Abstract
Tumor metastasis is the major cause of mortality from cancer. Metabolic rewiring and the metastatic cascade are highly intertwined, co-operating to promote multiple steps of cancer metastasis. Metabolites generated by cancer cells influence the metastatic cascade, encompassing epithelial-mesenchymal transition (EMT), survival of cancer cells in circulation, and metastatic colonization at distant sites. A variety of molecular mechanisms underlie the prometastatic effect of tumor-derived metabolites, such as epigenetic deregulation, induction of matrix metalloproteinases (MMPs), promotion of cancer stemness, and alleviation of oxidative stress. Conversely, metastatic signaling regulates expression and activity of rate-limiting metabolic enzymes to generate prometastatic metabolites thereby reinforcing the metastasis cascade. Understanding the complex interplay between metabolism and metastasis could unravel novel molecular targets, whose intervention could lead to improvements in the treatment of cancer. In this review, we summarized the recent discoveries involving metabolism and tumor metastasis, and emphasized the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these aberrant situations in cancer.
Highlights
It has been appreciated since the early days of oncology research that the metabolic profiles of tumor cells differ from normal cells
Metabolic rewiring could drive metastasis by (1) generating oncometabolites to hijack metastatic signaling cascades via regulating gene expression, (2) generating metabolites/cofactors that act as agonists/antagonists for functional proteins involved in metastasis, and (3) modulating metabolic demands of cancer cells, allowing adaptation to the various stages of metastatic cascade
We provide a summary of molecular mechanisms linking cancer metastasis and cell metabolism, their underlying roles in metastasis and highlight the potential metabolic targets that could be harnessed to suppress cancer metastasis
Summary
It has been appreciated since the early days of oncology research that the metabolic profiles of tumor cells differ from normal cells. Metabolic rewiring could drive metastasis by (1) generating oncometabolites to hijack metastatic signaling cascades via regulating gene expression, (2) generating metabolites/cofactors that act as agonists/antagonists for functional proteins involved in metastasis, and (3) modulating metabolic demands of cancer cells, allowing adaptation to the various stages of metastatic cascade. EMT is primarily driven by the transcription factors SNAIL1/2, zinc-finger E-box-binding (ZEB1/2), and basic helix-loop-helix transcription factors (TWIST1/2) that repress epithelial marker genes whilst inducing expression of mesenchymal markers. These transcription factors are overexpressed in response to extracellular mitogenic signals. ZEB1 knockdown or miR200 re-expression reverted IDH1/ 2-mutant cells to an epithelial phenotype, suggesting that the effect of 2-HG on EMT is dependent on ZEB1/miR-200 pathway. Higher D-2HG in colorectal tumors was associated with distant organ metastasis. 2-HG promotes a prometastatic phenotype via epigenetic activation of ZEB expression
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