PARENT SESSION

Cell and Tissue Signaling

(PP217) A new model of the tumor microenvironment.

Freyer, James^*,1, Albertini, Rebecca¹, Guerra, Anabel¹, ¹ Bioscience Division, Los Alamos, NM, USA

ABSTRACT- The biochemical microenvironment surrounding cells in a solid tumor is vastly different from that in normal tissues due to the poorly functioning vasculature. The resultant gradients in nutrients, wastes, growth factors and growth inhibitors is well known to induce multiple alterations in cellular physiology (proliferation, survival, metabolism) and gene/protein expression, which in turn directly inhibit the effectiveness of all forms of cancer therapy. Current 3-D in vitro tumor models suffer from the limitation of not being able to provide spatially-correlated measures of both the microenvironment and the cellular response to the imposed stresses. We have developed a novel three-dimensional tumor model with which we can measure spatial distributions of microenvironmental parameters and directly compare these with alterations in cellular physiology and functional genomics. The cell culture chamber provides steady-state gradients of microenvironmental factors that are spatially correlated with gradients in cellular physiology, metabolism and gene/protein expression. We are developing NMR imaging methods to assay concentrations of oxygen, pH, glucose/lactate and cell density/flow, providing maps of concentration gradients that are spatially correlated with the corresponding gradients in cellular parameters. We are also developing a mass transport model for fitting the NMR concentration profiles in order to obtain cellular metabolic parameters. We will show the design of the chamber and associated perfusion system, along with preliminary data demonstrating spatially-resolved measurements of cellular physiology and microenvironmmental parameters. This will be the first 3-D cell culture system available for measuring the effects on tumor cells of exposure to known combinations of metabolite and catabolite gradients. We anticipate application of this new system to answer fundamental questions about the regulation of cellular metabolism, proliferation, physiology, radiobiology and gene/protein expression under multi-component microenvironmental stress, which closely mimics the situation in tumors.

Key words: tumor model, microenvironment, NMR imaging, metabolism