Induction of iPS Cells and of Cancer Stem Cells: The Stem Cell or Reprogramming Hypothesis of Cancer?

Abstract

This article as designed to examine whether the "stoichiometric" or "elite models" of the origin of the "induced pluripotent stem" (iPS) cells fits some experiment facts from the developmental biology of adult stem cells and from the field of cancer research. In brief, since the evidence presented to support the stoichiometric model failed to recognize the factual existence of adult organ specific stem cells, the model has not been rigorously tested. In addition, the demonstration of a subset of cells (MUSE cells) in normal primary in vitro cultures of human fibroblasts (the usual source of iPS cells) seems to be the origin of the iPS cells. Moreover, from the field of carcinogenesis, the "stem cell" versus "dedifferentiation" or "reprogramming" hypotheses were examined. Again, using the role of glycolysis, known to be associated with the Warburg effect in cancer cells, a list of experiments showing that (a) normal stem cells, which have few mitochondria, metabolize via glycolysis; (b) the stem cells are targets for "initiation" or "immortalization" or the blockage of differentiation and apoptosis of the stem cells by "immortalizing viruses"; (c) Lactate dehydrogenase A (LDHA), when expressed, is associated with glycolysis and therefore, must be expressed in normal adult stem cells, as well as in cancer cells; and (d) p53, depleted or rendered dysfunctional by SV40 Large T antigen, is associated with the reduction of mitochondrial function and mass and is associated with the Warburg effect. Together, these observations from the iPS and "cancer stem cell" fields support the idea that both iPS cells and cancer stem cell are derived from adult organ-specific stem cells that do not restore or switch their metabolism of glucose from oxidative metabolism to glycolysis but, rather, in both cases, the adult stem cell, which metabolizes by glycolysis, is prevented from differentiation or from metabolizing by oxidative phosphorylation. Anat Rec,

Stem cell manipulation, gene therapy and the risk of cancer stem cell emergence

“…It is therefore possible that cancer SCs originate from a spontaneous in vivo-in situ reprogramming of either adult cells or de-differentiated mature cells (129,130). In this context, in order to transform an experimental approach into a feasible clinical application, efforts have recently been made to increase the number of re-programmed cells, either by working on the efficiency of the conversion process, to reach a deterministic process (100% efficiency) (131), or by designing simpler culture conditions, independently of the nature of the somatic cells used.…”

Perspectivas de terapia celular em neurologia

“…Por exemplo, um trabalho recente buscou reduzir a carcinogênese dessas células por meio da inserção dos genes indutores de pluripotência em lócus específicos do genoma humano, que sejam mais seguros contra esses eventos (por exemplo, a região AAVS1, do cromossomo 19) 66 . Outro trabalho busca compreender se IPS são necessariamente carcinogênicas, e quais são as associações entre elas e as células neoplásicas 67 . Contudo, fica evidente que esse é um grande entrave a ser superado, caso desejemos utilizar no futuro esse tipo celular para transplantes bem sucedidos.…”

A mystery unraveled: nontumorigenic pluripotent stem cells in human adult tissues

“…Mature iPS cells have been found to possess that mature iPS cells possess an epigenetic memory, defined by the remnants of post-translational histone and DNA modifications, preventative of entirely successful reprogramming, often restricting their physiological function to that of a cell within the same lineage as the original stem cell source [34,42,43]. This phenomenon may be attributable to an organ-specific adult stem cell origin [44,45]. Despite momentous efforts invested in the study of both ES cells and iPS cells, little progress has come in resolving in resolving the defects that stand in the way of the use of these stem cells toward cell therapy in humans.…”

“…In addition to the notion that iPS cells are derived from organ-specific adult stem cells [44,45], it has been reported that in adult human fibroblasts iPS cells are generated exclusively from Muse cells, supporting the elite model of iPS cell generation rather than the stochastic model [55]. The stochastic model posits that iPS cells can be generated from every cell type, with varying efficiencies, through the induction of the Yamanaka factors [13].…”