidic to lepidic growth in lung adenocarcinomas. The study will rely on clones of human lung adenocarcinoma cells that are identical except for the presence or absence of PTHrP. Our specific aims are to compare adhesion and migration of the PTHrP-negative and positive lung cancer cells on fibronectin, to evaluate the effects of PTHrP overexpression on integrin expression in three different human BAC lines and to contrast the growth pattern of orthotopic lung carcinomas formed from PTHrP-negative and PTHrP-positive adenocarcinoma cells. Scant effort has been applied to the mechanisms that direct lepidic growth in bronchioloalveolar carcinoma. The issue is significant because an understanding of the pathways that switch from lepidic to aggressive growth could lead to treatments that would reduce lung carcinoma invasiveness. In this project, we will gain an understanding of whether specific integrins mold the growth pattern in lung adenocarcinoma and whether PTHrP is part of the regulatory loop.