Melittin suppresses tumor progression by regulating tumor-associated macrophages in a Lewis lung carcinoma mouse model

// Chanju Lee 1 , Sung-Joo S. Bae 2 , Hwansoo Joo 1 and Hyunsu Bae 1 1 Department of Physiology, College of Korean Medicine, Kyung Hee University, Dongdaemoon-Gu, Seoul 02447, Republic of Korea 2 Department of Biology, University of California Riverside, Riverside, CA 92521, USA Correspondence to: Hyunsu Bae, email: hbae@khu.ac.kr Keywords: melittin, tumor-associated macrophages (TAM), CD206 Received: October 19, 2016      Accepted: May 29, 2017      Published: June 27, 2017 ABSTRACT Tumor-associated macrophages (TAM) are a major component of tumor stroma. It has been reported that TAMs have M2-like phenotype and facilitate tumor progression by promoting angiogenesis and immunosuppression. Melittin, a major polypeptide of bee venom, has been widely studied as an anti-cancer drug due to its cytotoxicity to malignant cells. However, very little is known regarding the effect of melittin on immune cells in the tumor microenvironment. This study focuses on the effect of melittin on TAMs in a Lewis lung carcinoma mouse model. Melittin inhibited the rapid tumor growth compared to the control in vivo . Melittin increased the M1/M2 ratio of TAMs by selectively reducing the number of CD206 + M2-like TAMs while not altering the population of CD86 + M1-like TAMs. Melittin also preferentially binds to M2 macrophages, and this binding was not associated with phagocytosis. Gene and protein expression of vascular endothelial growth factor (Vegf) and mannose receptor C type 1 (Mrc1/CD206) was reduced in M2-like bone marrow-derived macrophages by melittin treatment, but there was no significant change in the gene level of Vegf and FMS-like tyrosine kinase 1 (Flt1/VEGFR1) in tumor cells in vitro . Additionally, the levels of VEGF and CD31, markers of angiogenesis, were significantly decreased by melittin treatment in tumor tissues. This study revealed a novel role for melittin in tumor treatment and suggested that melittin could be a promising therapeutic agent for targeting M2-like TAMs.