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How Ordinary Stem Cells Create Tumors—The Mechanism

Ossifying fibroma (OF) is a commonly seen orofacial benign tumor, which leads to craniofacial malformations. The occurrence mechanism of this disease remains unknown. Recently, a new research from the Ostrow School of Dentistry Center for Craniofacial Molecular Biology at the University of South California successfully revealed the occurrence mechanism of ossifying fibroma and the results was published on recent Cell Stem Cell.

In tumors, there are usually small portion of cells that are poorly differentiated and have high proliferation rate, known as tumor stem cells. These cells play vital role in proliferating, transferring and recurring of tumors. Scientists often use tumor stem cells as experiment subject to study on the occurrence mechanism of tumors and associated therapy methods. In this study, researchers revealed how ordinary stem cells go corrupted step by step. If people understand how this process works, we may be able to stop tumors from forming and proliferating.

The researchers performed signaling pathway analysis on ossifying fibroma mesenchymal stem cells (OFMSCs) and found that the signaling pathways of TGF-b, Notch and BMP were of great significance. Though epigenetic upregulation of TGF-b signaling pathway, the researchers managed to convert ordinary mesenchymal stem cells into tumors. Epigenetic upregulation – switching existing but inactive genes “on” – the TGF-b cell signaling loop appears to enhance the formation of ossifying fibroma tumors. On the contrary, suppressing TGF-b signaling appears to quell the tumor’s proliferation rate, says Songtao Shi, the Principal Investigator and Professor at USC.

The researchers performed primary culture on ordinary mesenchymal stem cells from surgery-cut ossifying fibroma to obtain OFMSCs. They found that OFMSCs had osteogenesis defects and strong proliferation ability, which are characteristics of tumor stem cells. Then, the researchers analyzed the exocytosis of OFMSCs and found that the nutrition solution was rich in active TGF-b.

The activated TGF-b could activate Notch pathway and suppress BMP pathway. Notch pathway and BMP pathway are positively related with cell proliferation and cell osteogenesis, respectively. As a result, OFMSCs activate North pathway and improve their proliferation ability, while on the other hand, they also suppress BMP signaling pathway and lower their osteogenesis ability. This observation explains why OFMSCs are lack of the osteogenesis capability of ordinary facial mesenchymal stem cells but enhance their self-renewal ability.

What’s more, the researchers also explored the regulating mechanism of activated TGF-b. It was found that activated TGF-b can upregulate the gene expression of demethylase in a histone called JHDM1D and eventually activate TGF-b that were originally in inactive status, further enhancing signaling pathway. The entire process formed a positive feedback loop.

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The formation of benign tumor and the positive feedback loop model of JHDM1D/TSP1/TGF-β/SMAD3. Activated TGF-b activate Notch pathway,enhance cell proliferation, suppress BMP pathway and reduce osteogenesis, forming benign tumor phenotype. Activated TGF-b facilitates gene expression of JHDM1D and so upregulates the expression of TSP1 and further activates TGF-b that are in inactive status. *Image source: Haiyan Qin, et al. (2013) Cell Stem Cell.

These findings provide new insights in ossifying fibroma and are helpful in further development of its clinic treatment. Although we might need more research before we call actually apply these knowledge into clinical treatment, the findings offer us a new approach of tumor therapy—by studying and understanding of how tumors develop, suppress them before deterioration and lower the surgical risk as possible as we can.

Source:Eurekalert!

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