An interactive crosstalk between tumor and stroma cells is essential for metastatic melanoma progression. We evidenced that ESDN/DCBLD2/CLCP1 plays a crucial role in endothelial cells during the spread of melanoma. Precisely, increased extravasation and metastasis formation were revealed in ESDN-null mice injected with melanoma cells, even if the primary tumor growth, vessel permeability, and angiogenesis were not enhanced. Interestingly, improved adhesion of melanoma cells to ESDN-depleted endothelial cells was observed, due to the presence of higher levels of E-selectin transcripts/proteins in ESDN-defective cells. In accordance with these results, anticorrelation was observed between ESDN and E-selectin in human endothelial cells. Most importantly, our data revealed that cimetidine, an E-selectin inhibitor, was able to block cell adhesion, extravasation, and metastasis formation in ESDN-null mice, underlying a major role of ESDN in E-selectin transcription upregulation, which according to our data, may presumably be linked to STAT3. Based on our results, we propose a protective role for ESDN during the spread of melanoma and reveal its therapeutic potential.

ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3

Coppo R.;Orso F.;Virga F.;Baruffaldi D.;Clapero F.;Dettori D.;Quirico L.;Grassi E.;Defilippi P.;Provero P.;Valdembri D.;Serini G.;Mazzone M.;Taverna D.
2021

Abstract

An interactive crosstalk between tumor and stroma cells is essential for metastatic melanoma progression. We evidenced that ESDN/DCBLD2/CLCP1 plays a crucial role in endothelial cells during the spread of melanoma. Precisely, increased extravasation and metastasis formation were revealed in ESDN-null mice injected with melanoma cells, even if the primary tumor growth, vessel permeability, and angiogenesis were not enhanced. Interestingly, improved adhesion of melanoma cells to ESDN-depleted endothelial cells was observed, due to the presence of higher levels of E-selectin transcripts/proteins in ESDN-defective cells. In accordance with these results, anticorrelation was observed between ESDN and E-selectin in human endothelial cells. Most importantly, our data revealed that cimetidine, an E-selectin inhibitor, was able to block cell adhesion, extravasation, and metastasis formation in ESDN-null mice, underlying a major role of ESDN in E-selectin transcription upregulation, which according to our data, may presumably be linked to STAT3. Based on our results, we propose a protective role for ESDN during the spread of melanoma and reveal its therapeutic potential.
510
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23
Adhesion; Cimetidine; ESDN; Melanoma metastasis; Tumor microenvironment
Coppo R.; Orso F.; Virga F.; Dalmasso A.; Baruffaldi D.; Nie L.; Clapero F.; Dettori D.; Quirico L.; Grassi E.; Defilippi P.; Provero P.; Valdembri D.; Serini G.; Sadeghi M.M.; Mazzone M.; Taverna D.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1791282
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