Tumor Ddr1 Deficiency Reduces Liver Metastasis By Colon Carcinoma And Impairs Stromal Reaction

AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY(2021)

引用 10|浏览9
暂无评分
摘要
Colorectal cancer (CRC) colonization of the liver and its further metastatic growth are the result of complex interaction between the tumor cell, the collagenous extracellular matrix (ECM), and the hepatic sinusoidal cells (SCs). Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor activated by collagen and a bad prognosis factor in cancer. DDR1 signaling regulates key cell functions for tumor development, such as proliferation, migration, invasion, and metalloproteinases (MMPs) secretion. However, the mechanisms underlying the implication of DDR1 in the conformation of the metastatic niche in the liver remain poorly known. In this study, we used an experimental model of liver metastasis from CRC to investigate the role of DDR1 in the context of the prometastatic crosstalk between tumor cells and the hepatic stroma. Bioinformatics and immunohistochemical analysis revealed that DDR1 was highly expressed in tumor tissues from patients with primary CRC and hepatic CRC metastasis. Besides, DDR1 overexpression was associated with poor outcome. In vitro, SCs-derived soluble factors promoted DDR1 phosphorylation and MMP2 production by CRC cells. In vivo, tumor DDR1 participated in hepatic ECM remodeling by modulating the expression of collagen and MMP2, and stimulated the recruitment of stromal cells into the tumor microenvironment. In addition, tumor DDR1 favored SCs ability to modify the ECM organization by controlling the expression of collagen and MMPs. Altogether, our results show that tumor DDR1 plays an important role in the desmoplastic response of hepatic tumor microenvironment during CRC invasion and growth.NEW & NOTEWORTHY Tumor DDR1 acts as a key factor during the desmoplastic response surrounding hepatic colorectal metastasis. Hepatic sinusoidal cell-derived soluble factors stimulate tumor DDR1 activation. DDR1 modulates matrix remodeling to promote metastasis in the liver through the interaction with hepatic stromal cells, specifically liver sinusoidal endothelial cells and hepatic stellate cells.
更多
查看译文
关键词
desmoplasia, discoidin domain receptor 1, hepatic stellate cells, liver metastasis from colorectal cancer, liver sinusoidal endothelial cells
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要