Multi-parametric imaging of the invasiveness-permissive acidic microenvironment in human glioma xenografts

Gliomas, the intrinsic tumors of the brain, are currently incurable because they are extremely invasive. The infiltrative nature of gliomas makes them difficult to completely excise and leads to a high recurrence rate. Acidification of extracellular microenvironment plays an important role in the invasion, migration and metastasis of solid tumors. To elucidate the relationship between acidic microenvironment and the invasiveness of gliomas, multi-parametric imaging studies were conducted between a highly invasive orthotopic (ortho.) human U87MG glioma xenograft and a lowly invasive subcutaneous (s.c.) U87MG xenograft. In vivo optical imaging showed higher overall acidity of the ortho. tumor than that of the s.c. tumor after administration of a pH responsive near-infrared (NIR) fluorescence probe. Positron emission tomography/computed tomography (PET/CT) imaging demonstrated higher glucose uptake in the ortho. tumor after injection of [¹⁸F]-fluorodeoxyglucose (¹⁸F-FDG). Photoacoustic microscopy imaging (PAM) revealed a higher vascular density but a more aberrant vessel morphology in the ortho. tumor. Immunofluorescence microscopic imaging indicated significantly up-regulated acidification associated enzymes in the gliomas than in normal brain tissue. This work not only reveals the acidity correlated glioma invasiveness, but also shows the promise for curbing glioma invasiveness by neutralizing intratumoral acidity via down-regulation of glucose uptake, normalizing tumor vasculatures or blocking the acidification associated metabolic/physiological processes.