High-resolution thermal imaging to delineate effects of cancer-induced aerobic glycolysis and endothelial dysfunction

Abstract Background Glioblastoma multiforme (GBM) is an aggressive brain tumor with abysmal prognosis because cancer cell growth in the tumor microenvironment (TME) is orchestrated by complex interplay between aerobic glycolysis (AG) and endothelial dysfunction (ED). AG acidifies extracellular pH (pHe) to promote tumor invasion and suppress immune response, whereas ED leads to leaky blood vessels which hampers perfusion and stimulates hypoxia. Since metabolism generates heat and perfusion removes heat, we hypothesized that temperature could reflect both metabolic and vascular reprogramming in the TME mediated by AG and ED. Methods We used multiple magnetic resonance methods and bioheat modeling to dissect temperature contributions from metabolic and vascular sources in rat gliomas. Results Upregulated AG in the TME results from enhanced glycolysis (∼4.2× higher) and reduced glucose oxidation (∼4.8× lower), which leads to more acidic pHe (6.9 ± 0.1 vs 7.3 ± 0.1). Since TME is hypoperfused (∼40% lower) and glycolysis is less exothermic compared to glucose oxidation, simulations predict a cooler TME as in vivo measurements clearly demonstrate (0.5-1.5 °C). Moreover, temperature and pHe are correlated both inside and outside the TME for untreated and treated rats (r > 0.6). Conclusions Since TME is more glycolytic, acidic, hypoperfused, and cooler than neighboring milieu, thermal mapping can represent combined effects of AG and ED for early GBM detection and therapy optimization.