title: Tumour cell-derived extracellular vesicles interact with mesenchymal stem cells to modulate the microenvironment and enhance cholangiocarcinoma growth.
abstract: The contributions of mesenchymal stem cells (MSCs) to tumour growth and stroma formation are poorly understood. Tumour cells can transfer genetic information and modulate cell signalling in other cells through the release of extracellular vesicles (EVs). We examined the contribution of EV-mediated inter-cellular signalling between bone marrow MSCs and tumour cells in human cholangiocarcinoma, highly desmoplastic cancers that are characterized by tumour cells closely intertwined within a dense fibrous stroma. Exposure of MSCs to tumour cell-derived EVs enhanced MSC migratory capability and expression of alpha-smooth muscle actin mRNA, in addition to mRNA expression and release of CXCL-1, CCL2 and IL-6. Conditioned media from MSCs exposed to tumour cell-derived EVs increased STAT-3 phosphorylation and proliferation in tumour cells. These effects were completely blocked by anti-IL-6R antibody. In conclusion, tumour cell-derived EVs can contribute to the generation of tumour stroma through fibroblastic differentiation of MSCs, and can also selectively modulate the cellular release of soluble factors such as IL-6 by MSCs that can, in turn, alter tumour cell proliferation. Thus, malignant cells can "educate" MSCs to induce local microenvironmental changes that enhance tumour cell growth.
authors.affiliation: Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Haga
authors.affiliation: Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA.
authors.forename: Irene K
authors.initials: IK
authors.lastname: Yan
authors.affiliation: Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Wood
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Abba
authors.initials: A
authors.lastname: Zubair
authors.affiliation: Department of Cancer Biology, Mayo Clinic Jacksonville, FL, USA; Department of Transplantation, Mayo Clinic Jacksonville, FL, USA; patel.tushar@mayo.edu.
authors.forename: Tushar
authors.initials: T
authors.lastname: Patel
keywords: RNA genes; biliary tract cancer; exosomes; gene expression; paracrine signalling; stem cells