Randolph Hastings M.D., Ph.D.

Recipient of the Joan Scarangello Research Grant.

Lay Description

Bronchioalveolar carcinoma (BAC) is a form of lung cancer characterized by non-invasive growth. The tumors expand within the confines of the existing air space in the lung without invading the connecting tissues or blood stream. BAC cancers have a relatively low risk of spreading to other organs in the body (metastasis) compared to a related type of lung cancer called adenocarcinoma. As a result, patients with BAC lung cancer tend to survive longer than patients with lung adenocarcinoma and have a better chance of cure. The difference in growth pattern and the divergence in outcomes may arise, in part, from a disparity in how BAC tumors and adenocarcinomas interact with the structural framework of the lung, known as the extracellular matrix, or ECM. Tumor cells attach to the ECM through cell surface proteins, called integrins, that recognize and bind specific proteins in the ECM. BAC tumors make integrins that recognize ECM proteins that are present along the normal air space corridors. Thus, BAC growth along the airways is a natural pattern. On the other hand, lung adenocarcinomas make an integrin, called alpha 5/beta 1, that recognizes fibronectin, a protein that is normally not exposed to cells in the airways but would be accessible if cancer cells broke through the normal lung framework and invaded connective tissue or blood vessels. The reasons why BAC tumors do not make alpha 5/beta 1 and why they have a less aggressive pattern of growth are not well understood. Our pilot data suggest that parathyroid hormone-related protein (PTHrP), a protein made in some lung cancers but not all, might be involved. Lung cancers that make PTHrP have less alpha 5/beta 1 than lung cancers that do not make the hormone. Furthermore, the presence of PTHrP appears to affect how the lung cancer cells interact with ECM proteins. The goal of this project is to determine whether PTHrP controls production of alpha 5/beta 1 in lung cancer and whether the hormone can cause cancers to behave like BAC tumors rather than invasive adenocarcinomas. To test this hypothesis, we have developed several lines of lung cancer cells that are identical except that some lines make no PTHrP at all and others make high levels of the protein. Our specific aims are to compare how well the PTHrP-negative lung cancer cells and the PTHrP-positive lung cancer cells recognize and bind to fibronectin and to investigate whether the cells that make PTHrP have increased levels of alpha 5/beta 1. We will also inject these cells into the lungs of models and will contrast the growth pattern of orthotopic lung carcinomas that are formed from PTHrP-negative and PTHrP-positive lung carcinoma cells. We expect that the PTHrP-negative cells will grow like adenocarcinomas and that the positive cells will behave like BAC tumors. The results of these studies will help us understand why some lung cancers grow aggressively and others do not. We will discover the molecular mechanisms that affect growth patterns and learn whether PTHrP and integrins are important. The findings could set the stage to develop treatments that would make lung cancers less invasive and would improve patient survival and the chance for cure.

Scientific Abstract

Bronchioalveolar 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 bronchioalveolar 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.