Abstract
During the progression of malignant peritoneal mesothelioma (MPeM), tumor nodules propagate diffusely within the abdomen and tumors are characterized by distinct phenotypic sub-types. Recent studies in solid organ cancers have shown that cancer stem cells (CSCs) play a pivotal role in the initiation and progression of tumors. However, it is not known whether tumorigenic stem cells exist and whether they promote tumor growth in MPeM. In this study, we developed and characterized a CSC model for MPeM using stably expandable tumorigenic stem cells derived from patient tumors. We found morphologically distinct populations of CSCs that divide asymmetrically or symmetrically in MPeM in vitro cell culture. The MPeM stem cells (MPeMSCs) express stem cell markers c-MYC, NES and VEGFR2 and in the presence of matrix components cells form colony spheres. MPeMSCs are multipotent, differentiate into neuronal, vascular and adipose progeny upon defined induction and the differentiating cells express lineage-specific markers such as TUBB3, an early neuronal marker; vWF, VEGFA, VEGFC and IL-8, endothelial markers; and PPARγ and FABP4, adipose markers. Xenotransplantation experiments using MPeMSCs demonstrated early tumor growth compared with parental cells. Limiting dilution experiments using MPeMSCs and endothelial lineage-induced cells derived from a single MPeMSC resulted in early tumor growth in the latter group indicating that endothelial differentiation of MPeMSCs is important for MPeM tumor initiation. Our observation that the MPeM tumors contain stem cells with tumorigenic potential has important implications for understanding the cells of origin and tumor progression in MPeM and hence targeting CSCs may be a useful strategy to inhibit malignant progression.
Highlights
Cancer stem-(like)-cells with self-renewal and tumor initiating potential have been identified in different tumor types [1,2,3] and recent evidence suggests that these cells play a central role in the progression of malignant tumors
We found that during symmetric cell division both daughter cells shared the template DNA (Fig. 1C). Another morphologically distinct population of cancer stem cells (CSCs) was identified in malignant peritoneal mesothelioma (MPeM) culture with an encapsulating outer covering that formed from the parental cells as dark bubble-like protrusions
The important finding from this study is the identification of CSCs with characteristic asymmetric stem cell division and tumorigenicity in human MPeM tumors
Summary
Cancer stem-(like)-cells with self-renewal and tumor initiating potential have been identified in different tumor types [1,2,3] and recent evidence suggests that these cells play a central role in the progression of malignant tumors. Recent studies suggest that a major proportion of cells within tumors maintain stem cell properties and even more differentiated cells can be transformed into stem-like cells [4,5]. If this is the case, elimination of CSCs might not be a useful strategy for the abatement of tumor growth. We investigated the presence of tumorigenic mesothelioma cells with properties of CSCs in stable cell lines derived from MPeM patient tumors
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