The metabolic addiction of cancer stem cells

Abstract

Cancer stem cells (CSC) are the minor population of cancer originating cells that have the capacity of self-renewal, differentiation, and tumorigenicity (when transplanted into an immunocompromised animal). These low-copy number cell populations are believed to be resistant to conventional chemo and radiotherapy. It was reported that metabolic adaptation of these elusive cell populations is to a large extent responsible for their survival and distant metastasis. Warburg effect is a hallmark of most cancer in which the cancer cells prefer to metabolize glucose anaerobically, even under normoxic conditions. Warburg’s aerobic glycolysis produces ATP efficiently promoting cell proliferation by reprogramming metabolism to increase glucose uptake and stimulating lactate production. This metabolic adaptation also seems to contribute to chemoresistance and immune evasion, a prerequisite for cancer cell survival and proliferation. Though we know a lot about metabolic fine-tuning in cancer, what is still in shadow is the identity of upstream regulators that orchestrates this process. Epigenetic modification of key metabolic enzymes seems to play a decisive role in this. By altering the metabolic flux, cancer cells polarize the biochemical reactions to selectively generate “onco-metabolites” that provide an added advantage for cell proliferation and survival. In this review, we explored the metabolic-epigenetic circuity in relation to cancer growth and proliferation and establish the fact how cancer cells may be addicted to specific metabolic pathways to meet their needs. Interestingly, even the immune system is re-calibrated to adapt to this altered scenario. Knowing the details is crucial for selective targeting of cancer stem cells by choking the rate-limiting stems and crucial branch points, preventing the formation of onco-metabolites.

The hidden architects of glioblastoma multiforme: Glioma stem cells

“…Genetic changes and mutations in IDH1 were also seen to be quite frequent in early gliomas, leading to inhibition of demethylases like TET1 and TET2, thereby causing aberrant methylation of DNAs and histones 56 . Thus, as suggested by Sahoo et al, it can be postulated that the extensive links established between the metabolome and epigenetic programmes and their influence on tumor pathogenesis can be a possible target for the treatment of GBM 39 …”

“…56 Thus, as suggested by Sahoo et al, it can be postulated that the extensive links established between the metabolome and epigenetic programmes and their influence on tumor pathogenesis can be a possible target for the treatment of GBM. 39…”

“…Characterized by high proliferative rates, GSCs, like other CSCs, adapt to several changes in cellular metabolism. 39 Several shreds of evidence have stated the upregulation of nutrient transporters like GLUT3 and aberrant activation of other integrin signalling networks to increase glucose influx and secure carbon flow in neurons, thereby supporting the rapid metabolism and proliferation of GSCs. 40,41 So as to support glucose homeostasis, other substrates like glutamine and acetate also play a role in the bioenergetics of GSC maintenance.…”

“…Metabolic dysregulation has always played a pivotal part in documenting GBM initiation, growth and adaptation. Characterized by high proliferative rates, GSCs, like other CSCs, adapt to several changes in cellular metabolism 39 . Several shreds of evidence have stated the upregulation of nutrient transporters like GLUT3 and aberrant activation of other integrin signalling networks to increase glucose influx and secure carbon flow in neurons, thereby supporting the rapid metabolism and proliferation of GSCs 40,41 .…”

Potential Therapies Targeting the Metabolic Reprogramming of Diabetes-Associated Breast Cancer

“…Cancer cells can change the metabolic environment of tumors through sequestering nutrients (such as glucose, tryptophan, and arginine) and producing toxic wastes (such as adenosine, lactic acid, and kynurenine). This tumor environment promotes the depletion of anti-tumor immune cells, the expansion of Tregs, and the expression of immune checkpoints [ 145 , 146 , 147 ]. The establishment of this immunosuppressive tumor environment reduces the therapeutic response of cancer patients to immunotherapy.…”