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.

Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression

“…According to our experience on using esomeprazole, a proton pump inhibitor able to inhibit NF-kB in acidic melanoma cells, 22 we treated acidic MSC with esomeprazole and consequently abrogated TGFb mRNA expression (Fig. 8A).…”

The acidic microenvironment as a possible niche of dormant tumor cells

“…We also demonstrated that esomeprazole, a proton pump inhibitor (PPI) activated by a low pH, inhibits VEGF-C expression in acidic melanoma cells down-regulating NF-κB [80]. VEGF-C, in addition to the well-known role of VEGF-A in relapse, might represent a new causal link between lymphangiogenesis, lymph node colonization, and progression [81].…”

“…By studying acidosis-induced signalings in tumor cells, we observed that extracellular acidity (pH 6.7 ± 0.1) stimulates the expression and secretion of lymphangiogenic growth factor C (VEGF-C) by melanoma cells, mediated by NF-κB transcription factor activity [80]. We also demonstrated that esomeprazole, a proton pump inhibitor (PPI) activated by a low pH, inhibits VEGF-C expression in acidic melanoma cells down-regulating NF-κB [80].…”

The SIRT1/HIF2α Axis Drives Reductive Glutamine Metabolism under Chronic Acidosis and Alters Tumor Response to Therapy

“…Acidosis is known to contribute to the genetic instability of tumor cells (7) and to profoundly alter their transcriptomic profile (8), leading to phenotypes that are particularly suited for survival and growth in an acidic environment. A low pHe has for instance a wide impact on cancer progression by promoting tumor cell migration, invasion, and metastasis (9)(10)(11) and by stimulating angiogenesis (12)(13)(14). Although tumor metabolic peculiarities directly account for the acidification of the tumor microenvironment, whether acidosis may itself influence metabolism remains elusive.…”