Abstract:
:Tumour growth and metastatic colonization is strongly influenced by the tumour stroma, including cancer-associated fibroblasts (CAF). Multipotent mesenchymal stromal cells (MSC) are a possible source of CAF following myofibroblastic differentiation, and we have previously shown that MSC support tumour growth. Triggered by tumour cell-derived factors like transforming growth factor β1 (TGF-β1), myofibroblastic MSC differentiation is associated with the increased expression of markers including alpha smooth muscle actin (α-SMA). Here we show that myocardin-related transcription factor A (MRTF-A) plays an important role in myofibroblastic differentiation of primary human MSC in vitro and their tumour-supporting function in vivo. Recombinant TGF-β1 or tumour cell conditioned medium (TCM) elevated α-SMA, calponin 1 and collagen 1 A1 (COL1A1) amount on mRNA and protein level in MSC. This correlated with increased MRTF-A activity during MSC differentiation. MRTF-A knockdown by siRNA or shRNA impaired TGF-β1 and TCM induction of α-SMA and calponin 1, but not of COL1A1. Mixed xenograft experiments using HCT8 colorectal carcinoma cells and primary MSC of different donors revealed a significant reduction in tumour weight and volume upon MRTF-A knockdown in MSC. Our study suggests that MRTF-A is involved in the functional differentiation of MSC towards a tumour-promoting CAF phenotype in vivo.
journal_name
Sci Repjournal_title
Scientific reportsauthors
Werner S,Lützkendorf J,Müller T,Müller LP,Posern Gdoi
10.1038/s41598-019-48142-zsubject
Has Abstractpub_date
2019-08-13 00:00:00pages
11725issue
1issn
2045-2322pii
10.1038/s41598-019-48142-zjournal_volume
9pub_type
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