Tumor cells often exhibit altered metabolic behaviors that are influenced by the heterogeneity of the tumor microenvironment. This heterogeneity arises from the presence of multiple cell types, variable ECM compositions, and variable protein expression due to the presence of oxygen and nutrient gradients. Conventional methods of identifying tumor therapies fail to account for these metabolic variations in the context of a heterogeneous microenvironment. To address this shortfall, we have developed a layered, three-dimensional, heterogeneous tumor model that allows spatiotemporal metabolite collection on a timescale relevant for metabolomics profiling. SKOV-3 ovarian cancer cells were mixed with collagen and infiltrated into a scaffolding material to create a thin layer. Multiple layers were then stacked to make a thick section of tumor tissue which is then combined with a customized oxygen impermeable bioreactor. EF5 immunofluorescence was used to confirm the presence of an oxygen gradient and to quantify the spatial PO2 values, which mimic those found in solid tumors. Cell viability and nutrient, and drug distribution profiles were also characterized and profiles were found to resemble those found in spheroid culture and in vivo. Cellular response to hypoxia was confirmed through qPCR analysis of mRNA of hypoxia-inducible genes such as CA9 and CHOP, and with HIF1α staining. Our technology allows for the creation of complex, yet controlled tumor microenvironments while facilitating “snap shot” data acquisition, and will allow researchers to decouple the influence of heterogeneity on metabolic response in cancerous solid tumors.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A203.
Citation Format: Darren Rodenhizer, Dan Cojocari, Bradley G. Wouters, Alison P. McGuigan. An in vitro tumor model to characterize tumor cell metabolism in heterogeneous complex microenvironments. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A203.