IADR Abstract Archives
Tumor Cell Energy Metabolism in Basal Cell Carcinoma Development
Objectives: Sporadic keratocystic odontogenic tumors (KCOTs) and basal cell carcinomas (BCCs) can be treated by surgical procedures. These treatments are more challenging in inherited basal cell carcinoma nevoid syndrome patients, who develop multiple KCOTs and hundreds of BCCs from young age. Alterations in the sonic hedgehog (SHh) pathway are key in BCC development. While the SHh inhibitor Vismodegib effectively reduces tumor burden in BCCNS patients, it leads to considerable morbidity and appearance of drug-resistant tumors. To delineate mechanisms beyond SHh that contribute to the growth of these tumors, we investigated the effect of Vismodegib on metabolism and growth of BCC cells and tumor spheres in cultures.
Methods: Cultures of human BCC cells (ATCC TE 354.T) and tumor spheres were treated with 10nM – 1uM Vismodegib or DMSO (control) for 21 days, and imaged daily to monitor their growth. Media conditioned by the cultures were analyzed by nuclear magnetic resonance (NMR).
Results: Preliminary NMR analysis revealed that under DMSO and Vismodegib treatment, both culture types consumed glutamine rather than glucose, and secreted significant amounts of lactate and acetate. Glutamate secretion and pyruvate consumption were markedly increased in cultures with BCC cells only, when compared to cultures with tumor spheres. In contrast to DMSO, Vismodegib treatment modestly reduced acetate levels in cultures without tumor spheres, and decreased glutamine levels in cultures with those spheres. Over time and under both treatments, new tumor spheres continued to accumulate in the cultures with tumor spheres, and began to develop in cultures that initially included merely BCC cells.
Conclusions: Cultures continued to grow and develop even when treated with Vismodegib, which indicates resistance to the physiologically-relevant drug concentrations used. The altered metabolic profiles seen in these cultures can potentially contribute to the development of drug-resistant tumors in human; thus, the corresponding cellular metabolic pathways may serve as future targets for therapy.
Methods: Cultures of human BCC cells (ATCC TE 354.T) and tumor spheres were treated with 10nM – 1uM Vismodegib or DMSO (control) for 21 days, and imaged daily to monitor their growth. Media conditioned by the cultures were analyzed by nuclear magnetic resonance (NMR).
Results: Preliminary NMR analysis revealed that under DMSO and Vismodegib treatment, both culture types consumed glutamine rather than glucose, and secreted significant amounts of lactate and acetate. Glutamate secretion and pyruvate consumption were markedly increased in cultures with BCC cells only, when compared to cultures with tumor spheres. In contrast to DMSO, Vismodegib treatment modestly reduced acetate levels in cultures without tumor spheres, and decreased glutamine levels in cultures with those spheres. Over time and under both treatments, new tumor spheres continued to accumulate in the cultures with tumor spheres, and began to develop in cultures that initially included merely BCC cells.
Conclusions: Cultures continued to grow and develop even when treated with Vismodegib, which indicates resistance to the physiologically-relevant drug concentrations used. The altered metabolic profiles seen in these cultures can potentially contribute to the development of drug-resistant tumors in human; thus, the corresponding cellular metabolic pathways may serve as future targets for therapy.