PI Partha Roy
Co-Investigators Marina Kameneva
Title Drag-reducing polymers to curb breast cancer metastasis
Description Adhesion of circulating tumor cells to microvascular endothelial cells is key for extravasation of tumor cells and therefore an important step for tumor metastasis. There is growing evidence that systemic inflammation facilitates adhesion of circulating tumor cells to endothelial cells hence promoting metastasis and progression of cancer. It has been hypothesized that leukocytes enhance attachment of tumor cells to endothelial cells by creating formation of a tripartite linkage between these three different cell types. Presence of leukocytes in the tumor microenvironment also leads to local release of cytokines that further promotes junctional disruption of endothelial cells and extravasation of tumor cells. Current strategies to inhibit extravasation which involve molecular targeting of either a single adhesion receptor on tumor cells or a specific signaling pathway are therapeutically inefficient because of involvement of multiple adhesion receptors and signaling pathways in the extravasation process. In complete contrast to these currently envisioned strategies, we proposed a conceptually novel paradigm that hemodynamic perturbation that inhibits attachment of inflammatory cells to endothelial cells is an efficient way to impair tumor cell attachment to endothelium thereby reducing extravasation and metastasis. Systemic administration of so called drag reducing polymers (DRP – long-chain viscoelastic polymers that are non-toxic and blood-soluble) at nanomolar concentrations was shown to reduce/eliminate the near-wall cell-free layer naturally existing in microvessels (Fåhraeus effect) and to increase blood flow in microcirculation. DRP-induced occupation of the near-wall space by red blood cells and increasing of near-wall shear rates may inhibit leukocyte rolling and attachment to blood vessel wall which can drastically reduce inflammatory responses (demonstrated in animals implanted with biodegradable scaffolds) and transendothelial migration of tumor cells. We therefore propose a working postulate that “systemic administration of DRP is a novel interventional approach to reduce extravasation and metastasis of tumor cells” and this hypothesis will be tested by
Determining whether presence of DRP impairs the ability of circulating breast cancer cells to attach and transmigrate through endothelial monolayer in vitro (Aim 1), and
Determining whether systemic administration of DRP reduces spontaneous metastasis of breast cancer cells in vivo (Aim 2).
Source Department of Defense, USAMRMC (Concept Award)
Term 2/1/2011 – 2/29/2012 (Research Ends 1/31/2012)