Modeling sarcomagenesis using multipotent mesenchymal stem cells

Abstract

Because of their unique properties, multipotent mesenchymal stem cells (MSCs) represent one of the most promising adult stem cells being used worldwide in a wide array of clinical applications. Overall, compelling evidence supports the long-term safety of ex vivo expanded human MSCs, which do not seem to transform spontaneously. However, experimental data reveal a link between MSCs and cancer, and MSCs have been reported to inhibit or promote tumor growth depending on yet undefined conditions. Interestingly, solid evidence based on transgenic mice and genetic intervention of MSCs has placed these cells as the most likely cell of origin for certain sarcomas. This research area is being increasingly explored to develop accurate MSC-based models of sarcomagenesis, which will be undoubtedly valuable in providing a better understanding about the etiology and pathogenesis of mesenchymal cancer, eventually leading to the development of more specific therapies directed against the sarcoma-initiating cell. Unfortunately, still little is known about the mechanisms underlying MSC transformation and further studies are required to develop bona fide sarcoma models based on human MSCs. Here, we comprehensively review the existing MSC-based models of sarcoma and discuss the most common mechanisms leading to tumoral transformation of MSCs and sarcomagenesis.

Figure 1

Schematic cartoon depicting how distinct sarcomas may result from a coordinated acquisition of cooperating oncogenic hits in the appropriate target cell throughout the mesenchymal hierarchy. In the absence of oncogenic hits the normal MSC (black circle; left) differentiates down the mesenchymal hierarchy eventually giving rise to mature and functional mesenchymal derivatives including adipocytes, chondrocytes and osteocytes. The “two-hit” model is thought to be necessary for explaining the eventual development of cancer: one hit is presumed to promote differentiation impairment while the second hit more frequently targets proliferation/apoptosis. Distinct early cancer-initiating hits (white-colored; hits A1-A4) are supposed to arise in long-lived MSCs, or perhaps, in early committed mesenchymal progenitors. It is very unlikely that a single early cancer-initiating hit induces sarcomagenesis on its own, and therefore sequential secondary cooperating hits (green, blue or red-coloured hits) are commonly required to achieve a malignant clonal expansion of mesenchymal derivatives. The more differentiated the stage (less MSC potency) along the mesenchymal hierarchy targeted by the secondary oncogenic mutation, the more differentiated the sarcoma appears. This model stresses both the importance of the intrinsic transforming ability of specific mutations and the need to target the appropriate cell type along the mesenchymal lineages.