Induced Pluripotency and Oncogenic Transformation Are Related Processes

Abstract

Induced pluripotent stem cells (iPSCs) have the potential for creating patient-specific regenerative medicine therapies, but the links between pluripotency and tumorigenicity raise important safety concerns. More specifically, the methods employed for the production of iPSCs and oncogenic foci (OF), a form of in vitro produced tumor cells, are surprisingly similar, raising potential concerns about iPSCs. To test the hypotheses that iPSCs and OF are related cell types and, more broadly, that the induction of pluripotency and tumorigenicity are related processes, we produced iPSCs and OF in parallel from common parental fibroblasts. When we compared the transcriptomes of these iPSCs and OF to their parental fibroblasts, similar transcriptional changes were observed in both iPSCs and OF. A significant number of genes repressed during the iPSC formation were also repressed in OF, including a large cohort of differentiation-associated genes. iPSCs and OF shared a limited number of genes that were upregulated relative to parental fibroblasts, but gene ontology analysis pointed toward monosaccharide metabolism as upregulated in both iPSCs and OF. iPSCs and OF were distinct in that only iPSCs activated a host of pluripotency-related genes, while OF activated cellular damage and specific metabolic pathways. We reprogrammed oncogenic foci (ROF) to produce iPSC-like cells, a process dependent on Nanog. However, the ROF had reduced differentiation potential compared to iPSC, suggesting that oncogenic transformation leads to cellular changes that impair complete reprogramming. Taken together, these findings support a model in which OF and iPSCs are related, yet distinct cell types, and in which induced pluripotency and induced tumorigenesis are similar processes.

Metabolic control of cancer cell stemness: Lessons from iPS cells

“…[2][3][4][5][6][7][8][9][10][11] Nonetheless, the striking similarity of the molecular features shared between iPS cell generation and tumorigenesis is providing key mechanistic insights on how CSC could actually arise, in some cases, from differentiated cells through a process of "pathological nuclear reprogramming." [12][13][14][15][16][17][18][19][20][21] A proof-of-concept demonstration of the close association between acquisition of stem cell properties by induced pluripotency and CSC-driven tumorigenesis has been recently carried out in a landmark study, showing that transient in vivo expression of reprogramming factors generates tumors with altered epigenetic states which cause abnormal growth of incompletely reprogrammed cells. 22 Though these findings are the first to confirm that premature termination of induced pluripotency can result in cancer development, it should be noted that oncogenic-transformed cells and iPS cells generated from common parental fibroblasts have been found to represent highly related, yet distinct, cell types based on expression profiling,share common "cellular ancestors" that develop along an equivalent molecular pathway(s) before they diverge.…”

“…Indeed, a model comparing malignant transformation and (non-malignant) nuclear cell reprogramming demonstrated that differentiated cells should first acquire epigenetic changes that lead to a downregulation of the differentiation machinery, which is paralleled by an activation of glycolysis and other metabolic pathways. 15 Crucially, only then are the oncogenic or the pluripotent phenotypes fully acquired, depending on other stimuli such as stemness factors. Moreover, whereas reprogrammed pluripotent stem cells can acquire oncogenic traits, the converse is not true because oncogenic cells cannot acquire the bona fide pluripotent state possessed by stem cells.…”

“…Moreover, whereas reprogrammed pluripotent stem cells can acquire oncogenic traits, the converse is not true because oncogenic cells cannot acquire the bona fide pluripotent state possessed by stem cells. 15 If the acquisition of stem cell properties in induced pluripotency is closely associated with CSC-driven tumorigenesis, it then follows that determining the mechanisms that positively regulate the efficiency and kinetics of somatic reprogramming to iPS cellular states may provide a proof-ofconcept validation for the novel selfrenewing tumor-initiating mechanisms that regulate both the number and aberrant functionality of CSC. 23 Following this line of reasoning, Tung and Knoepfler 24 have recently reviewed the shared epigenetic machinery by which pluripotency and oncogenicity are established and regulated.…”

Pluripoteny and Cancer, Two Sides of The Same Coin?

“…The mechanisms underlying the reprogramming process are not well understood yet; however the three main transcription factors Oct4, Sox2 and Nanog, called master regulators of pluripotency, have proved responsible for maintaining the undifferentiated state. Basically both processes, reprograming and transformation, need the expression or activation of oncogenes (expression of Oct4, Sox2 and Nanog has been repeatedly observed in tumors), inactivation of tumor suppressor genes, overriding the senescence and apoptotic barriers and both processes also involve epigenetic changes and a metabolic switch towards a glycolytic metabolism [3,4]. The tumor suppressor p53 poses a barrier for pluripotency induction [5].…”

Estudo da ação do gene TCL1 na reprogramação de células-tronco de pluripotência induzida (iPS) humanas

“…Recentemente, Riggs et al (2013) avaliaram a semelhança entre iPS e foco oncogênico e constataram que, apesar de tipos celulares diferentes, os processos de indução de pluripotência e de indução de tumor são processos relacionados.…”