Abstract
Current hypothesis suggest that tumors can originate from adult cells after a process of 'reprogramming' driven by genetic and epigenetic alterations. These cancer cells, called cancer stem cells (CSCs), are responsible for the tumor growth and metastases. To date, the research effort has been directed to the identification, isolation and manipulation of this cell population. Independently of whether tumors were triggered by a reprogramming of gene expression or seeded by stem cells, their energetic metabolism is altered compared with a normal cell, resulting in a high aerobic glycolytic 'Warburg' phenotype and dysregulation of mitochondrial activity. This metabolic alteration is intricately linked to cancer progression.The aim of this work has been to demonstrate the possibility of differentiating a neoplastic cell toward different germ layer lineages, by evaluating the morphological, metabolic and functional changes occurring in this process. The cellular differentiation reported in this study brings to different conclusions from those present in the current literature. We demonstrate that 'in vitro' neuroblastoma cancer cells (chosen as experimental model) are able to differentiate directly into osteoblastic (by rapamycin, an mTOR inhibitor) and hepatic lineage without an intermediate 'stem' cell step. This process seems owing to a synergy among few master molecules, metabolic changes and scaffold presence acting in a concerted way to control the cell fate.
Highlights
The development of methods for reprogramming somatic cells to induced pluripotent stem cells through ectopic expression of a few pluripotency factors holds the promise for disease modeling, drug screening studies and treatment of several diseases.[3]
RamosMejia et al.[4] in a recent review emphasize the importance of deciphering the barriers underlying the reprogramming process of primary cancer cells to obtain information on the links between pluripotency and oncogenic transformation that would be instrumental for therapy development
The neuroblastoma cells begin to get in contact with the support already on the early days of differentiation
Summary
The development of methods for reprogramming somatic cells to induced pluripotent stem cells (iPSCs) through ectopic expression of a few pluripotency factors holds the promise for disease modeling, drug screening studies and treatment of several diseases.[3]. Recent studies are increasingly highlighting the importance of metabolic manipulation in cancer cells and how bioenergetic and biosynthetic changes could be exploited to stop tumor cells progression.[15,16,17] Reprogramming, pluripotency, oncogenic transformation and metabolic changes are connected processes that share interesting similarities.[18,19] The fact that the same alterations driving tumorigenesis can influence the reprogramming of non-cancer somatic cells is a double-edged sword It poses safety concerns for the cell therapy applications with iPSCs, while at the same time it promotes further studies aimed to analyzing the mechanisms and barriers underlying the direct reprogramming of cancer cells. We show how these cells can differentiate toward a germ line different from the original one, modifying their morphology and acquiring metabolic changes which are distinctive of a more normal phenotype
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