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Mesenchymal stem cell signaling in cancer progression

https://doi.org/10.1016/j.ctrv.2012.03.005Get rights and content

Abstract

Mesenchymal (multipotent) stem/stromal cells (MSCs) may affect cancer progression through a number of secreted factors triggering activation of various cell signaling pathways. Depending on receptor status, phosphatase and tensin homolog (PTEN) status, or Wnt activation in the cancer cells, the signals may either result in increased growth and metastasis or lead to inhibition of growth with increased cell death. Thus, MSCs can play a dual role in cancer progression depending on the cellular context wherein they reside. The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway has a central role in regulating tumor growth, and several MSC secreted factors stimulate activation of this pathway. A comprehensive understanding of the signals regulating MSC–tumor cross-talk is highly important for the development of MSCs as potential therapeutic vehicles. Thus, the presented review focuses on factors released by MSCs and on the dual role they may have on various stages of tumorigenesis.

Introduction

During the last decade considerable focus has been given to MSCs based on their biological properties, such as their potential capacity to replace diseased cells in various organs and their potential use as suppressors for graft-versus-host disease due to immunomodulatory functions. Also, their homing ability to tumor tissue makes them promising vectors for cancer therapy. However, the use of MSCs in cancer treatment has been met by a general concern related to the biosafety of using MSCs. This concern has been supported by various reports indicating that MSCs may be involved in cancer initiation in vivo1, 2, 3, 4, 5 and also by the suggestion that MSCs may spontaneously transform into malignant cells in vitro.6, 7, 8, 9, 10, 11, 12 A recent report has also shown fusion between MSCs and gastrointestinal epithelial cells, suggesting the generation of a more cancer prone cell type.13 However, based on the information available there is currently no solid evidence supporting spontaneous in vitro transformation of human MSCs.14, 15, 16

The field of MSC research is quite confusing both with respect to the definition of MSCs as well as by contradicting reports regarding the role of MSCs in cancer development. It is clear that MSCs secrete a number of paracrine factors that may influence tumor growth; however, the cellular mechanisms induced by these factors are poorly understood. Also variations in experimental designs and a mixed use of cell lines impede the interpretation of the role of MSCs in tumor development. Here we present a critical review focusing on the function of MSCs in the tumor stroma and on various model systems used to study MSC–tumor cell interactions. Emphasis will be given to cell signaling pathways that are induced during cross-talk between tumor cells and MSCs, and also on how these pathways act as negative or positive regulators of tumor growth and metastasis.

Section snippets

Activation of MSCs in the tumor stroma

The tumor stroma, involving tumor–host cellular interactions, plays an important role in tumor growth, angiogenesis, and metastasis.17, 18 It consists of a complex extracellular matrix wherein fibroblasts, immune and inflammatory cells, fat cells and blood-vessels reside. Activated fibroblasts (also designated myofibroblasts) in the tumor stroma are commonly referred to as carcinoma-associated fibroblasts (CAFs) or tumor associated fibroblasts (TAFs). It has been suggested that CAFs/TAFs can be

MSC–tumor cell cross-talk

Interactions between MSCs and tumor cells involves a number of MSC secreted signaling molecules that may stimulate various signaling pathways, in particular related to cell growth and apoptosis regulation in the tumor cells. However, the tumor–MSC cross-talk is complex, also involving signaling from tumor cells that stimulates MSCs as well as MSC activation of inflammatory cells and angiogenesis by recruitment of endothelial cells. The various signaling molecules and pathways at the different

Model systems used to study MSC–tumor interactions

As indicated above there is a considerable inconsistency related to the stimulatory and inhibitory functions of MSCs on tumor cells. A comprehensive overview of the different model systems used to study the promoting and inhibiting effects of MSCs on tumor growth has recently been provided,91 where proposed explanations for the contradicting results are linked to cellular heterogeneity of MSCs (source of tissue, age and donor-to-donor variability) as well as variations in animal tumor models.

Conclusions

Despite inconsistencies in the literature, a considerable number of studies have provided a better overview of the cross-talk that occurs between MSCs and tumor cells. It has been shown that MSCs make up a certain fraction of CAFs and they can be activated in a similar manner as CAFs. Also, natural biological properties of MSCs, such as niche formation, immunomodulation and homing, are used by the tumor cells to survive and grow. The tumor tropism of MSCs has led researchers to explore the

Acknowledgements

This work was supported by the Norwegian Cancer Society, the Norwegian Research Council, Innovest AS, Strategic Research Programme, Helse-Vest, Haukeland University Hospital, the Bergen Translational Research Program, the Centre Recherche de Public de la Santé Luxembourg and the Medical Faculty, University of Bergen.

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