Depletion of cytosolic phospholipase A2 in bone marrow-derived macrophages protects against lung cancer progression and metastasis.
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.
Weiser-Evans
Mary C M
MC
Division of Renal Diseases and Hypertension and Pulmonary Sciences, University of Colorado Denver, Denver, Colorado 80262, USA.
Wang
Xue-Qing
XQ
Amin
Jay
J
Van Putten
Vicki
V
Choudhary
Rashmi
R
Winn
Robert A
RA
Scheinman
Robert
R
Simpson
Peter
P
Geraci
Mark W
MW
Nemenoff
Raphael A
RA
D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology*; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000502:physiology; D018450:Disease Progression; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000201:enzymology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D054510:Phospholipases A2, Cytosolic / Q000502:physiology*
D015850:Interleukin-6; D054510:Phospholipases A2, Cytosolic; D015232:Dinoprostone