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

Chanju Lee,Sung-Joo S Bae,Hwansoo Joo,Hyunsu Bae

doi:10.18632/oncotarget.18627

Chanju Lee, Sung-Joo S Bae + Show 2 more

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https://doi.org/10.18632/oncotarget.18627

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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.

Highlights

The tumor microenvironment which contributes to proliferation and survival of malignant cells, angiogenesis, metastasis, abnormal adaptive immunity and reduced response to hormones and chemotherapeutic agents is largely being considered as a therapeutic target [1, 2]
Treatment with 0.5 mg/kg or 1 mg/kg of melittin did not result in significant changes in hematological parameters, including the level of white blood cells (WBC), red blood cells (RBC), hemoglobin (Hgb), hematocrit (HCT), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) (Figure 1C)
This resulted in the reduction of VEGF+ and CD31+ cells in tumor tissues, suggesting that angiogenesis was hindered by the reduction of the Tumor-associated macrophages (TAM) population

Summary

Introduction

The tumor microenvironment which contributes to proliferation and survival of malignant cells, angiogenesis, metastasis, abnormal adaptive immunity and reduced response to hormones and chemotherapeutic agents is largely being considered as a therapeutic target [1, 2]. M2-like TAMs have weak antigen presenting function and high phagocytosis capacity. They are known to be immunosuppressive, pro-tumorigenic, pro-angiogenic by releasing various extracellular matrix components, angiogenic and chemotactic factors. M2-like TAMs are distinguished with M1-like TAMs by expressing some markers like CD163, CD204, CD206, IL-10 [6,7,8,9] In most tumors such as breast, ovarian, prostate, lung carcinoma, and cutaneous www.impactjournals.com/oncotarget melanoma, the tumor microenvironment includes a number of factors, such as CSF-1, VEGF, CCL2, IL-4, IL-13, TGF-β, and IL-10, which can recruit monocytes and lead to differentiation for M2-like phenotype [10,11,12]

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