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.
Highlights
The tumour microenvironment plays an essential role in the pathophysiology of tumours and comprises extracellular matrix (ECM) and non-malignant cells
We tested tumour cell conditioned medium (TCM) from the CRC cell line HCT8 for which we reported a promotion of xenograft growth by MSC9
Similar to the results obtained with transforming growth factor β1 (TGF-β1) treatment, the mRNA of α-SMA, calponin 1 and collagen 1 A1 (COL1A1) were significantly induced in mesenchymal stromal cells (MSC) by TCM treatment (Fig. 1c)
Summary
The tumour microenvironment plays an essential role in the pathophysiology of tumours and comprises extracellular matrix (ECM) and non-malignant cells. CAF are myofibroblast-like cells characterized by an elevated expression of various cytoskeletal and matrix components including α-SMA, collagens and calponin 12,3. MSC reside throughout life as pericytes in many tissues, can be isolated and are defined by standard criteria, including adherence to plastic, a defined immune phenotype and multi-lineage differentiation ability[5,6] Their location as perivascular cells suggest a possible role for MSC in initial cell-to-cell contacts with circulating tumour cells thereby providing a pre-metastatic niche. We previously demonstrated that the MSC-mediated growth support of CRC xenografts depends on expression of ECM components and integrins[9]. Primary MSC isolated from human bone marrow were differentiated by TGF-β1 and tumour-cell conditioned medium to myofibroblasts with induced expression of the differentiation markers α-SMA, calponin 1 and COL1A1. The results show that MRTF-A controls myofibroblastic differentiation and CAF functions in primary human MSC
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