Cancer cell metabolic plasticity in migration and metastasis

Abstract

Metabolic reprogramming is a hallmark of cancer metastasis in which cancer cells manipulate their metabolic profile to meet the dynamic energetic requirements of the tumor microenvironment. Though cancer cell proliferation and migration through the extracellular matrix are key steps of cancer progression, they are not necessarily fueled by the same metabolites and energy production pathways. The two main metabolic pathways cancer cells use to derive energy from glucose, glycolysis and oxidative phosphorylation, are preferentially and plastically utilized by cancer cells depending on both their intrinsic metabolic properties and their surrounding environment. Mechanical factors in the microenvironment, such as collagen density, pore size, and alignment, and biochemical factors, such as oxygen and glucose availability, have been shown to influence both cell migration and glucose metabolism. As cancer cells have been identified as preferentially utilizing glycolysis or oxidative phosphorylation based on heterogeneous intrinsic or extrinsic factors, the relationship between cancer cell metabolism and metastatic potential is of recent interest. Here, we review current in vitro and in vivo findings in the context of cancer cell metabolism during migration and metastasis and extrapolate potential clinical applications of this work that could aid in diagnosing and tracking cancer progression in vivo by monitoring metabolism. We also review current progress in the development of a variety of metabolically targeted anti-metastatic drugs, both in clinical trials and approved for distribution, and highlight potential routes for incorporating our recent understanding of metabolic plasticity into therapeutic directions. By further understanding cancer cell energy production pathways and metabolic plasticity, more effective and successful clinical imaging and therapeutics can be developed to diagnose, target, and inhibit metastasis.

Keywords: ATP; Collective migration; Extracellular matrix; Glycolysis; Oxidative phosphorylation.