Interaction des cellules cancéreuses avec l'endothélium vasculaire dans le processus métastatique
|Abstract:||Metastasis is a dreadful complication of cancer. Adhesion and migration of tumor cells on and through the vascular endothelium are critical steps of the metastatic process. We investigated the roles of the adhesion molecules E-selectin and integrins, as well as the role of the MAP kinase SAPK2/p38 (stress-activated protein kinase-2/p38), in modulating endothelial adhesion and transendothelial migration of HT-29 colon carcinoma cells. TNFα strongly increases the expression of E-selectin in human endothelial cells HUVEC. This effect is independent of the activation of SAPK2/p38 induced by TNFα. Adhesion of HT-29 cells on a monolayer of HUVEC pre-treated with TNFα is dependent on E-selectin expression but is independent of SAPK2/p38 activity of both HUVEC and tumor cells. Blocking the integrins from HT-29 cells (α2, α3, α6, αvβ5, β1 and β4) with specific antibodies reveals a role for β4 integrin in their adhesion to TNFα-treated HUVEC. The sequence of events showed that β4 integrin adhesion is involved later then E-selectin adhesion. The adhesion of HT-29 cells to TNFα-treated HUVEC leads to the activation of SAPK2/p38 in the tumor cells, as reflected by the increased phosphorylation of its downstream target, the actin polymerizing factor HSP27. Moreover, a recombinant E-selectin/Fc chimera induces the specific activation of SAPK2/p38 and ERK (extracellular signal-regulated kinases) in HT-29 cells, suggesting that the binding of E-selectin to HT-29 cells involves a functional and signaling receptor. However, the binding of E-selectin to HT-29 cells does not lead to phosphorylation of β4 integrin suggesting that the two adhesion events are not signalingly linked. The adhesion of HT-29 cells to TNFα-treated HUVEC also implicates a soluble unidentified factor. This indicates that the adhesion of cancer cells to the endothelium uses the same sequence as lymphocytes namely, selectins, chemokines and integrins. Blocking the adhesion-mediated increase of SAPK2/p38 activity of HT-29 cells inhibits their transendothelial migration. Overall, our results suggest that the specific regulation of transendothelial migration of tumor cells involves two essential steps: 1) adhesion to the endothelium by the sequential use of adhesion molecules, such as E-selectin and β4 integrin, 2) increased motogenic potential through adhesion-mediated activation of the SAPK2p38 pathway.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||11 April 2018|
|Collection:||Thèses et mémoires|
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