Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma

Our plain-English summary of Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma, by S. Jube, Z.S. Rivera, M.E. Bianchi, et al (Cancer Research, 2012).

The study

• Authors: S. Jube, Z.S. Rivera, M.E. Bianchi, A. Powers, E. Wang, I. Pagano, H.I. Pass, G. Gaudino, M. Carbone, H. Yang
• Journal: Cancer Research
• Published: 2012;72(13):3290-301
• Cited by: 219 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

©2012 AACR.

In plain English

This was a laboratory study of the protein HMGB1 in malignant mesothelioma. It used human tumor and blood samples, mesothelioma cell lines and mice. All 31 tumor biopsies (21 epithelioid, 6 biphasic, 4 sarcomatoid) showed strong HMGB1 staining in cell nuclei, and 26 of 31 also showed it in the cytoplasm. Higher tumor stage was associated with stronger cytoplasmic staining (r = 0.61, P = 0.002), which the authors said a larger sample may be needed to confirm. Blood HMGB1 averaged 77.9 ng/mL in 20 untreated mesothelioma patients and 17.5 ng/mL in 20 matched healthy people (P less than 0.0001). Six of 7 mesothelioma cell lines released more HMGB1 than normal mesothelial cells. Blocking HMGB1 reduced the viability of two high-secreting lines but had little or no effect on a low-secreting line. In mice injected in the abdomen with high-secreting human mesothelioma cells, an anti-HMGB1 antibody slowed tumor growth and extended survival by about 15%. In a cell experiment with crocidolite asbestos, HMGB1 blockers reduced the number of transformed cell clusters. The authors concluded that their findings support inhibiting HMGB1 as a possible new targeted therapy. The article did not report the patients' asbestos exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study combining experiments on cultured cells, staining of human tumor biopsies, measurement of HMGB1 in human blood serum, and a treatment experiment in mice carrying human mesothelioma tumors (xenografts)
• Who was studied: 31 human malignant mesothelioma biopsies (21 epithelioid, 6 biphasic, 4 sarcomatoid) and normal pleura; serum from 20 untreated mesothelioma patients and 20 age- and gender-matched healthy individuals; several human mesothelioma cell lines and primary mesothelial cells from pleural effusions of 8 patients without malignancy; 21 female SCID mice. Where and when the human samples were collected is not stated.
• Exposure: The main factor studied was the protein HMGB1 and its blockade with inhibitors (BoxA, an anti-HMGB1 antibody, an anti-RAGE antibody). Crocidolite asbestos was used only in a cell experiment on transformation of human mesothelial cells. The asbestos exposure histories of the patients were not reported.
• Main results:
  • In the asbestos-exposed mesothelial cell and macrophage cocultures, the mean number of foci (clusters of transformed cells) was 53.5 with BoxA and 70.0 with the anti-HMGB1 antibody. Untreated cocultures had 136.5 foci (SEMs 6.4, 9.9 and 7.8; P less than 0.05).
  • All 31 mesothelioma biopsies showed strong nuclear HMGB1 staining. 26 of 31 also showed cytoplasmic staining. In normal pleura, staining was only in the nucleus.
  • Among the biopsies, higher tumor stage was associated with stronger cytoplasmic HMGB1 staining (r = 0.61, P = 0.002).
  • Mean serum HMGB1 was 77.9 ng/mL (SEM 9.4) in 20 mesothelioma patients and 17.5 ng/mL (SEM 3.2) in 20 healthy controls (P less than 0.0001).
  • 6 of 7 mesothelioma cell lines released significantly more HMGB1 into culture medium over 24 hours than primary mesothelial cells.
  • HMGB1 inhibitors significantly reduced the viability of the high-secreting REN and Phi cell lines but had mild or no effects on the low-secreting Mill line. They did not change viability, proliferation or cytotoxicity in primary human mesothelial cells.
  • In SCID mice injected with high-secreting REN cells (groups of 7), the anti-HMGB1 antibody significantly reduced tumor growth (P less than 0.05).
  • In these REN-injected mice, the anti-HMGB1 antibody extended survival by about 15% compared with control groups (P less than 0.05).
  • In mice inoculated with the low-secreting Mill cells, the anti-HMGB1 antibody did not significantly inhibit tumor growth.
• The authors' conclusion: The authors concluded that mesothelioma cells that upregulate HMGB1 together with its receptor RAGE become dependent ('addicted') on it. They said this provides a rationale for inhibiting HMGB1 as a novel targeted therapy for malignant mesothelioma. They also suggested HMGB1 may be a biomarker, a hypothesis they planned to test.
• Limitations the authors state:
  • The authors stated that the correlation between tumor stage and HMGB1 staining may need validation in a larger sample.
  • The authors stated they could not exclude that all mesothelioma cells are initially dependent on HMGB1 and that some cell clones later lose this dependence.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: High Mobility Group Box 1 (HMGB1), Malignant Mesothelioma, erionite, Prognosis, Mesothelial Cells, Monoclonal.

Related studies

• HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma — L. Pellegrini, J. Xue, et al. (2017)
• Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-α signaling — F. Qi, G. Okimoto, et al. (2013)
• HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma — J.S. Suarez, F. Novelli, et al. (2023)
• Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy — J. Xue, S. Patergnani, et al. (2020)
• Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation — H. Yang, Z. Rivera, et al. (2010)
• BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos — F. Novelli, A. Bononi, et al. (2021)

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