Cancer Stem Cell Metabolism and Potential Therapeutic Targets

Abstract

Malignant tumors contain heterogeneous populations of cells in various states of proliferation and differentiation. The presence of cancer stem or initiating cells is a well-established concept wherein quiescent and poorly differentiated cells within a tumor mass contribute to drug resistance, and under permissive conditions, are responsible for tumor recurrence and metastasis. A number of studies have identified molecular markers that are characteristic of tissue-specific cancer stem cells (CSCs). Isolation of CSCs has enabled studies on the metabolic status of CSCs. As metabolic plasticity is a hallmark of cancer cell adaptation, the intricacies of CSC metabolism and their phenotypic behavior are critical areas of research. Unlike normal stem cells, which rely heavily on oxidative phosphorylation (OXPHOS) as their primary source of energy, or cancer cells, which are primarily glycolytic, CSCs demonstrate a unique metabolic flexibility. CSCs can switch between OXPHOS and glycolysis in the presence of oxygen to maintain homeostasis and, thereby, promote tumor growth. Here, we review key factors that impact CSC metabolic phenotype including heterogeneity of CSCs across different histologic tumor types, tissue-specific variations, tumor microenvironment, and CSC niche. Furthermore, we discuss how targeting key players of glycolytic and mitochondrial pathways has shown promising results in cancer eradication and attenuation of disease recurrence in preclinical models. In addition, we highlight studies on other potential therapeutic targets including complex interactions within the microenvironment and cellular communications in the CSC niche to interfere with CSC growth, resistance, and metastasis.

Nandrolone induces a stem cell-like phenotype in human hepatocarcinoma-derived cell line inhibiting mitochondrial respiratory activity

“…Depression of mitochondrial oxygen consumption in cancer cells is associated to a stem cell-like phenotype due to the lower energy demand characterizing the metabolic quiescent cancer stem cells 37,38 . Indeed, mitochondrial OxPhos is mandatory to engage epithelial/mesenchymal transition 39 .…”

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

“…The presence of a high level of CSCs in tumours carries a bad prognosis and is associated with poor overall survival, high incidence of disseminated cancer and recurrence, indicating a strong negative prognostic indicator for CSCs containing tumours [211]. Some of the defining characteristics of CSCs such as cell surface markers, altered metabolism, altered signaling pathways; regulatory factors in the tumour microenvironment sustaining and enriching CSC volumes have the potential to be targeted for efficient eradication of CSCs [211,212]. In that context, targeting the cell surface receptors overexpressed in OC cells has shown credibility in preclinical models.…”

Stemness features in liver cancer

“…All these findings prompt metabolic plasticity as a central force that enables CSCs to modify their replicative capabilities according to specific needs [ Figure 2]. Further, emerging evidence suggests that CSCs may adopt specific metabolic phenotypes based on their location within tumor mass [147] .…”