Abstract
Liver metastasis depends on the collagenous microenvironment generated by hepatic sinusoidal cells (SCs). DDR1 is an atypical collagen receptor linked to tumor progression, but whether SCs express DDR1 and its implication in liver metastasis remain unknown. Freshly isolated hepatic stellate cells (HSCs), Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs), that conform the SCs, expressed functional DDR1. HSCs expressed the largest amounts. C26 colon carcinoma secretomes increased DDR1 phosphorylation in HSCs and KCs by collagen I. Inhibition of kinase activity by DDR1-IN-1 or mRNA silencing of DDR1 reduced HSCs secretion of MMP2/9 and chemoattractant and proliferative factors for LSECs and C26 cells. DDR1-IN-1 did not modify MMP2/9 in KCs or LSECs secretomes, but decreased the enhancement of C26 migration and proliferation induced by their secretomes. Gene array showed that DDR1 silencing downregulated HSCs genes for collagens, MMPs, interleukins and chemokines. Silencing of DDR1 before tumor inoculation reduced hepatic C26 metastasis in mice. Silenced livers bore less tumor foci than controls. Metastatic foci in DDR1 silenced mice were smaller and contained an altered stroma with fewer SCs, proliferating cells, collagen and MMPs than foci in control mice. In conclusion, hepatic DDR1 promotes C26 liver metastasis and favors the pro-metastatic response of SCs to the tumor.
Highlights
Liver metastasis depends on the collagenous microenvironment generated by hepatic sinusoidal cells (SCs)
Discoidin domain receptor 1 (DDR1) is mostly expressed by epithelial cells, previous studies indicated that non-epithelial cells, such as myofibroblast-like cells in cancerous tissues, express D DR141
We demonstrated for the first time that freshly isolated hepatic stellate cells (HSCs), Kupffer cells (KCs) and liver sinusoidal endothelial cells (LSECs) of the murine liver capillaries express DDR1
Summary
Liver metastasis depends on the collagenous microenvironment generated by hepatic sinusoidal cells (SCs). DDR1 is an atypical collagen receptor linked to tumor progression, but whether SCs express DDR1 and its implication in liver metastasis remain unknown. Isolated hepatic stellate cells (HSCs), Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs), that conform the SCs, expressed functional DDR1. Metastatic foci in DDR1 silenced mice were smaller and contained an altered stroma with fewer SCs, proliferating cells, collagen and MMPs than foci in control mice. Abbreviations DDR1 Discoidin domain receptor 1 PDDR1 PhosphoDDR1 ECM Extracellular matrix SCs Sinusoidal cells HSC Hepatic stellate cell KC Kupffer cell LSEC Liver sinusoidal endothelial cell CRC Colorectal carcinoma α-SMA Alpha-smooth muscle actin MMP Matrix metalloproteinase. Allowed Sun et al to show that DDR1 drives stromal secretion of IL6 to promote invasive breast cancer[15], and allowed Hou et al to demonstrate that DDR1 regulates vascular smooth muscle cell attachment to collagen, chemotaxis, proliferation, and metalloproteinases (MMPs) p roduction[16]. Whether sinusoidal cells (SCs) express DDR1 and its potential implication in liver physiology and pathology remains unknown
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