Title: Implication de la protéine matricielle SPARC dans la dissémination métastatique des mélanomes cutanés
Abstract: Cutaneous melanoma is one of the most aggressive cancers capable of distant and lethal metastatic spread. Tumor cell intravasation into blood vessel at primary tumor sites and subsequent extravasation are critical steps in the formation of metastases. These steps entail disruption of the endothelial barrier by tumor cells to facilitate their transendothelial passage and metastatic seeding. However, the way by which tumor cells modulate vascular junction integrity is still poorly understood. In an attempt to determine permeability factors secreted by metastatic cells, we identified the matricellular protein SPARC as a critical signaling factor that contributes to elevated vascular permeability and tumor cell extravasation. We show that SPARC released by melanoma cells enhances vascular leakiness by inducing opening of intercellular junctions of endothelial monolayers and drives melanoma cell transendothelial migration. In vivo vascular permeability and metastatic assays demonstrate that SPARC deficiency abrogates tumor-induced permeability of lung capillaries and prevents extravasation from blood vessels and metastasis, whereas overexpression of SPARC increases the lung metastatic potential of melanoma cells. Mechanistically, SPARC-induced endothelial gap formation and transmigration is dependent on vascular cell adhesion molecule (VCAM1) and p38 MAPK signaling pathway in endothelial cells. Importantly, blocking VCAM1 impedes melanoma cell extravasation. The clinical relevance of our findings is highlighted by the high levels of SPARC detected in tumor cells from human pulmonary melanoma lesions.
Publication Year: 2013
Publication Date: 2013-12-17
Language: en
Type: dissertation
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