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Co-migration of colon cancer cells and CAFs induced by TGFβ1 enhances liver metastasis
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Co-migration of colon cancer cells and CAFs induced by TGFβ1 enhances liver metastasis
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Journal Article
Co-migration of colon cancer cells and CAFs induced by TGFβ1 enhances liver metastasis
2015
Overview
Colorectal cancer (CRC) cells often metastatize to the liver. Cancer-associated fibroblasts (CAFs) enhance metastasis by providing cytokines that create a favorable microenvironment and by inducing co-dissemination with tumor cells. However, the mechanisms of co-metastatization remain elusive. The aim of this study is to assess the role of TGFβ₁in CRC cell–CAFs attachment and its impact on liver metastasis. CAFs were obtained after xenotransplantation of Mc38 cells into EGFP-C57BL/6 mice. Attachment experiments with CRC cells and CAFs (with or without TGFβ₁and the inhibitory peptide P17) were carried out, as well as in vivo liver metastasis assays. TGFβ₁induced adhesion of CRC cells to CAFs, whereas exposure to P17 abrogated this effect. Co-injection of Mc38 cells with CAFs intrasplenically increased liver metastasis, as compared to injection of tumor cells alone. Pretreatment of Mc38 cells with TGFβ₁enhanced the metastatic burden, in comparison to untreated Mc38 + CAFs. TGFβ₁-pretreated Mc38 cells co-metastatized with CAFs to the liver in a highly efficient way. Importantly, the metastatic burden was significantly reduced (p < 0.001) when P17 was administered in mice. The number of PCNA+ and CD-31+ cells was also reduced by P17 in these animals, indicating a decrease in proliferation and angiogenesis upon TGFβ₁signaling blockade. Through microarray analysis, we identified potential TGFβ₁-regulated genes that may mediate cancer cell–stroma interactions to increase metastasis. In conclusion, TGFβ₁promotes co-travelling of CRC cells and CAFs to the liver to enhance metastasis. Our results strongly support the use of TGFβ₁targeted drugs as a novel strategy to reduce liver metastasis in CRC patients.
Publisher
Springer-Verlag,Springer Berlin Heidelberg
Subject
/ Animals
/ Biomedical and Life Sciences
/ Cell Adhesion - drug effects
/ Cell Movement - drug effects
/ Colonic Neoplasms - genetics
/ Colonic Neoplasms - pathology
/ drugs
/ Endothelial Cells - drug effects
/ Endothelial Cells - pathology
/ Extracellular Matrix - drug effects
/ Extracellular Matrix - metabolism
/ Fluorescent Antibody Technique
/ Gene Expression Regulation, Neoplastic - drug effects
/ genes
/ Green Fluorescent Proteins - metabolism
/ liver
/ mice
/ patients
/ transforming growth factor beta 1
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