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

Abstract

Cancer progression and metastasis involves interactions between tumor cells and the tumor microenvironment (TME). We reported that mice deficient for cytosolic phospholipase A 2 (cPLA 2 -KO) are protected against the development of lung tumors. The goal of this study was to examine the role of cPLA 2 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 cPLA 2 -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 cPLA 2 -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 cPLA 2 -KO macrophages. Correspondingly, IL-6 staining was decreased in tumors grown in cPLA 2 -KO mice. These data suggest that stromal cPLA 2 plays a critical role in tumor progression by altering tumor-macrophage interactions and cytokine production.

Mononuclear phagocyte heterogeneity in cancer: Different subsets and activation states reaching out at the tumor site

“…Interestingly, the effect of PGE 2 in tumor-associated macrophages is even amplified by a downregulation of the PGE 2 -catabolizing enzyme 15-PGDH and an induction of the PGE 2 -synthesizing enzymes COX-2 and mPGES1, resulting in high intracellular levels of this metabolite (Eruslanov et al 2009(Eruslanov et al , 2010. This finding is further corroborated by the observation that the absence of cPLA 2 , an enzyme upstream in the PGE 2 biosynthesis pathway, in macrophages results in reduced tumor progression (Weiser-Evans et al 2009). …”

Low Molecular Weight Hyaluronan Activates Cytosolic Phospholipase A2α and Eicosanoid Production in Monocytes and Macrophages

“…cPLA 2 ␣ knock-out mice used in models of asthma (27), pulmonary fibrosis (28), ARDS (29), multiple sclerosis (30), and rheumatoid arthritis (31) present with reduced symptoms when compared with wild-type mice (32). cPLA 2 ␣ (70), COX2 (34), or PGE 2 receptor EP2 (71) deficiency decreases the size and number of intestinal polyps in the experimental model of colon cancer, whereas cPLA 2 ␣ depletion in bone marrow-derived macrophages protects against lung cancer progression and metastasis (33). Our current findings indicate a novel, direct link of ubiquitously present HA with cPLA 2 ␣ and downstream lipid mediators both in murine macrophages and human primary monocytes and differentially polarized macrophages.…”

Cytosolic phospholipase A2: physiological function and role in disease

“…Using the chemical carcinogen urethane to initiate lung cancer, cPLA 2 ␣ KO mice developed fewer lung tumors than WT mice, and much lower levels of tumor-associated PGs ( 219 ). Another study investigated whether the presence of cPLA 2 ␣ in the tumor microenvironment infl uenced lung cancer progression and metastasis ( 220 ). The injection of mouse lung tumor cells into mouse lungs induced primary tumors of similar size in cPLA 2 ␣ WT and KO mice.…”