Cancer metabolism: a therapeutic perspective

Abstract

Awareness that the metabolic phenotype of cells within tumours is heterogeneous - and distinct from that of their normal counterparts - is growing. In general, tumour cells metabolize glucose, lactate, pyruvate, hydroxybutyrate, acetate, glutamine, and fatty acids at much higher rates than their nontumour equivalents; however, the metabolic ecology of tumours is complex because they contain multiple metabolic compartments, which are linked by the transfer of these catabolites. This metabolic variability and flexibility enables tumour cells to generate ATP as an energy source, while maintaining the reduction-oxidation (redox) balance and committing resources to biosynthesis - processes that are essential for cell survival, growth, and proliferation. Importantly, experimental evidence indicates that metabolic coupling between cell populations with different, complementary metabolic profiles can induce cancer progression. Thus, targeting the metabolic differences between tumour and normal cells holds promise as a novel anticancer strategy. In this Review, we discuss how cancer cells reprogramme their metabolism and that of other cells within the tumour microenvironment in order to survive and propagate, thus driving disease progression; in particular, we highlight potential metabolic vulnerabilities that might be targeted therapeutically.

Cancer metabolism in space and time: Beyond the Warburg effect

“…Many chal lenges are up com ing in the field of can cer me tab o lism, rep re sented by sev eral cur rently on go ing clin i cal tri als [270]. De spite to day's vi brant re search on can cer me tab o lism and the high po ten tial of this field for can cer ther apy, the next years will be cru cial for un der stand ing the cur rent con tri bu tion of re search on tu mor me tab o lism to the de vel op ment of novel treat ments.…”

A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX

“…Tumors and their microenvironment are incredibly heterogeneous structures, which behave like metabolic ecosystems [1–12]. In accordance with this cellular and metabolic heterogeneity, it is now well accepted that more than a single type of cancer cell exists [1–12].…”

“…In accordance with this cellular and metabolic heterogeneity, it is now well accepted that more than a single type of cancer cell exists [1–12]. For example, within a given epithelial cancer cell line (such as MCF7), there are “bulk” cancer cells (~ 85–95%; the majority of the population), as well as various types of progenitor cells (< 5%), and cancer stem cells (CSCs; < 1%).…”

“…To functionally enrich for CSCs, the entire cell population can be trypsinized and seeded as a single-cell suspension onto low-attachment plates [1,2]. Under these conditions, the majority of “bulk” cancer cells die (> 90%) via apoptosis, while only the CSCs survive and propagate, ultimately resulting after 5 d in the formation of 3D spheroid structures.…”

“…Under these conditions, each 3D spheroid is clonally formed from a single CSC. For breast CSCs, these 3D spheroids are also known as tumor-spheres or mammo-spheres [1–12]. The generation of these 3D spheroids is thought to mimic the process of tumor formation and/or metastasis, providing an excellent model for drug discovery and functional validation.…”