Modulation of VEGF signaling by extracellular matrix and neuropilins: impact on tumor progression, angiogenesis and anti-angiogenic therapy in prostate and pancreatic cancer
Hematology, Oncology
Final Report Abstract
The objective of this project was to test whether hematogenous metastasis in pancreatic cancer can be prevented by enhancing the integrity of the endothelial barrier, through an innovative approach that directly targets the endothelium, thereby stabilizing junctional complexes and preventing cytoskeletal collapse. This main research topic evolved out of observations that were made in the experimental course of the initially proposed project focusing on the modulation of VEGF by the extracellular matrix. Within a panel of known modulators of Rho GTPases, we identified the molecule CNF03, that fully blocked the observed tumor cellmediated retraction of endothelial cells, and showed the unique ability to reduce the number of extravasating tumor cells. Thus, CNF03 prevented the formation of tumor cell-induced intercellular gaps between endothelial cells, and increased the barrier resistance in a dose-dependent manner. We revealed that the barrier-enhancing mechanism of CNF03 includes an increased expression of the junctional proteins ZO-1 and VE-cadherin, and focal adhesion proteins such as paxillin and talin. Meanwhile, we have established an pancreatic cancer mouse model, that will allow us to study the effects of CNF03 on distant metastasis in vivo. In addition, we have adapted our extravasation assay to a high throughput screening format, that enabled us to run a compound screening to identify new substances with barrier-enhancing and anti-invasive properties in the context of tumor cell extravasation. With this screening approach, so far we have found 46 compounds that meet our criteria. Within the next few months, we will further characterize these substances and test its anti-metastatic effects using our in vivo model. Conclusion: While existing therapeutic options target either the cancer cell or the microenvironment of solid tumor sites, modulating the endothelial barrier by systemic administration of substances like CNF03 have the potential to prevent initial vascular intravasation, as well as extravasation at the premetastatic niche sites. This approach holds additional advantages in regard to combination therapies and therapeutic resistance.
Publications
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Enhancing the integrity of the endothelial barrier to prevent metastasis in pancreatic cancer. Gordon Research Conference - Vascular Cell Biology, Ventura, CA; 01/2015
Hilfenhaus G, Dana Song, Ryan Freshman, M. Luisa Iruela-Arispe
