The role of mesenchymal stem cells in the tumour microenvironment

Peeney, David
The role of mesenchymal stem cells in the tumour microenvironment. PhD thesis, University of Liverpool.

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The tumour microenvironment consists of a diverse range of cell types, which work together to create favorable conditions to support tumour growth and metastasis. It has been repeatedly reported that bone marrow-derived mesenchymal stem cells (MSCs), also referred to as multipotent stromal cells, infiltrate into the site of developing tumours. These adult multipotent cells show significant therapeutic potential in wound healing, tissue regeneration, immunosuppression and the treatment of cancer. However, there have been numerous contradictory reports on the role and fate of MSCs following engraftment into the tumour microenvironment. Evidence suggests that MSCs may constitute >20% of the stromal component of some solid tumours. In addition, there is evidence that paracrine signalling from cancer cells may cause MSCs to differentiate into cancer-associated myofibroblasts (CAMs), Soluble factors produced by CAMs have been shown to enhance further MSC recruitment and promote tumour progression and metastasis. In light of this information, the aims of this project were: (1) to investigate the changes that occur in MSCs following exposure to cancer cells or CAMs, and conversely, (2) to study the effects that MSCs may have on cancer cells and stromal cells using in vitro co-culture techniques. Exposure to the secretome of the AGS gastric adenocarcinoma cell-line induced a distinct gene expression profile in MSCs that was strongly associated with immune and inflammatory responses. Exposure to primary CAMs did not induce similar changes and exhibited little correlation across MSC and CAM cell-lines. Furthermore, exposure to AGS- or CAM-CM did not promote the acquisition of CAM-like characteristics in MSCs. However, extended exposure to AGS-CM or TNFα prompts the formation of a tumour-promoting MSC (tMSC) phenotype that is supportive of AGS growth via direct cell contact. Nrf2 is a transcription factor that is classically associated with cellular responses to stress that also induces the transcription of various anti-inflammatory genes and can be chemically induced by the synthetic triterpenoid CDDO-Me. Although CDDO-Me could inhibit various pro-inflammatory genes in MSCs that are induced in response to AGS-CM, it also propagates the formation of a tMSC phenotype. Finally, a key trait associated with MSCs is their ability to modulate the immune response. It is widely reported that MSCs have the ability to strongly repress the immune response. We found that MSCs can differentially modulate the maturation of dendritic cells depending on the ratio of cells used, and whether MSCs have been pre-exposed to AGS-CM. These findings suggest that the role and fate of MSCs is heavily dependent on the tissue niche in which they reside. MSCs are a highly responsive set of cells that can be directed towards various functional phenotypes that may inhibit or promote local cellular growth and activity. This highlights the need for high-throughput studies to define MSCs responses to external stimuli that may assist in increasing the efficacy of MSC-based therapies.

Item Type: Thesis (PhD)
Additional Information: Date: 2015-02 (completed)
Subjects: ?? QP ??
Depositing User: Symplectic Admin
Date Deposited: 07 Sep 2015 09:57
Last Modified: 16 Dec 2022 04:43
DOI: 10.17638/02014041