title: Acidic pH via NF-κB favours VEGF-C expression in human melanoma cells.
abstract: Malignant melanomas are characterized by the ability of early metastatic dissemination to regional lymph nodes and the detection of sentinel lymph node metastases serves as an important prognostic parameter. There is clear evidence that melanoma cells and stromal cells of tumor environment can induce lymphangiogenesis, e.g. growth of lymphatic vessels, and this phenomenon is correlated with lymph node metastases. Vascular endothelial growth factor (VEGF) C represents the most potent and well-recognized lymphangiogenic growth factor secreted in tumor milieu by melanoma cells and tumor-associated macrophages, however the mechanism underlying VEGF-C secretion is not completely understood. We demonstrate that an acidic extracellular pH promotes the expression of VEGF-C in A375P melanoma cells and in melanoma cells isolated from a human spontaneous metastatic lesion, through the NF-κB transcription factor. We also demonstrate that esomeprazole, a proton pump inhibitor which requires acidosis to be activated, is able to prevent VEGF-C expression in acidic melanoma cells by interfering with NF-κB activation. Furthermore, we show that esomeprazole abrogates the enhanced VEGF-C expression in tumor cells grown in a acidic medium and stimulated by IL-1β. On the whole, the present study reveals that acidity may be considered a strong promoter of VEGF-C expression in melanoma cells and provides a new pharmacological target to limit the development of tumor lymphangiogenesis.
authors.affiliation: Sezione di Patologia e Oncologia Sperimentali, Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università di Firenze, Viale G.B.Morgagni, 50-50134, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Peppicelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchini
authors.forename: Claudia
authors.initials: C
authors.lastname: Contena
authors.forename: Donatella
authors.initials: D
authors.lastname: Tombaccini
authors.forename: Lido
authors.initials: L
authors.lastname: Calorini
mesh_terms: D000138:Acidosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D064098:Esomeprazole / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007124:Immunoenzyme Techniques; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D054328:Proton Pump Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; D064098:Esomeprazole