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

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.

Keywords: Cancer stem cell; Cancer/testis antigen; Epithelial-mesenchymal transition; Mesenchymal stem/stromal cell.

Graphical abstract

Fig. 1

The developmental origin and fetal tissue localization of the naive MSCs. During early mammal development, all cells are identical and undifferentiated before the formation of the blastula. The cells of the inner cell mass (ICM) begin to differentiate and divide rapidly during blastocyst stage. The ICM proliferates and differentiates to generate the epiblast and eventually to form the all three primary germ layers ,. Meanwhile, the epiblast cells in ectoderm undergo the epithelial-mesenchymal transition (EMT) to generate MSCs ,. Mesodermal cell-derived mesenchymoangioblast (MB) can differentiate into endothelial and mesenchymal cells and MB-derived endothelial cells can transform into mesenchymal stem-like cells through endothelial-to-mesenchymal transition (EndMT) , , . MB-derived mesenchymal cells have potential to differentiate into MSCs.

Fig. 2

Factors implicated in MSC transformation. There are different approaches to induce the transformation of MSCs, including over-expression of certain oncogenes (e.g. Fos, RAS and hTERT), loss of tumor suppressor genes (e.g. P21 and TP53), expression of fusion genes (e.g. FWS-FLI1, FUS-CHOP, SYT-SSX), drug or chemical treatment, virus infection, inflammatory or tumor microenvironment (TME), spontaneous transformation and others. Combination approaches have been frequently applied to transform MSCs in vitro and in vivo studies.

Fig. 3

Models of MSC-associated tumorigenesis. (A) Primary tumor is composed of various tumor cell subpopulations and tumor-associated stroma, including cancer stem cells (CSCs), mesenchymal stem cells (MSCs), tumor-associated MSCs (TA-MSCs), and other stromal cells. MSCs are “educated” by tumor microenvironment (TME) to reprogram into TA-MSCs . Anti-cancer therapy may not eradicate all cancer cells due to MSCs/CSCs-mediated compound resistance. MSCs/TA-MSCs increase CSCs population and maintain cancer stemness. Thus, CSCs and MSCs sustain cancer cell growth and drive cancer relapse once and again. (B) MSCs-derived extracellular vesicle (e.g. exosome), carrying a variety of substance (e.g. TGF-β), can directly induce the epithelial-mesenchymal transition (EMT) in the cancer cells to generate the new CSCs. (C) MSCs have limited proliferative capacity and multi-differentiation potential. MSCs might be transformed due to abnormal genetic events. Transformed MSCs probably develop into cancer progenitor cells and increase CSCs populations.