Fasting inhibits colorectal cancer growth by reducing M2 polarization of tumor-associated macrophages.

Pengfei Sun,Zhirong Sun,Minmin Zhu,Duan Ma,Wankun Chen,Zhiyong He,Qichao Wu,Huihui Wang,Changhong Miao,Xiangyuan Chen,Meilin Weng

doi:10.18632/oncotarget.20301

Abstract

Dietary restriction has been recognized as a healthy and natural therapy for cancer. It is reported that different forms of dietary restriction can promote anti-tumor immunity. However, it is not clear how fasting affects tumor-associated macrophages (TAMs). This study aims to investigate the relationship between fasting and antitumor immunity in terms of tumor-associated macrophages. In vivo, the results showed that alternate day fasting for 2 weeks inhibitted the tumor growth of mice without causing a reduction of body weight. Meanwhile, M2 polarization of tumor-associated macrophages in tumor tissues of alternate day fasting group was also decreased. In vitro, fasting induced the autophagy of CT26 cells, decreased the generation of extracellular adenosine by supressing the expression of CD73 in CT26 cells. Decreasing adenosine inhibitted M2 polarization of RAW264.7 cells through inactivating JAK1/STAT3 signal pathway in fasting condition. Eventually, the proliferation of CT26 cancer cells declined on account of fasting-facilitated antitumor immunity. These results suggested that fasting suppressed M2 polarization of tumor-associated macrophages to inhibit tumor growth through decreasing the level of adenosine in the tumor microenvironment both in vivo and in vitro. This process was associated with increasing autophagy of tumor cells.

Highlights

The morbidity and mortality of colorectal cancer is increasing year by year, which threatens human health severely
These results suggested that fasting suppressed M2 polarization of tumorassociated macrophages to inhibit tumor growth through decreasing the level of adenosine in the tumor microenvironment both in vivo and in vitro
We found that the proliferation of CT26 cells was suppressed in fasting medium (Figure 1D)

Summary

Introduction

The morbidity and mortality of colorectal cancer is increasing year by year, which threatens human health severely. It is generally believed that colorectal cancer is associated with high fat, high carbohydrate and high protein diet [1, 2]. Preliminary data indicates that short-term fasting or ketogenic diet, both to induce physiological hungry state, can reverse immunosuppressive character of the tumor microenvironment through decreasing lactic acid or increasing ATP in the tumor microenvironment [5, 6]. Most of these studies focus on immune cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), or NK cells [5, 6]. Few studies are reported about fasting and tumor-associated www.impactjournals.com/oncotarget macrophages, which are among the most important immune components of tumor microenvironment

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