title: Do inflammatory pathways drive melanomagenesis?
abstract: Inflammatory pathways serve to protect the host and promote tissue healing/repair; however, over-activation or dysregulation can be pathological with unintended consequences including malignant progression. A correlation between inflammation and cancer has been well established, and anti-inflammatory medications have been shown to be chemopreventive in certain malignancies. Data are now becoming available that outline an inflammatory pathway that may have a critical role in melanomagenesis. ATP-regulated membrane channels/receptors P2X7 and PANX1 have been directly implicated in melanoma tumor growth. Among other potential effects, opening of the P2X7/PANX1 channel results in activation of the NALP3 inflammasome, which in turn leads to caspase-1 activation and increased levels of activated IL-1β. Elevated levels of caspase-1 and IL-1β have been correlated with melanoma progression, and inhibitors of the inflammasome, caspase and IL-1β activity have all been shown to inhibit melanoma growth. Among many other potential actions, IL-1β increases cyclooxygenase-2 expression leading to local increases in inflammatory mediators such as prostaglandin E2 (PGE2). Anti-inflammatory medications targeting the end of this pathway have had positive results for certain cancers but overall remain mixed for melanoma. A better understanding of the pathways and appropriate intervention points may help direct future therapies. In this viewpoint, we will review data and attempt to model an inflammatory pathway that may be critical for melanomagenesis and propose future directions for exploration.
authors.affiliation: Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA; Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Schneider
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Ross
authors.forename: James M
authors.initials: JM
authors.lastname: Grichnik
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D008545:Melanoma / Q000473:pathology*; D008546:Melanoma, Experimental; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D014411:Neoplastic Stem Cells / Q000166:cytology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D012878:Skin Neoplasms / Q000503:physiopathology*; D013234:Stem Cells / Q000166:cytology
chemical_list: D002352:Carrier Proteins; D017630:Connexins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009419:Nerve Tissue Proteins; C492764:PANX1 protein, human; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D051546:Cyclooxygenase 2; D020170:Caspase 1; D015232:Dinoprostone
keywords: melanoma; stem cell; tumor stem cell