Mesenchymal stem/stromal cells: Developmental origin, tumorigenesis and translational cancer therapeutics

Highlights

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  Acknowledging the developmental origin of MSCs and the localization of MSCs in the primary tumor sites and the fetal and extraembryonic tissues is conducive to better understanding MSC contributions to the cellular origin of cancer.

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  Several direct and/or indirect mechanisms of MSC action contribute to the cellular origin of cancer including: (i) induction of an EMT to generate cancer stem cell-like state in cancer cells; (ii) likely to act as tumorigenic progenitors in sarcoma; and (iii) maintenance of cancer stemness.

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  Using combination therapeutic approaches can enhance MSC-mediated anti-cancer safety and efficacy.

Abstract

While a large and growing body of research has demonstrated that mesenchymal stem/stromal cells (MSCs) play a dual role in tumor growth and inhibition, studies exploring the capability of MSCs to contribute to tumorigenesis are rare. MSCs are key players during tumorigenesis and cancer development, evident in their faculty to increase cancer stem cells (CSCs) population, to generate the precursors of certain forms of cancer ( e.g. sarcoma), and to induce epithelial-mesenchymal transition to create the CSC-like state. Indeed, the origin and localization of the native MSCs in their original tissues are not known. MSCs are identified in the primary tumor sites and the fetal and extraembryonic tissues. Acknowledging the developmental origin of MSCs and tissue-resident native MSCs is essential for better understanding of MSC contributions to the cellular origin of cancer. This review stresses that the plasticity of MSCs can therefore instigate further risk in select therapeutic strategies for some patients with certain forms of cancer. Towards this end, to explore the safe and effective MSC-based anti-cancer therapies requires a strong understanding of the cellular and molecular mechanisms of MSC action, ultimately guiding new strategies for delivering treatment. While clinical trial efforts using MSC products are currently underway, this review also provides new insights on the underlying mechanisms of MSCs to tumorigenesis and focuses on the approaches to develop MSC-based anti-cancer therapeutic applications.

Graphical abstract

MSCs derived from the ectoderm and mesoderm during embryonic development can differentiate towards mesoderm-derived lineages and MSCs can be identified in fetal and extraembryonic tissues. MSCs are able to migrate into tumor's niches and they may be “educated” by the tumor microenvironment (TME) to evolve into the tumor-associated MSCs (TA-MSCs). MSCs/TA-MSCs can induce the EMT in the cancer cells to increase the cancer stem cells (CSCs) populations. TA-MSCs may be derived directly from CSCs on rare occasions. MSCs/transformed MSCs are likely to act as tumorigenic progenitors in sarcoma.