Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production

TLDR

Tumor cells are thought to depend on glycolysis for ATP, but it is unclear whether this Warburg effect arises from intrinsic metabolic changes or hypoxia. The authors transformed human adult mesenchymal stem cells using the same genetic alterations employed for differentiated cells. Transformed MSC require the same pathway disruptions as differentiated cells, are more glycolytic than fibroblasts yet do not rely on aerobic glycolysis for ATP during transformation, indicating that the Warburg effect is not intrinsic to adult stem cell transformation but that oxidative phosphorylation can support oncogenic adaptation, with any glycolytic enzyme up‑regulation in resulting tumors being a reversible, microenvironment‑driven response.

Abstract

An increased dependency on glycolysis for ATP production is considered to be a hallmark of tumor cells. Whether this increase in glycolytic activity is due mainly to inherent metabolic alterations or to the hypoxic microenvironment remains controversial. Here we have transformed human adult mesenchymal stem cells (MSC) using genetic alterations as described for differentiated cells. Our data suggest that MSC require disruption of the same pathways as have been shown for differentiated cells to confer a fully transformed phenotype. Furthermore, we found that MSC are more glycolytic than primary human fibroblasts and, in contrast to differentiated cells, do not depend on increased aerobic glycolysis for ATP production during transformation. These data indicate that aerobic glycolysis (the Warburg effect) is not an intrinsic component of the transformation of adult stem cells, and that oncogenic adaptation to bioenergetic requirements, in some circumstances, may also rely on increases in oxidative phosphorylation. We did find, however, a reversible increase in the transcription of glycolytic enzymes in tumors generated by transformed MSC, indicating this is a secondary phenomenon resulting from adaptation of the tumor to its microenvironment.