The Role of Energy Metabolism in Driving Disease Progression in Inflammatory, Hypoxic and Angiogenic Microenvironments
Cellular metabolism plays a crucial role in primed inflammatory, hypoxic and angiogenic microenvironments by supporting disease progression in a range of disease entities.
To adapt to fluctuating stress-induced microenvironments, pre-neoplastic and neoplastic tissue
must utilise a diverse range of molecular mediators to alter their metabolism. Despite being
widely documented to play independent roles in disease prevalence, these complex processes
exploit a range of key cellular components that act in tandem to restore metabolic equilibrium.
Therefore, this review examines the primary molecular mechanisms linking energy metabolism
with inflammation, hypoxia and angiogenesis. Furthermore, the review considers a diverse
range of conventional and novel mediators that link energy metabolism and hypoxia. Moreover, to investigate their reciprocal relationship and the mechanisms employed to execute their
functional effect in greater detail, the roles of glycolysis and oxidative phosphorylation in rheumatoid arthritis and circadian rhythms respectively are reviewed. Lastly, this review explores
some current metabolic-based treatments and multi-targeted therapies that could potentially
target these fundamental cellular processes.
Otto Warburg’sinitial observation in 1956 demonstrated that tumours exhibit increased
levels of aerobic glycolysis.1 This observation has since resulted in numerous studies investigating the role of mitochondrial energy metabolism in disease progression across many disease
entities. As a reflection of its importance in the development of various cancers, the reprogramming of cellular energetics is now beginning to establish itself as one of the new hallmarks of
cancer.2,3 In addition to significant quantities of adenosine triphosphate (ATP), metabolically
demanding tumours require glucose for lipid and protein synthesis and de novo synthesis of
nucleotides for rapid proliferation.4 More importantly, this altered metabolic phenotype allows
tumours to maintain higher proliferative rates and resist apoptosis orchestrated by increased
oxidative damage.5 Moreover, these metabolic phenotypes persist and are sometimes altered
in distinct metabolically demanding microenvironments. Therefore, elucidating how diverse
metabolic processes converse with distinct functional inflammatory, hypoxic and angiogenic
pathways may infer significant insights into how several heterogeneous malignancies arise and
subsequently advance beyond therapeutic intervention
Gastro Open J. 2015; 1(2): 44-58. doi: 10.17140/GOJ-1-108
