Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma
Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel la surexpression de la protéine HMGB1 favorise la prolifération des cellules de mésothéliome malin
Human malignant mesothelioma (MM) 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 due to late-stage diagnosis and resistance to current conventional therapies. The damage-associated molecular pattern (DAMP) protein HMGB1 has been implicated previously in transformation of mesothelial cells. Here we show that HMGB1 establishes an autocrine circuit in MM cells that influences their proliferation and survival. MM cells strongly expressed HMGB1 and secreted it at high levels in vitro. Accordingly, HMGB1 levels in MM patient sera were higher than that found in healthy individuals. The motility, survival and anchorage-independent growth of HMGB1-secreting MM cells was inhibited in vitro by treatment with monoclonal antibodies directed against HMGB1 or against the receptor for advanced glycation end products (RAGE), a putative HMGB1 receptor. HMGB1 inhibition in vivo reduced the growth of MM xenografts in SCID mice and extended host survival. Taken together, our findings indicate that MM 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 MM treatment.