Tumors display different cell populations with distinct metabolic phenotypes. Thus, subpopulations can adjust to different environments particularly regarding oxygen and nutrient availability. Our results indicate that progression to metastasis requires mitochondrial function. Our research, centered on cell lines that display increasing degrees of malignancy, focuses on metabolic events, especially those involving mitochondria, which could reveal which stages are mechanistically associated to metastasis. These cells were subjected to several cycles of adhesion impediment, producing stable cell lines exhibiting phenotypes representing a progression from non-tumorigenic to metastatic cells. Metastatic cells (4C11+) released the highest amounts of lactate part of which derived from glutamine catabolism. 4C11+ cells also displayed an increased oxidative metabolism, accompanied by enhanced rates of oxygen consumption coupled to ATP synthesis. Enhanced mitochondrial function could not be explained by an increase in mitochondrial content, or mitochondrial biogenesis. Furthermore, 4C11+ cells, had higher ATP content, increased succinate oxidation (complex II activity) and fatty-acid oxidation. In addition, 4C11+ cells exhibited a two fold increase in mitochondrial membrane potential (Δ Ψ mit). Consistently, functional assays showed that the migration of cells depended on glutaminase activity. Metabolomic analysis revealed that 4C11+ cells could be grouped as a subpopulation whose profile was quite distinct from the other cells investigated here. The results presented here have centered on how the multiple metabolic inputs of tumor cells may converge to compose the so called metastatic phenotype.
- Copyright 2015 The Author(s)
Archiving permitted only in line with the archiving policy of Portland Press Limited. All other rights reserved.