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

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

Requests for reprints: Raphael A. Nemenoff, University of Colorado, Denver, Department of Medicine, 4200 East Ninth Avenue, Denver, CO 80262. Phone: 303-315-6733; Fax: 303-315-4852; E-mail: Raphael.Nemenoff{at}UCHSC.edu.

Key Words: cytosolic phospholipase A2 • lung cancer • macrophages

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):1733–8]