Abstract
PARP inhibition can induce anti-neoplastic effects when used as monotherapy or in combination with chemo- or radiotherapy in various tumor settings; however, the basis for the anti-metastasic activities resulting from PARP inhibition remains unknown. PARP inhibitors may also act as modulators of tumor angiogenesis. Proteomic analysis of endothelial cells revealed that vimentin, an intermediary filament involved in angiogenesis and a specific hallmark of EndoMT (endothelial to mesenchymal transition) transformation, was down-regulated following loss of PARP-1 function in endothelial cells. VE-cadherin, an endothelial marker of vascular normalization, was up-regulated in HUVEC treated with PARP inhibitors or following PARP-1 silencing; vimentin over-expression was sufficient to drive to an EndoMT phenotype. In melanoma cells, PARP inhibition reduced pro-metastatic markers, including vasculogenic mimicry. We also demonstrated that vimentin expression was sufficient to induce increased mesenchymal/pro-metastasic phenotypic changes in melanoma cells, including ILK/GSK3-β-dependent E-cadherin down-regulation, Snail1 activation and increased cell motility and migration. In a murine model of metastatic melanoma, PARP inhibition counteracted the ability of melanoma cells to metastasize to the lung. These results suggest that inhibition of PARP interferes with key metastasis-promoting processes, leading to suppression of invasion and colonization of distal organs by aggressive metastatic cells.
Highlights
Metastatic melanoma is a fatal malignancy that is remarkably resistant to treatment; the mechanisms regulating the transition from the primary local tumor growth to distant metastasis remain poorly understood
Metastasis is the spread of malignant tumor cells from their original site to other parts of the body and is responsible for the vast majority of solid cancer-related mortality
Cadherin in malignant melanoma cells confers this tumor the capability to form vessel-like structures that contributes to the lack of efficient therapeutic strategies and increases the risk of metastatic disease [4]
Summary
Metastatic melanoma is a fatal malignancy that is remarkably resistant to treatment; the mechanisms regulating the transition from the primary local tumor growth to distant metastasis remain poorly understood. Metastasis, defined as the spread of malignant tumor cells from the primary tumor mass to distant sites, involves a complex series of interconnected events. The metastatic cascade is thought to be initiated by a series of genetic alterations, leading to changes in cell-cell interactions that allow the dissociation of cells from the primary tumor mass. These events are followed by local invasion and migration through proteolitically modified extracellular matrix (ECM). Tumor cells can invade the local ECM, proliferate, recruit new blood vessels by induction of angiogenesis, and expand to form secondary metastatic foci [1]
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