Metabolic Constrains Rule Metastasis Progression

Abstract

Metastasis formation accounts for the majority of tumor-associated deaths and consists of different steps, each of them being characterized by a distinctive adaptive phenotype of the cancer cells. Metabolic reprogramming represents one of the main adaptive phenotypes exploited by cancer cells during all the main steps of tumor and metastatic progression. In particular, the metabolism of cancer cells evolves profoundly through all the main phases of metastasis formation, namely the metastatic dissemination, the metastatic colonization of distant organs, the metastatic dormancy, and ultimately the outgrowth into macroscopic lesions. However, the metabolic reprogramming of metastasizing cancer cells has only recently become the subject of intense study. From a clinical point of view, the latter steps of the metastatic process are very important, because patients often undergo surgical removal of the primary tumor when cancer cells have already left the primary tumor site, even though distant metastases are not clinically detectable yet. In this scenario, to precisely elucidate if and how metabolic reprogramming drives acquisition of cancer-specific adaptive phenotypes might pave the way to new therapeutic strategies by combining chemotherapy with metabolic drugs for better cancer eradication. In this review we discuss the latest evidence that claim the importance of metabolic adaptation for cancer progression.

Keywords: cancer therapy; epithelial-mesenchymal transition; metastasis; oncometabolism.

Figure 1

Metabolic reprogramming in cancer progression. (A) Driver mutations of cancer leads to metabolic reprogramming in primary tumors. (B) epithelial to mesenchymal transition (EMT) progression leads to a further shift towards glycolysis, fatty acid oxidation, and glutamine metabolism. (C) circulating tumor cells (CTCs) activate a prominent antioxidant response while, at the same time, maintaining the glycolytic flux. (D) MET revert the metabolic reprogramming of EMT, with mitochondrial respiration and lipogenesis upregulation. (E) Dormant cells in metastases mainly rely on mitochondrial respiration, autophagy, and fatty acid oxidation. (F) The progression towards overt metastases requires a dense interplay with the surrounding niche, with a simultaneous addiction to glycolysis, mitochondrial respiration, and fatty acid oxidation.

Figure 2

Metabolic Heterogeneity of cancer lesions. Tumoral cells experience different metabolic profile according to spatial and functional needs (the green arrow up indicates increase, the red arrow down indicates decrease).

Figure 3

Targeting metabolic pathways to eradicate tumor growth. Inhibitors for several metabolic pathways have been described. The inhibition of glucose, amino acid and fatty acid metabolism was shown to be promising for a successful eradication of tumoral disease.