Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, ESDN, Melanoma metastasis, Adhesion, Tumor microenvironment, Cimetidine, CANCER CELLS, TUMOR MICROENVIRONMENT, METASTATIC MELANOMA, ADHESION, CIMETIDINE, ACTIVATION, IDENTIFICATION, AP-2-ALPHA, AP-2-GAMMA, CARCINOMA, Animals, Disease Models, Animal, Disease Progression, E-Selectin, Endothelial Cells, Humans, Melanoma, Membrane Proteins, Mice, STAT3 Transcription Factor, Tumor Microenvironment, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3211 Oncology and carcinogenesis

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.