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Cancer stem cells theory and the warburg effect, two sides of the same coin?

Significance Statement

One of the most revolutionary and innovative aspects in the biology of the neoplastic process is represented by the discovery and isolation of stem cells and by the so-called cancer stem cell theory, which, through several and independent studies that confirm its validity, is radically changing concepts and interpretative models of the neoplastic process. Simultaneously, in recent years, an equally high number of experiments conducted in vitro, in vivo and in anatomical-pathological reports, strongly reevaluated the link existing between neoplastic cell and  metabolome. The original paradigm that sees the neoplastic cell rely primarily on glycolysis, with a high lactate production, whether or not the presence of oxygen, a phenomenon known as the Warburg Effect, has been highly studied and in this jigsaw puzzle several pieces have been fitted together. For example, if historically Warburg and the other scientists believed that as a mechanism of origin of the phenomenon there was the inability of the mitochondria to use oxygen properly, nowadays we  know that the mitochondria of neoplastic cells have a very high oxygen consumption and a high transport through the electron transport chain. Moreover, according to the data available it is clear that the metabolome, in its plastic dynamism, can affect many aspects of genetics and epigenetics. However, there is an essential and well confirmed aspect that may open new perspectives in the close link between metabolomics and undifferentiated cell state. In fact, totipotent embryonic stem cells and adult stem cells (ASCs) themselves, which govern the physiological processes of self-renewing, show a metabolic panel, which, although different in some subtle characteristics, is in the majority comparable to the cancer cell metabolism. Similarly, in the process of reprogramming and induction of pluripotency (IPSCs), there is a metabolic reprogramming vs the metabolic panel of the undifferentiated state, the blocking or the drug stimulation of this metabolic reprogramming confirm the close interconnection between metabolomics and stem cell. If we recognize that the neoplastic process is supported by cancer stem cells (CSCs), which in the side population presides over the self-renewing of the neoplastic tissue, then a vital issue is represented by the origin of Cancer stem cells. If Cancer stem cells derive from ASCs, then those ones have already a metabolism invoking the Warburg Effect, which can help to give gene instability and specific epigenetic patterns, not least an increased sensitivity to many predisposing factors. Thus, the transition from ASCs to CSCs is potentially facilitated by their metabolic condition. On the contrary, if we recognize that Cancer stem cells arise in connection with a process of somatic reprogramming, then the acquisition of these metabolic characteristics represents a not acquired condition and subject to the neoplastic transformation, although necessary for the reprogramming. And, on the other hand, regardless of the path that led to the genesis of the Cancer stem cells, an altered metabolic state can largely affect the abnormal processes of self-renewing and of abnormal differentiation of the neoplastic parenchyma. Therefore, basing on a careful analysis of the literature concerning a number of biophysical and thermodynamic considerations, we have developed a model that predicts how the neoplastic process onset is related to the synchronous alteration of the metabolome, of the epigenetic patterns and of the gene stability. In our model, each of these conditions is necessary and cooperative, but it is not sufficient separately. It should also be noted that the metabolic state appears to be important in the regulation of the processes of metastasization and it may represent a boost towards the epithelial-mesenchymal transition. Recent confirmations, subsequent to our publication, seem to confirm this point of view on the epithelial-mesenchymal transition and in general on the entire model. It could therefore be developed, at a general level, a new and integrated conception of the entire neoplastic process, which could also lead to essential therapeutic implications, based on the links between the self-renewing and metabolome, and between metabolome and epigenetic mechanisms and genome integrity.

Cancer stem cells theory and the warburg effect, two sides of the same coin? Global Medical Discovery











Journal Reference

Pacini N1, Borziani F2.

Int J Mol Sci. 2014;15(5):8893-930.

1Laboratorio Privato di Biochimica F. Pacini, via trabocchetto 10, 89126 Reggio Calabria, Italy. [email protected]

2Laboratorio Privato di Biochimica F. Pacini, via trabocchetto 10, 89126 Reggio Calabria, Italy. [email protected]



 Over the last 100 years, many studies have been performed to determine the biochemical and histopathological phenomena that mark the origin of neoplasms. At the end of the last century, the leading paradigm, which is currently well rooted, considered the origin of neoplasms to be a set of genetic and/or epigenetic mutations, stochastic and independent in a single cell, or rather, a stochastic monoclonal pattern. However, in the last 20 years, two important areas of research have underlined numerous limitations and incongruities of this pattern, the hypothesis of the so-called cancer stem cell theory and a revaluation of several alterations in metabolic networks that are typical of the neoplastic cell, the so-called Warburg effect. Even if this specific “metabolic sign” has been known for more than 85 years, only in the last few years has it been given more attention; therefore, the so-called Warburg hypothesis has been used in multiple and independent surveys. Based on an accurate analysis of a series of considerations and of biophysical thermodynamic events in the literature, we will demonstrate a homogeneous pattern of the cancer stem cell theory, of the Warburg hypothesis and of the stochastic monoclonal pattern; this pattern could contribute considerably as the first basis of the development of a new uniform theory on the origin of neoplasms. Thus, a new possible epistemological paradigm is represented; this paradigm considers the Warburg effect as a specific “metabolic sign” reflecting the stem origin of the neoplastic cell, where, in this specific metabolic order, an essential reason for the genetic instability that is intrinsic to the neoplastic cell is defined.

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