Depletion of Cytosolic Phospholipase A₂ in Bone Marrow–Derived Macrophages Protects against Lung Cancer Progression and Metastasis

¹Divisions of Renal Diseases and Hypertension and Pulmonary Sciences and ²Critical Care Medicine, Department of Medicine, and ³School of Pharmacy, University of Colorado Denver, Denver, Colorado

^* To whom correspondence should be addressed. E-mail: Raphael.Nemenoff{at}UCHSC.edu.

	Abstract

Cancer progression and metastasis involves interactions between tumor cells and the tumor microenvironment (TME). We reported that mice deficient for cytosolic phospholipase A₂ (cPLA₂-KO) are protected against the development of lung tumors. The goal of this study was to examine the role of cPLA₂ in the TME. Mouse lung cancer cells (CMT167 and Lewis lung carcinoma cells) injected directly into lungs of syngeneic mice formed a primary tumor, and then metastasized to other lobes of the lung and to the mediastinal lymph nodes. Identical cells injected into cPLA₂-KO mice showed a dramatic decrease in the numbers of secondary metastatic tumors. This was associated with decreased macrophage staining surrounding the tumor. Wild-type mice transplanted with cPLA₂-KO bone marrow had a marked survival advantage after inoculation with tumor cells compared with mice receiving wild-type (WT) bone marrow. In vitro, coculturing CMT167 cells with bone marrow–derived macrophages from WT mice increased production of interleukin 6 (IL-6) by cancer cells. This increase was blocked in cocultures using cPLA₂-KO macrophages. Correspondingly, IL-6 staining was decreased in tumors grown in cPLA₂-KO mice. These data suggest that stromal cPLA₂ plays a critical role in tumor progression by altering tumor-macrophage interactions and cytokine production. [Cancer Res 2009;69(5):OF1–6]

Key Words: cytosolic phospholipase A2, lung cancer, macrophages