Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis

Abstract

The ability of cancer cells to adjust their metabolism in response to environmental changes is a well-recognized hallmark of cancer. Diverse cancer and non-cancer cells within tumors compete for metabolic resources. Metabolic demands change frequently during tumor initiation, progression and metastasis, challenging our quest to better understand tumor biology and develop novel therapeutics. Vascularization, physical constraints, immune responses and genetic instability promote tumor evolution resulting in immune evasion, opportunities to breach basement membrane barriers and spread through the circulation and lymphatics. In addition, the unfolded protein response linked to the ubiquitin proteasome system is a key player in addressing stoichiometric imbalances between nuclear and mitochondrially-encoded protein subunits of respiratory complexes, and nuclear-encoded mitochondrial ribosomal protein subunits. While progressive genetic changes, some of which affect metabolic adaptability, contribute to tumorigenesis and metastasis through clonal expansion, epigenetic changes are also important and more dynamic in nature. Understanding the role of stromal and immune cells in the tumor microenvironment in remodeling cancer cell energy metabolism has become an increasingly important area of research. In this perspective, we discuss the adaptations made by cancer cells to balance mitochondrial and glycolytic energy metabolism. We discuss how hypoxia and nutrient limitations affect reductive and oxidative stress through changes in mitochondrial electron transport activity. We propose that integrated responses to cellular stress in cancer cells are central to metabolic flexibility in general and bioenergetic adaptability in particular and are paramount in tumor progression and metastasis.

Keywords: bioenergetic flexibility; glycolysis-OXPHOS continuum; mito-nuclear gene expression; tumor microenvironment (TME); tumor progression and metastasis.

Figure 1

Factors that influence the position of a cancer cell on the Glycolysis-OXPHOS energy metabolism continuum. See text for a more detailed description. CTC, circulating tumor cells; EMT, epithelial to mesenchymal transition; MET, mesenchymal to epithelial transition.

Figure 2

Formation of functional respiratory complexes in the presence (A) and absence (B) of mtDNA. (A) In the presence of adequate mtDNA transcription and translation, the nuclear- encoded subunits enter the mitochondria through the outer (TOM) and inner (TIM) mitochondrial membrane transporters and combine stoichiometrically with mitochondrially-encoded subunits to form functional respiratory complexes. (B) In the absence of mtDNA, no mitochondrially-encoded subunits are synthesized, and nuclear-encoded subunits are either directly degraded by the cytosolic UPR through the proteasome or enter mitochondria and are degraded by the mitochondrial UPR via mitochondrial proteases. Some of these subunits leave the mitochondria again through reverse transport through TOM and TIM and are degraded by the cytosolic proteasome.