Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma.
Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma.
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DOI：
10.1158/0008-5472.can-11-3481
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发表时间：
2012-07-01
期刊：
影响因子：
11.2
通讯作者：
Yang H
中科院分区：
文献类型：
--
作者：
Jube S;Rivera ZS;Bianchi ME;Powers A;Wang E;Pagano I;Pass HI;Gaudino G;Carbone M;Yang H
人类恶性间皮瘤（MM）是一种侵袭性和高致死性的癌症，据信是由长期暴露于石棉和毛沸石引起的。由于晚期诊断和对目前常规治疗的抵抗，这种癌症的预后通常很差。损伤相关分子模式（DAMP）蛋白HMGB1先前已涉及间皮细胞的转化。在这里，我们表明HMGB1在MM细胞中建立了一个自分泌回路，影响其增殖和存活。MM细胞强烈表达HMGB1，并在体外以高水平分泌。因此，MM患者血清中的HMGB1水平高于健康个体中发现的水平。HMGB1分泌型MM细胞的运动性、存活性和锚定非依赖性生长在体外通过针对HMGB1或针对晚期糖基化终产物受体（一种假定的HMGB1受体）的单克隆抗体治疗而受到抑制。体内HMGB1抑制减少了SCID小鼠中MM异种移植物的生长并延长了宿主存活期。综上所述，我们的研究结果表明MM细胞依赖于HMGB1，并且它们提供了一个临床前原则证明，即抗体介导的HMBG1消融足以引发治疗活性，这表明MM治疗的新治疗方法。
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.