The mechanism of the premetastatic niche facilitating colorectal cancer liver metastasis generated from myeloid-derived suppressor cells induced by the S1PR1\u2013STAT3 signaling pathway

Mi Jian,Meilin Ji,Qingyang Feng,Ye Wei,Peng Zheng,Jianmin Xu,Li Ren,Qi Lin,Pingping Xu,Liangliang Yang,Jun Li

doi:10.1038/s41419-019-1922-5

Abstract

The tumor-derived factors involved in the expansion and accumulation of myeloid-derived suppressor cells (MDSCs) in metastatic dissemination of colorectal cancer (CRC) to the liver has not been studied. Immunohistochemistry was used to detect sphingosine-1-phosphate receptor 1 (S1PR1) and signal transducer and activator of transcription-3 (STAT3) in human colorectal tumors. IL-6 and interferon-γ were detected by enzyme-linked immunosorbent assay (ELISA). Tumor growth, invasion, and migration were evaluated by MTT, transwell, and wound healing assays, respectively. Subcutaneous tumor-bearing and CRC liver metastasis (CRLM) nude mouse models were constructed. The percentage of MDSCs was measured using multicolor flow cytometry. Western blot assay was used to evaluate S1PR1 and p-STAT3 expression in MDSCs after separation from the liver and tumor by magnetic antibody. T-cell suppression assay was detected by carboxyfluorescein succinimidyl ester (CFSE). Aberrant co-expressed S1PR1 and p-STAT3 was correlated with metachronous liver metastasis and poor prognosis in CRC. A mutual activation loop between S1PR1 and STAT3 can enhance CRC cell proliferation, migration, and invasion in vitro and in vivo. The expression of p-STAT3 and its downstream proteins can be regulated by S1PR1. p-STAT3 was the dependent signaling pathway of S1PR1 in the promotion of cell growth and liver metastasis in CRC. The level of IL-6 and the associated MDSCs stimulated by the S1PR1–STAT3 correlated with the number of liver metastatic nodes in the CRLM mouse models and patients. Increased CD14+HLA-DR−/low MDSCs from CRLM patients inhibited autologous T-cell proliferation and predict poor prognosis. The S1PR1–STAT3–IL-6–MDSCs axis operates in both tumor cells and MDSCs involved in the promotion of growth and liver metastasis in CRC. MDSCs induced by S1PR1–STAT3 in CRC cells formed the premetastatic niche in the liver can promote organ-specific metastasis.

Highlights

25% of patients with colorectal cancer (CRC) present with liver metastases at initial diagnosis and almost 50% will develop liver metastases
Aberrant co-expressed sphingosine-1phosphate receptor 1 (S1PR1) and p-signal transducer and activator of transcription-3 (STAT3) was correlated with metachronous liver metastasis and poor prognosis in CRC As a transcriptional factor, STAT3 plays a crucial role in promoting the progression of human cancers, including
These results demonstrated that in the colorectal liver metastasis (CRLM) model, the level of IL-6 and the associated myeloid-derived suppressor cells (MDSCs) stimulated by the S1PR1–STAT3 signaling pathway was positively correlated with the number of liver metastatic nodes

Summary

Introduction

25% of patients with colorectal cancer (CRC) present with liver metastases at initial diagnosis and almost 50% will develop liver metastases. Lin et al Cell Death and Disease (2019)10:693 to tumor metastasis This enhanced understanding may present interesting new targets for anticancer therapy[2]. MDSCs is a heterogeneous population of immature hematopoietic cells comprised of the monocyte or granulocyte lineage that expand dramatically under conditions such as trauma, tumor growth, and various chronic inflammatory disorders, including infection, sepsis, and immunization. These cells have a role in immune tolerance, tumor progression, and metastasis[5,6]. The tumor-derived factors involved in the expansion and accumulation of MDSCs in the metastatic dissemination of CRC to the liver has not been studied

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