Centre for Cancer Biomarkers CCBIO
CCBIO Seminar series

CCBIO Seminar March 17th - Lutz P. Müller

Growth promotion of colorectal cancer by mesenchymal stromal cells – when and how?

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Apart from the interesting talks, the CCBIO seminars are a good way to meet CCBIO members and associates. Please feel free to inform others about this seminar as all are welcome both to the lecture and the pizza get-together afterwards.

Invited speakerLutz P. Müller, MD; Clinic for Internal Medicine IV - Hematology / Oncology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.

Time: 14:30
Host: Donald Gullberg.

Title and abstract:

Growth promotion of colorectal cancer by mesenchymal stromal cells – when and how?

Colorectal carcinoma (CRC) constitutes a common malignancy with limited therapeutic options in metastasized stages. Tumor–stroma interactions play an essential role in the biology of CRC. Given their ubiquitous presence as perivascular cells as well as their resistance to genotoxic damage multipotent mesenchymal stromal cells (MSC) may represent a pivotal part of the stroma in primary as well as metastasizing CRC. MSC can differentiate to carcinoma-associated fibroblasts (CAF). However, the relevance of this differentiation for the interaction of MSC and CRC cells as well as the mechanisms controlling it are not understood. In addition, the impact of the stroma and particularly of MSC or MSC-derived CAF on the CRC growth may depend on the variable mutational background of the tumor cells.

In our mixed xenograft studies we observed that MSC promote the xenograft growth of CRC cell-lines with differential mutational status. This growth support was largely independent of the immunomodulatory capacity of MSC. In comparison to normal colon fibroblasts, MSC specifically supported the growth of an α-catenin-deficient CRC cell line. For all other CRC cell lines, MSC and fibroblasts showed nearly similar support of xenograft growth. In-vivo-imaging suggested an effect of MSC on the early tumor seeding and growth. Using an in vitro 3D-model to simulate tumor architecture at an early stage, we showed that MSC specifically supported spheroid formation in CRC cells with a dysfunctional E-cadherin system.

Further experiments including lentiviral knock-down revealed that the MSC-facilitated spheroid formation depends on the expression of β1-integrin in CRC cells. However, only in the α-catenin-deficient CRC cell line this β1-integrin-dependent interaction was indispensable for MSC-mediated growth promotion in vivo. Growth of all other CRC cells was supported by MSC despite the lack of β1-integrin expression in the CRC cells.

Regarding the potential ligand of β1-integrin, our data suggest a distinct role of extracellular matrix (ECM) and specifically of MSC expressed collagen. Expression of collagen in MSC increased upon stimulation with TGF-β as well as with tumor cell-conditioned media. This stimulation also lead to an induction of a CAF phenotype in MSC. Induction of this CAF-phenotype was controlled by myocardin related transcription factor (MRTF). However, preliminary data suggest that expression of collagen in MSC is independent of MRTF but regulated by micro-RNAs.

Taken together our data demonstrate that MSC specifically support the growth of α-catenin deficient CRC cells during an early phase of tumor growth through CRC cell expressed β1-integrin. This growth promoting activity of MSC seems to be mediated by MSC-expressed collagen and independent of their CAF-differentiation. In our view, these data argue for a specific role of MSC in the early phase of metastasis growth of specific CRC cells. This mechanism could serve as a future target for therapy and metastasis prevention.