Depletion of Tumor-Associated Macrophages Slows the Growth of Chemically Induced Mouse Lung Adenocarcinomas

Abstract

Chronic inflammation is a risk factor for lung cancer, and low-dose aspirin intake reduces lung cancer risk. However, the roles that specific inflammatory cells and their products play in lung carcinogenesis have yet to be fully elucidated. In mice, alveolar macrophage numbers increase as lung tumors progress, and pulmonary macrophage programing changes within 2 weeks of carcinogen exposure. To examine how macrophages specifically affect lung tumor progression, they were depleted in mice bearing urethane-induced lung tumors using clodronate-encapsulated liposomes. Alveolar macrophage populations decreased to ≤50% of control levels after 4–6 weeks of liposomal clodronate treatment. Tumor burden decreased by 50% compared to vehicle treated mice, and tumor cell proliferation, as measured by Ki67 staining, was also attenuated. Pulmonary fluid levels of insulin-like growth factor-I, CXCL1, IL-6, and CCL2 diminished with clodronate liposome treatment. Tumor-associated macrophages expressed markers of both M1 and M2 programing in vehicle and clodronate liposome-treated mice. Mice lacking CCR2 (the receptor for macrophage chemotactic factor CCL2) had comparable numbers of alveolar macrophages and showed no difference in tumor growth rates when compared to similarly treated wild-type mice suggesting that while CCL2 may recruit macrophages to lung tumor microenvironments, redundant pathways can compensate when CCL2/CCR2 signaling is inactivated. Depletion of pulmonary macrophages rather than inhibition of their recruitment may be an advantageous strategy for attenuating lung cancer progression.

IRE1α inhibition by natural compound genipin on tumour associated macrophages reduces growth of hepatocellular carcinoma

“…This is associated with reduced secondary infiltration of inflammatory monocytes and TAMs into tumour microenvironment. Besides, we also found that treatment of macrophage scavenger, liposome clodronate unexpectedly led to reduced growth of HCC, which was consistent with the observations in other previous studies [27, 28]. This indicates that removal of TAMs from tumour microenvironment regardless its phenotype may render tumour inhibition.…”

Tumor-associated macrophages in cancers

“…In chemically induced mouse model of lung adenocarcinoma, depletion of TAMs slows the tumor growth, possibly due to that the inactivation of CCL2/CCR2 signaling led to the downregulation of TAM recruitment [57].…”

The Second-Generation PGI2 Analogue Treprostinil Fails to Chemoprevent Tumors in a Murine Lung Adenocarcinoma Model

“…Ki-67 immunostaining was conducted on tumors from treprostinil treated and control animals as as previously described(22, 23). In brief, 5 micron lung sections from the urethane, ET, and LT groups were deparaffinized, peroxidases blocked with 3% hydrogen peroxide, and antigen retrieval performed in boiling Diva Decloaker (Biocare Medical, DV2004G1) reagent under pressure for 10 min.…”