Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model

Our plain-English summary of Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model, by Y. Ohara, S.H. Chew, N. Misawa, et al (Oncotarget, 2018).

The study

• Authors: Y. Ohara, S.H. Chew, N. Misawa, S. Wang, D. Somiya, K. Nakamura, H. Kajiyama, F. Kikkawa, Y. Tsuyuki, L. Jiang, K. Yamashita, Y. Sekido, K.E. Lipson, S. Toyokuni
• Journal: Oncotarget
• Published: 2018;9(26):18494-18509
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is an aggressive neoplasm with no particularly effective treatments. We previously reported that overexpression of connective tissue growth factor (CTGF/CCN2) promotes mesothelioma growth, thus suggesting it as a novel molecular target. A human monoclonal antibody that antagonizes CTGF (FG-3019, pamrevlumab) attenuates malignant properties of different kinds of human cancers and is currently under clinical trial for the treatment of pancreatic cancer. This study reports the effects of FG-3019 on human mesothelioma in vitro and in vivo. We analyzed the effects of FG-3019 on the proliferation, apoptosis, migration/invasion, adhesion and anchorage-independent growth in three human mesothelioma cell lines, among which ACC-MESO-4 was most efficiently blocked with FG-3019 and was chosen for in vivo experiments. We also evaluated the coexistent effects of fibroblasts on mesothelioma in vitro, which are also known to produce CTGF in various pathologic situations. Coexistent fibroblasts in transwell systems remarkably promoted the proliferation and migration/invasion of mesothelioma cells. In orthotopic nude mice model, FG-3019 significantly inhibited mesothelioma growth. Histological analyses revealed that FG-3019 not only inhibited the proliferation but also induced apoptosis in both mesothelioma cells and fibroblasts. Our data suggest that FG-3019 antibody therapy could be a novel additional choice for the treatment of mesothelioma.

In plain English

This was a laboratory and mouse study of a possible treatment, not a study of asbestos exposure. The authors tested FG-3019 (pamrevlumab), an antibody that blocks connective tissue growth factor (CTGF), on human mesothelioma cell lines. In culture, FG-3019 showed no apparent effect on cell growth compared with a control antibody. On its own, it increased cell death in two lines (ACC-MESO-4 and NCI-H290) and reduced how well cells attached. Normal human lung fibroblasts grown alongside the cancer cells significantly increased their growth, migration and invasion in all three lines. The authors then implanted ACC-MESO-4 cells into the left pleural cavity of 24 nude mice, six per group. Average tumor weight was significantly lower with FG-3019 than with the control antibody (p less than 0.05). FG-3019 combined with the chemotherapy drug pemetrexed also gave lower tumor weight than the control antibody, with or without pemetrexed. The authors concluded that FG-3019 was effective in this mouse model, "at least in a limited human mesothelioma cell line." They noted that little is known about its effects on the immune system.

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 (cell culture) experiments plus an animal experiment: an orthotopic xenograft model in which human mesothelioma cells were implanted in the chest cavity of nude mice
• Who was studied: Three human mesothelioma cell lines (ACC-MESO-4 and NCI-H290, epithelioid; Y-MESO-8D, sarcomatoid), chosen from a larger panel; normal human lung fibroblasts (NHLF) for co-culture; and 24 male BALB/c nu/nu mice, 4 weeks old, in four groups of 6
• Exposure: Treatment, not asbestos. FG-3019 (anti-CTGF human monoclonal antibody) was compared with non-specific human IgG, alone or with pemetrexed (PEM). In culture the doses were 100 μg/ml FG-3019 or IgG and 1 μM PEM. In mice, FG-3019 or IgG was given at 40 mg/kg into the pleural cavity twice a week, and PEM at 50 mg/kg into the abdominal cavity once a week, for 8 weeks.
• Main results:
  • In cell culture, FG-3019 showed no apparent effect on proliferation of the three cell lines compared with control IgG.
  • In cell culture, FG-3019 alone induced apoptosis (cell death) in ACC-MESO-4 (P < 0.01) and NCI-H290 (P < 0.05), but not in Y-MESO-8D.
  • In cell culture, FG-3019 alone inhibited cell adhesion, and this effect was significantly enhanced when combined with PEM (P < 0.05).
  • Co-culture with normal human lung fibroblasts significantly promoted proliferation, migration and invasion of mesothelioma cells in all three cell lines (P < 0.05).
  • In mice, average tumor weight was significantly lower in the FG-3019 group than in the IgG control group (P < 0.05).
  • In mice, average tumor weight in the FG-3019 + PEM group was significantly lower than in the IgG group (P < 0.001) and than in the IgG + PEM group (P < 0.05).
  • In mouse tumors, FG-3019 inhibited proliferation and induced apoptosis in both mesothelioma cells and stromal (supporting) cells (P < 0.05).
  • Levels of XIAP, a protein that blocks cell death, were significantly decreased in FG-3019-treated mouse tumors (P < 0.05). The decrease was strongest with FG-3019 + PEM.
  • In mice, the trend for FG-3019 + PEM to reduce tumor spread into the opposite pleural cavity, compared with IgG alone, was not statistically significant (P = 0.091).
  • One mouse in the IgG control group died of tumor progression at day 46 and had the largest tumor in the experiment (725 mg).
• The authors' conclusion: The authors concluded that FG-3019 was effective for mesothelioma in a mouse orthotopic implant model, at least in a limited human mesothelioma cell line. They said the data provide a rationale to consider testing FG-3019 in clinical trials as an addition to conventional therapies.
• Limitations the authors state:
  • PEM was given by injection into the abdominal cavity rather than into the pleural cavity, while FG-3019 was injected directly into the pleural cavity.
  • Little data are available on the effects of FG-3019 on the immune system, and further studies are needed before clinical study in mesothelioma.
  • The mouse results were obtained with a limited human mesothelioma cell line (only ACC-MESO-4 was used in mice).

Topics

Medical terms in this study, explained in our Lexicon: Monoclonal Antibody, Mesothelioma, Neoplasm, Clinical Trial, Apoptosis, Fibroblast.

Related studies

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• Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma — L. Jiang, Y. Yamashita, et al. (2014)
• Malignant pleural mesothelioma and epidermal growth factor receptor (EGF-R). Relationship of EGF-R with histology and survival using fixed paraffin embedded tissue and the F4, monoclonal antibody — H. Dazzi, P.S. Hasleton, et al. (1990)
• Convergent signaling in the regulation of connective tissue growth factor in malignant mesothelioma: TGFβ signaling and defects in the Hippo signaling cascade — M. Fujii, H. Nakanishi, et al. (2012)
• Nuclear localization of CD26 induced by a humanized monoclonal antibody inhibits tumor cell growth by modulating of POLR2A transcription — K. Yamada, M. Hayashi, et al. (2013)
• A humanized anti-CD26 monoclonal antibody inhibits cell growth of malignant mesothelioma via retarded G2/M cell cycle transition — M. Hayashi, H. Madokoro, et al. (2016)

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