Hallmarks of cancer stem cell metabolism

Abstract

Cancer cells adapt cellular metabolism to cope with their high proliferation rate. Instead of primarily using oxidative phosphorylation (OXPHOS), cancer cells use less efficient glycolysis for the production of ATP and building blocks (Warburg effect). However, tumours are not uniform, but rather functionally heterogeneous and harbour a subset of cancer cells with stemness features. Such cancer cells have the ability to repopulate the entire tumour and thus have been termed cancer stem cells (CSCs) or tumour-initiating cells (TICs). As opposed to differentiated bulk tumour cells relying on glycolysis, CSCs show a distinct metabolic phenotype that, depending on the cancer type, can be highly glycolytic or OXPHOS dependent. In either case, mitochondrial function is critical and takes centre stage in CSC functionality. Remaining controversies in this young and emerging research field may be related to CSC isolation techniques and/or the use of less suitable model systems. Still, the apparent dependence of CSCs on mitochondrial function, regardless of their primary metabolic phenotype, represents a previously unrecognised Achilles heel amendable for therapeutic intervention. Elimination of highly chemoresistant CSCs as the root of many cancers via inhibition of mitochondrial function bears the potential to prevent relapse from disease and thus improve patients' long-term outcome.

Figure 1

The cancer stem cell concept in cancer progression and metastasis. For various solid cancers it has been shown that intraclonal heterogeneity is formed by CSCs and their differentiated progenies (left) (Visvader and Lindeman, 2012; Miranda-Lorenzo et al, 2014). CSCs are capable of undergoing unlimited cell division while retaining their stem cell identity (self-renewal) and giving rise to more differentiated cells with limited or no tumour-initiating and metastatic capacity, despite their high proliferative capacity. CSCs evolve as the tumour progresses via (epi-) genetic alterations, but also in response to interactions with their niche, leading to diverse CSC subclones with distinct functionality (Sainz et al, 2014, 2015). While both CSCs and differentiated cancer may acquire enhanced mobility, for example, via epithelial–mesenchymal transition (EMT), to date only arising metastatic CSCs have been shown to initiate secondary lesions (Hermann et al, 2007; Malanchi et al, 2012) and are tractable as circulating CSCs in the blood (Clausell-Tormos et al, 2014; Yang et al, 2015) (centre). Importantly, these cells must survive the hostile environment of the blood stream, evade immune surveillance and extravasate at a distant location to form metastatic lesions, rendering the process extremely inefficient (right).

Figure 2

Targeting cancer stem cells through inhibition of mitochondrial function. CSCs dependent of OXPHOS can be eliminated by various strategies impairing mitochondrial energy metabolism. Direct inhibition of OXPHOS can be achieved with small molecules such as the antidiabetic agents metformin and phenformin, which inhibit the ETC Complex I and cause cell death by energy crisis in CSCs. Conjugation of pharmacologic agents to mitochondrial carriers such as TPP or mitochondria-penetrating peptides (MPPs) may allow their selective delivery and accumulation in mitochondria. This strategy has already been used for chemotherapeutic agents such as doxorubicin to selectively disrupt mtDNA integrity and the expression of ETC proteins. Mitochondrial protein biosynthesis can also be blocked by the inhibition of mitochondrial ribosomes using tigecycline and other FDA-approved antibiotics, which impair OXPHOS and bear toxicity against CSCs. Similarly, the functionality of ETC components can also be targeted by mitochondrial delivery of the chaperone inhibitor gamitrinib. Cell signalling by OXPHOS-generated mitochondrial ROS is crucial for cancer cell proliferation and can be targeted by the mitochondrial accumulation of antioxidants such as mito-chromanol. Conversely, CSCs can be eliminated by inducing toxic levels of ROS in mitochondria with the ROS-inducer menadione. Finally, OXPHOS can also be impaired at the level of mitochondrial carbon metabolism, either by altering the enzymes involved in the TCA cycle or fatty acid oxidation (FAO) or by interfering with the supply of mitochondrial fuels.