Inflammation and immunity in lung tumorigenesis.

CS08-01

Successful lung cancer chemoprevention will require identification of appropriately targeted effective agents with acceptable toxicity profiles. Identification of molecular pathways critical to lung carcinogenesis advances development of targeted therapies for prevention. Understanding these pathways facilitates the assessment of the appropriate molecular, histologic, or imaging endpoints to demonstrate preliminary safety and efficacy. While agents directed at certain targets have recently been suggested to have inappropriate risk/benefit ratios, studies that precisely define the relevant pathways involved may uncover more specific downstream targeting opportunities to prevent lung cancer. The promotion phase of tumorigenesis is often reversible and more readily manipulable by pharmacological agents, and therefore represents an important targeting point for preventive therapy. Growth factors and cytokines released in the lung during an inflammatory response provide multiple promotion stimuli to an initiated cell. The arachidonic acid pathway contributes key inflammatory mediators in the pulmonary microenvironment that may play a role in tumorigenesis. For example, a variety of stimuli induce cyclooxygenase-2 (COX-2) and it is over-expressed in many tumors, including non-small cell lung cancer (NSCLC). Transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) are two growth factors that influence COX-2 expression. Smoking increases lung concentrations of TGF-β and EGF, and high levels of these growth factors contribute to chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis, risk factors for lung cancer development To study involvement of TGF-β, EGF, and COX-2 in early stages of lung carcinogenesis, we evaluated COX-2 expression following treatment with TGF-β and EGF in immortalized human bronchial epithelial cells (HBECs). EGF significantly enhanced TGF-β1-mediated induction of COX-2 and corresponding prostaglandin E2 (PGE2) production. TGF-β1 and EGF induced COX-2 mRNA and protein. In the absence of EGF, EGFR inhibition, neutralizing antibody against amphiregulin, or MEK inhibition blocked TGF-β mediated COX-2 induction. COX-2 induction by TGF-β1 depended upon Smad3 signaling and required active EGFR or its downstream mediators, due to autocrine amphiregulin signaling. Thus, EGFR ligands, which are abundant in the pulmonary microenvironment of those at risk for lung cancer, potentiate and are required for COX-2 induction by TGF-β1 in HBEC. These findings emphasize the central role of EGFR signaling in COX-2 induction by TGF-β1 and suggest that inhibition of EGFR signaling should be investigated further for lung cancer prevention.Supported by: UCLA Lung Cancer SPORE and Texas Lung Cancer SPORE