title: Tumor-associated a2 vacuolar ATPase acts as a key mediator of cancer-related inflammation by inducing pro-tumorigenic properties in monocytes.
abstract: Cancer-related inflammation profoundly affects tumor progression. Tumor-associated macrophages (TAMs) are known regulators of that inflammation, but the factors that initiate cancer-related inflammation are poorly understood. Tumor invasiveness and poor clinical outcome are linked to increased expression of cell surface-associated vacuolar adenosine triphosphatases. The a2 isoform vacuolar adenosine triphosphatase is found on the surface on many solid tumors, and we have identified a peptide cleaved from a2 isoform vacuolar adenosine triphosphatase called a2NTD. a2NTD has properties necessary to induce monocytes into a pro-oncogenic TAM phenotype. The peptide upregulated both pro- and anti-inflammatory mediators. These included IL-1β and IL-10, which are important in promoting inflammation and immune escape by tumor cells. The secretion of inflammatory cytokine IL-1β was dependent on ATP, K(+) efflux, and reactive oxygen species, all mediators that activate the inflammasome. These findings describe a mechanism by which tumor cells affect the maturation of TAMs via a nontraditional cytokine-like signal, the a2NTD peptide.
authors.affiliation: Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Kwong
authors.forename: Alice
authors.initials: A
authors.lastname: Gilman-Sachs
authors.forename: Kenneth
authors.initials: K
authors.lastname: Beaman
mesh_terms: D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000502:physiology; D022162:Cytoplasmic Vesicles / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D053583:Interleukin-1beta / Q000378:metabolism; D007527:Isoenzymes / Q000502:physiology; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D009363:Neoplasm Proteins / Q000502:physiology; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D010455:Peptides / Q000502:physiology*; D011498:Protein Precursors / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D025262:Vacuolar Proton-Translocating ATPases / Q000502:physiology*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D007527:Isoenzymes; D009363:Neoplasm Proteins; D010455:Peptides; D011498:Protein Precursors; C462522:ATP6V1E2 protein, human; D025262:Vacuolar Proton-Translocating ATPases