Abstract
BackgroundThe aim of this study was to investigate the co-operative role of CXCR4/CXCL12 axis and IL-1Ra in metastatic processes mechanism by interactions between colorectal cancer cells and stromal cells in their microenvironment.MethodsExpression of IL-1α, interleukin-1 receptor type I (IL-1 RI), CXCL12 and CXCR4 mRNA and proteins were determined by RT-PCR and Western blot. The effect of secreted level of CXCL12 by IL-1Ra on fibroblasts was measured by ELISA. CXCL12 regulate metastatic potential of colorectal cancer was evaluated by proliferation, invasion and angiogenesis assays, respectively, in which invasion and angiogenesis assays used an in vitro system consisting of co-cultured colorectal cells and stromal cells.ResultsIL-1α was expressed in high liver metastatic colorectal cancer cell lines (HT-29 and WiDr). The colorectal cancer cell-derived IL-1α and rIL-1α significantly promoted CXCL12 expression by fibroblasts, and this enhancing effect can be significantly inhibited by IL-1Ra (P < 0.01). CXCL12 not only enhanced the migration and proliferation of human umbilical vein endothelial cells, but also significantly enhanced angiogenesis (P < 0.01). Furthermore, the high liver-metastatic colorectal cancer cell line (HT-29), which secretes IL-1α, significantly enhanced angiogenesis compared to the low liver-metastatic cell line (CaCo-2), which does not produce IL-1α (P < 0.01). On the contrary, IL-1Ra can significantly inhibit migration, proliferation and angiogenesis (P < 0.01).ConclusionAutocrine IL-1α and paracrine CXCL12 co-enhances the metastatic potential of colorectal cancer cells; IL-1Ra can inhibit the metastatic potential of colorectal cancer cells via decrease IL-1α/CXCR4/CXCL12 signaling pathways.Graphical 7Qx8An2hePDujdT1wSZV-LVideo
Highlights
The aim of this study was to investigate the co-operative role of Chemokine receptor 4 (CXCR4)/Chemokine ligand 12 (CXCL12) axis and IL-1 Receptor Antagonist (IL-1Ra) in metastatic processes mechanism by interactions between colorectal cancer cells and stromal cells in their microenvironment
CXCL12 derived from stromal cells in the tumor microenvironment depends on Phosphatidylinositol 3-kinase (PI3K)/ Protein kinase B (Akt)/mTOR signal to up-regulate the secretion of CXCL6 or down-regulate the expression of PTEN through PI3k/ Akt signal to enhance the liver metastasis of colorectal cancer
Is there a correlation between autocrine IL-1α and paracrine CXCL12 in colorectal cancer, and does this association affect liver metastasis of colorectal cancer? Can interleukin-1 receptor antagonist inhibit the occurrence of liver metastasis? Our study focuses on solving those problems
Summary
The aim of this study was to investigate the co-operative role of CXCR4/CXCL12 axis and IL-1Ra in metastatic processes mechanism by interactions between colorectal cancer cells and stromal cells in their microenvironment. Colorectal cancer (colorectal carcinoma, CRC) is one of the most common malignant tumors in the world, with the third highest incidence of male cancers and the second highest female cancer rate. Its fatality rate ranks second among cancer-related deaths, with more than 940,000 deaths per year. Colorectal cancer has an incidence rate of 24.26/100,000, and the number of new cases each year is about 1.93 million, accounting for 10.2% of all new cases of malignant tumors, ranking third [1]. More than 1/3 of patients die within five years after the initial diagnosis, the primary cause of which being liver metastasis [2]. Liver metastasis is one of the key points and difficulties in the treatment of colorectal cancer, as well as the key factors affecting the prognosis for patients
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