Document Detail


Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma.
MedLine Citation:
PMID:  22552293     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Sandro Jube; Zeyana S Rivera; Marco E Bianchi; Amy Powers; Ena Wang; Ian Pagano; Harvey I Pass; Giovanni Gaudino; Michele Carbone; Haining Yang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-02
Journal Detail:
Title:  Cancer research     Volume:  72     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-03     Completed Date:  2012-09-10     Revised Date:  2014-06-06    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3290-301     Citation Subset:  IM    
Copyright Information:
©2012 AACR.
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MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Western
Disease Progression
Enzyme-Linked Immunosorbent Assay
HMGB1 Protein / physiology,  secretion*
Humans
Immunohistochemistry
Mesothelioma / pathology,  secretion*
Mice
Transplantation, Heterologous
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
P01 CA114047/CA/NCI NIH HHS; R01 CA160715/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/HMGB1 Protein
Comments/Corrections

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