title: Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma.
abstract: Human malignant mesothelioma is an aggressive and highly lethal cancer that is believed to be caused by chronic exposure to asbestos and erionite. Prognosis for this cancer is generally poor because of late-stage diagnosis and resistance to current conventional therapies. The damage-associated molecular pattern protein HMGB1 has been implicated previously in transformation of mesothelial cells. Here we show that HMGB1 establishes an autocrine circuit in malignant mesothelioma cells that influences their proliferation and survival. Malignant mesothelioma cells strongly expressed HMGB1 and secreted it at high levels in vitro. Accordingly, HMGB1 levels in malignant mesothelioma patient sera were higher than that found in healthy individuals. The motility, survival, and anchorage-independent growth of HMGB1-secreting malignant mesothelioma cells was inhibited in vitro by treatment with monoclonal antibodies directed against HMGB1 or against the receptor for advanced glycation end products, a putative HMGB1 receptor. HMGB1 inhibition in vivo reduced the growth of malignant mesothelioma xenografts in severe-combined immunodeficient mice and extended host survival. Taken together, our findings indicate that malignant mesothelioma cells rely on HMGB1, and they offer a preclinical proof-of-principle that antibody-mediated ablation of HMBG1 is sufficient to elicit therapeutic activity, suggesting a novel therapeutic approach for malignant mesothelioma treatment.
authors.affiliation: University of Hawai'i Cancer Center, John A. Burns School of Medicine, University of Hawai'i, Honolulu, Hawaii 96813, USA.
authors.forename: Sandro
authors.initials: S
authors.lastname: Jube
authors.forename: Zeyana S
authors.initials: ZS
authors.lastname: Rivera
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.forename: Amy
authors.initials: A
authors.lastname: Powers
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Ian
authors.initials: I
authors.lastname: Pagano
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gaudino
authors.forename: Michele
authors.initials: M
authors.lastname: Carbone
authors.forename: Haining
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D024243:HMGB1 Protein