The Warburg effect version 2.0: Metabolic reprogramming of cancer stem cells

Abstract

When fighting cancer, knowledge on metabolism has always been important. Today, it matters more than ever. The restricted cataloging of cancer genomes is quite unlikely to achieve the task of curing cancer, unless it is integrated into metabolic networks that respond to and influence the constantly evolving cancer stem cell (CSC) cellular states. Once the genomic era of carcinogenesis had pushed the 1920s Otto Warburg's metabolic cancer hypothesis into obscurity for decades, the most recent studies begin to support a new developing paradigm, in which the molecular logic behind the conversion of non-CSCs into CSCs can be better understood in terms of the "metabolic facilitators" and "metabolic impediments" that operate as proximate openings and roadblocks, respectively, for the transcriptional events and signal transduction programs that ultimately orchestrate the intrinsic and/or microenvironmental paths to CSC cellular states. Here we propose that a profound understanding of how human carcinomas install a proper "Warburg effect version 2.0" allowing them to "run" the CSCs' "software" programs should guide a new era of metabolo-genomic-personalized cancer medicine. By viewing metabolic reprogramming of CSCs as an essential characteristic that allows dynamic, multidimensional and evolving cancer populations to compete successfully for their expansion on the organism, we now argue that CSCs bioenergetics might be another cancer hallmark. A definitive understanding of metabolic reprogramming in CSCs may complement or to some extent replace, the 30-y-old paradigm of targeting oncogenes to treat human carcinomas, because it can be possible to metabolically create non-permissive or "hostile" metabotypes to prevent the occurrence of CSC cellular states with tumor- and metastasis-initiating capacity.

Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1–Stat3

“…1E and F). A high rate of glycolysis is a metabolic signature of CSCs (Warburg effect version 2.0) (27). PF-03084014 significantly reduced glycolytic gene expression (Fig.…”

Reprogramming of non-genomic estrogen signaling by the stemness factor SOX2 enhances the tumor-initiating capacity of breast cancer cells

“…Acquisition of the self-renewal and tumor-initiating abilities of CSCs may arise from some of the molecular mechanisms underlying cellular reprogramming to pluripotency; i.e., spontaneous dedifferentiation and initiation of tumorigenesis in vivo may involve the reactivation of one or more pluripotency-associated factors. [1][2][3][4] In this regard, SOX2, a member of the SRYrelated HMG-box family of transcription factors, has mainly been studied in embryonic stem cells and in reprogramming of adult somatic cells to a pluripotent stem cell state, and it has been recently recognized to promote aberrant stem cell selfrenewal signaling in breast cancer. [5][6][7] First, normal breast tissues express low levels of SOX2, but SOX2 in early-stage breast carcinomas is differentially reactivated in the ductal areas of tumors that still show intact ductal structures, which strongly suggests that SOX2 may be expressed during the initial phases of tumorigenesis.…”

Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway

“…Recent studies suggest that CSCs may have special metabolic properties that distinguish them from the bulk of tumor cells, and that such biochemical properties may constitute a basis for developing new therapeutic strategies to eliminate CSCs. 16 Our recent study showed that brain tumor stem-like cancer cells exhibited low mitochondrial respiratory activity and preferred hypoxic microenvironment to maintain their stemness. 17 We further demonstrated that glioma stem cells were active in glycolysis and were intrinsically sensitive to glycolytic inhibition.…”