Abstract
Tumours recruit mesenchymal stem cells to facilitate healing, which induces their conversion into cancer-associated fibroblasts that facilitate metastasis. However, this process is poorly understood on the molecular level. Here we show that CXCL16, a ligand for CXCR6, facilitates mesenchymal stem cell or very small embryonic-like cells recruitment into prostate tumours. CXCR6 signalling stimulates the conversion of mesenchymal stem cells into cancer-associated fibroblasts, which secrete stromal-derived factor-1, also known as CXCL12. CXCL12 expressed by cancer-associated fibroblasts then binds to CXCR4 on tumour cells and induces an epithelial-to-mesenchymal transition, which ultimately promotes metastasis to secondary tumour sites. Our results provide the molecular basis for mesenchymal stem cell recruitment into tumours and how this process leads to tumour metastasis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Bone Marrow Cells / pathology
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Cell Proliferation
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Chemokine CXCL12 / metabolism
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Chemokine CXCL16
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Chemokine CXCL6 / metabolism
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Chemokines, CXC / metabolism
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Epithelial-Mesenchymal Transition
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Gene Knockdown Techniques
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Humans
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Male
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Mesenchymal Stem Cells / metabolism
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Mesenchymal Stem Cells / pathology*
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Mice
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Models, Biological
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Neoplasm Metastasis
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology*
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Receptors, CXCR / metabolism
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Receptors, CXCR4 / metabolism
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Receptors, CXCR6
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Receptors, Chemokine / metabolism
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Receptors, Scavenger / metabolism
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Receptors, Virus / metabolism
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Signal Transduction
Substances
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CXCL16 protein, human
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CXCR6 protein, human
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Chemokine CXCL12
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Chemokine CXCL16
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Chemokine CXCL6
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Chemokines, CXC
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Cxcl16 protein, mouse
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Cxcr6 protein, mouse
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Receptors, CXCR
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Receptors, CXCR4
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Receptors, CXCR6
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Receptors, Chemokine
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Receptors, Scavenger
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Receptors, Virus