Metabolism in cancer metastasis: bioenergetics, biosynthesis, and beyond

Abstract

Metabolic changes accompany tumor progression and metastatic dissemination of cancer cells. Yet, until recently, metabolism has received little attention in the study of cancer metastasis. Cancer cells undergo significant metabolic rewiring as they acquire metastatic traits and adapt to survive in multiple environments with varying nutrient availability, oxygen concentrations, and extracellular signals. Therefore, to effectively treat metastatic cancer, it is important to understand the metabolic strategies adopted by cancer cells during the metastatic process. Here, we focus on the metabolic pathways known to play a role in cancer metastasis, including glycolysis, the pentose phosphate pathway, tricarboxylic acid cycle, oxidative phosphorylation, amino acid metabolism, and fatty acid metabolism. Recent studies have uncovered roles for these pathways in cellular events that promote metastasis, including reactive oxygen species-mediated signaling, epigenetic regulation, and interaction with the extracellular matrix. We also discuss the metabolic interplay between immune cells and cancer cells supporting metastasis. Finally, we highlight the current limitations of our knowledge on this topic, and present future directions for the field. WIREs Syst Biol Med 2018, 10:e1406. doi: 10.1002/wsbm.1406 This article is categorized under: Biological Mechanisms > Metabolism.

p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms

“…This phenomenon implies that cancer cells prefer to utilize glycolysis rather than the much more efficient oxidative phosphorylation process, even in the presence of sufficient oxygen. Compared to oxidative phosphorylation, glycolysis more rapidly produces ATP in the presence of excess glucose and provide intermediates that are used as precursors for macromolecule biosynthesis through the pentose phosphate pathway (PPP) [30,31], which is crucial for several cancer-related and unrelated processes. In this context, p53 exerts is tumor suppressor function by enhancing mitochondrial respiration and limiting glycolysis and PPP.…”

Mitochondrial Involvement in Migration, Invasion and Metastasis

“…Cancer cells change their metabolism in order to satisfy increasing of bioenergetic and biosynthetic demand and maintain tumor growth (DeBerardinis and Chandel, 2016). Unlike normal cells, which generate much of their ATP via mitochondrial-dependent OXPHOS, cancer cells often demonstrate upregulation of glycolysis even under conditions when oxygen concentration is not limited (Lehuédé et al, 2016;Teoh and Lunt, 2018). This phenomenon was observed in the 1920s by Otto Warburg, who demonstrated that tumor tissues metabolize approximately ten-fold more glucose to lactate in a given time than do normal tissues, which led him to conclude that cancer cells rely on glycolysis more than do healthy cells.…”

“…Tumor cells can also switch from one type of metabolism to another under glucose-limiting conditions as observed in cervical cancer, breast carcinoma, hepatoma and pancreatic cancer cells (Rossignol et al, 2004;Beckner et al, 2005;Jose et al, 2011;Smolková et al, 2010). A growing number of studies provide the evidence that cancer cell migration is associated with significant metabolic alterations supporting metastatic dissemination (Morandi et al, 2017;Teoh and Lunt, 2018). Thus, it was reported that increased motility of cancer cells requires the shift toward utilization of glycolytic pathways (Shiraishi et al, 2015).…”

“…Glycolytic genes activation has been detected in different tumors and is often associated with malignant and aggressive phenotypes (Jose et al, 2011). For example, expression of hexokinase 2 (HK2), the embryonic isoform of hexokinase, the enzyme which defines the start of glycolysis, is associated with increased risk of recurrence, and adverse clinical outcome for breast cancer, pancreatic cancer, and neuroblastoma patients (Teoh and Lunt, 2018). Further studies have demonstrated that glycolytic enzymes also contribute to the metastatic progression of cancer cells (Teoh and Lunt, 2018).…”

Targeting metabolic vulnerabilities of cancer: Small molecule inhibitors in clinic

“…Metabolic fluxes are tuned according to environmental cues as well as the energy and biomass demands of cancer cells throughout tumorigenesis and in states of proliferation, nutrient attenuation, and quiescence . In addition to supporting primary tumors, the rewiring of cell metabolism can activate metabolic programs that confer metastatic capacity that allows cancer cells shed from primary tumors to overcome nutrient and energy deficit, survive, and initiate metastases . It is therefore important to elucidate and distinguish between metabolic alterations active within primary, tumor‐initiating and disseminated tumor cells.…”