title: EMAP-II-dependent lymphocyte killing is associated with hypoxia in colorectal cancer.
abstract: Endothelial-monocyte-activating polypeptide-II (EMAP-II) is a novel multifunctional polypeptide with proinflammatory activity. We have previously shown that the recombinant and native forms of EMAP-II can induce apoptosis in mitogen-stimulated lymphocytes, and that the release of this protein into the extracellular milieu is enhanced by hypoxia. We hypothesised that hypoxia may lead to death of tumour-infiltrating lymphocytes (TILs) via an EMAP-II-dependent mechanism, thereby assisting tumours to evade the immune system. In this study, we used immunohistochemistry to detect EMAP-II, active caspase-3 and cleaved Poly (ADP-ribose) Polymerase (PARP) as indicators of apoptosis in TILs, and carbonic anhydrase IX (CA IX) as a surrogate marker of hypoxia. EMAP-II expression is associated with regions of hypoxia, and furthermore there is a significant association between TILs apoptosis and the presence of hypoxia. Using a coculture model of colorectal cancer cell/lymphocyte interactions, we were also able to demonstrate lymphocyte apoptosis induced by tumour cells, with concomitant caspase-3 activity. Lymphocyte killing was enhanced by direct cell-cell contact, particularly by tumour cells exposed to hypoxic conditions. Our data support the hypothesis that hypoxia plays a role in immune evasion by tumour cells, through EMAP-II-dependent lymphocyte killing.
authors.affiliation: Wolfson Digestive Diseases Centre, University Hospital, Nottingham NG7 2UH, UK. mrxmmsy@nott.ac.uk
authors.forename: M M S
authors.initials: MM
authors.lastname: Youssef
authors.forename: P
authors.initials: P
authors.lastname: Symonds
authors.forename: I O
authors.initials: IO
authors.lastname: Ellis
authors.forename: J C
authors.initials: JC
authors.lastname: Murray
mesh_terms: D000951:Antigens, Neoplasm / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis; D053148:Caspase 3 / Q000096:biosynthesis / Q000276:immunology; D015687:Cell Hypoxia / Q000276:immunology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology*; D011065:Poly(ADP-ribose) Polymerases / Q000276:immunology; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases