BME PhD Proposal: Javier Lapeira
Calcium Dynamics in Tumor Angiogenesis: Applying Multiphoton
Supervised by Prof. Edward Brown
Over the last few years the paradigm of how to approach cancer therapy has shifted from solely trying to mitigate cancer cell proliferation to incorporating targeting agents against the production of new vessels, which allow the cancerous cells to thrive. Current anti-angiogenic therapies focus on the earliest steps in these signaling cascades and try to prevent angiogenic molecules like vascular endothelial growth factor (VEGF) from reaching endothelial cells or hinder the activation of their endothelial cell (EC) receptors. One or more of the downstream signaling steps might be a signaling
bottleneck that several angiogenic factors use in common and hence may provide a uniquely powerful therapeutic agent that circumvents the development of drug resistance.
Several studies have confirmed, through calcium-receptor blockades, the relationship between an increase in calcium (Ca2+) influx in ECs and the ability of the ECs to perform motility, adhesion, or proliferation. We hypothesize that extrinsic Ca2+ influx is relevant to the vascular endothelial growth factor receptor-2 (VEGFR-2) activation of tumor ECs in vivo, and that this activation occurs via the opening of specific transient receptor potential (TRPC) receptors via diacylglycerol (DAG).
The crux of the proposed research project involves multi-photon laser scanning fluorescence microscopy (MPLSM), an optical technique that allows the non-invasive imaging of processes in living systems. MPLSM is ideal for the in vivo study of Ca2+ changes that occur upon VEGFR-2 activation of ECs, as well as the identification of the GFP+ ECs in our mouse models. The ultimate goal of this work is to identify angiogenic signaling
bottlenecks, which multiple angiogenic compounds use to produce angiogenic responses in ECs. Targeting of these downstream
bottlenecks, instead of individual receptor active pockets or ligands, offers the hope of circumventing acquired resistance to anti-angiogenic therapy.