Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy.

Jiaqi Li,Yaw Chyn Lim,Lingzhi Wang,Li Ren Kong,Andrea L A Wong,Jie Qing Eu,Boon Cher Goh

doi:10.3390/molecules25204831

Abstract

Targeting altered tumour metabolism is an emerging therapeutic strategy for cancer treatment. The metabolic reprogramming that accompanies the development of malignancy creates targetable differences between cancer cells and normal cells, which may be exploited for therapy. There is also emerging evidence regarding the role of stromal components, creating an intricate metabolic network consisting of cancer cells, cancer-associated fibroblasts, endothelial cells, immune cells, and cancer stem cells. This metabolic rewiring and crosstalk with the tumour microenvironment play a key role in cell proliferation, metastasis, and the development of treatment resistance. In this review, we will discuss therapeutic opportunities, which arise from dysregulated metabolism and metabolic crosstalk, highlighting strategies that may aid in the precision targeting of altered tumour metabolism with a focus on combinatorial therapeutic strategies.

Highlights

To sustain the rapid proliferation characterising cancer cells, corresponding alterations to tumour metabolism must occur to fuel the elevated bioenergetic demands
This review aims to highlight the complex interplay of regulatory cell signalling pathways, interactions between cancer cells and their tumour microenvironment (TME), and the contributions of cancer stem cell (CSC) to the intricate and coordinated induction of metabolic pathways
Cancer therapy entered a new era with the discovery of two additional hallmarks of cancer, ‘reprogramming energy metabolism’ and ‘evading immune response.’

Summary

Introduction

To sustain the rapid proliferation characterising cancer cells, corresponding alterations to tumour metabolism must occur to fuel the elevated bioenergetic demands. This understanding has led to the introduction of ‘Deregulating Cellular Energetics’ as a new hallmark of cancer [1]. Initial observations by Otto Warburg described an unusual reliance of cancer cells on glycolysis despite sufficient oxygen, which was later termed the ‘Warburg effect’ to describe this form of aerobic glycolysis [2] This metabolic reprogramming, while less efficient in terms of ATP production, confers cancer cells with much-needed metabolic intermediates that can be channelled into biosynthetic pathways, such as the pentose-phosphate pathway (PPP) for nucleotide synthesis [3]. Recent studies suggest that certain subtypes of cancer cells may preferentially utilize oxidative phosphorylation (OXPHOS) for energy production in glucose-limiting conditions [4]

Objectives

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Discussion

Conclusion