HMGB1 released by irradiated tumor cells promotes living tumor cell proliferation via paracrine effect

Sijia He,Minghui Zhao,Ling Tian,Chuanyuan Li,Qian Huang,Chuangui Wang,Lianhui Sun,Yiwei Wang,Xinjian Liu,Zhengxiang Zhang,Yuntao Luo,Jin Cheng

doi:10.1038/s41419-018-0626-6

Abstract

Tumor repopulation during therapy is an important cause of treatment failure. Strategies to overcome repopulation are arising in parallel with advances in the comprehension of underlying biological mechanisms. Here, we reveal a new mechanism by which high mobility group box 1 (HMGB1) released by dying cells during radiotherapy or chemotherapy could stimulate living tumor cell proliferationInhibition or genetic ablation of HMGB1 suppressed tumor cell proliferation. This effect was due to binding of HMGB1with the member receptor for advanced glycation end-products (RAGE), which activated downstream ERK and p38 signaling pathway and promoted cell proliferation. Furthermore, higher HMGB1 expression in tumor tissue correlated with poor overall survival and higher HMGB1 concentration was detected in serum of patients who accepted radiotherapy. Collectively, the results from this study suggested that interaction between dead cells and surviving cells might influence the fate of tumor. HMGB1 could be a novel tumor promoter with therapeutic and prognostic relevance in cancers.

Highlights

Radiotherapy is often given in daily fractions with an average overall time of 5–7 weeks, which are divided off to allow the recovery of normal tissues from sublethal damage during treatment interphase
high mobility group box 1 (HMGB1) was released from tumor cells after irradiation As HMGB1 is reported as a necrosis marker, we analyzed the amount of HMGB1 released in tumor cell culture medium at different time points post irradiation
In order to illustrate HMGB1 releasing is a common appearance during cytotoxic therapy, we detected HMGB1 in tumor cell medium treated by chemotherapy

Summary

Introduction

Radiotherapy is often given in daily fractions with an average overall time of 5–7 weeks, which are divided off to allow the recovery of normal tissues from sublethal damage during treatment interphase. Szczepanski and Trott demonstrated that regrowth of a Official journal of the Cell Death Differentiation Association. He et al Cell Death and Disease (2018)9:648 of dead cell during cytotoxic cancer therapy, we wonder whether necrosis was involved in tumor repopulation and what is the mechanism of necrosis associated tumor repopulation?. These molecules are known as damage associated molecular patterns (DAMPs). Among these DAMPs, high mobility group box 1 (HMGB1) serves as the prototype[6]. We question what is the role of HMGB1 released by necrotic cells and whether it could stimulate the proliferation of surviving cells during cytotoxic therapy?

Methods

Results

Conclusion