gC1qR/HABP1/p32 Is a Potential New Therapeutic Target Against Mesothelioma

Our plain-English summary of gC1qR/HABP1/p32 Is a Potential New Therapeutic Target Against Mesothelioma, by E. Peerschke, K. Stier, X. Li, et al (Frontiers in Oncology, 2020).

The study

• Authors: E. Peerschke, K. Stier, X. Li, E. Kandov, E. de Stanchina, Q. Chang, Y. Xiong, K. Manova-Todorova, N. Fan, A. Barlas, B. Ghebrehiwet, P.S. Adusumilli
• Journal: Frontiers in Oncology
• Published: 2020;10:1413
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is an aggressive cancer of the serous membranes with poor prognosis despite combination therapy consisting of surgery, radiotherapy, and platinum-based chemotherapy. Targeted therapies, including immunotherapies, have reported limited success, suggesting the need for additional therapeutic targets. This study investigates a potential new therapeutic target, gC1qR/HABP1/p32 (gC1qR), which is overexpressed in all morphologic subtypes of mesothelioma. gC1qR is a complement receptor that is associated with several cellular functions, including cell proliferation and angiogenesis. In vitro and in vivo experiments were conducted to test the hypothesis that targeting gC1qR with a specific gC1qR monoclonal antibody 60.11 reduces mesothelioma tumor growth, using the biphasic mesothelioma cell line MSTO-211H (MSTO). In vitro studies demonstrate cell surface and extracellular gC1qR expression by MSTO cells, and a modest 25.3 ± 1.8% (n = 4) reduction in cell proliferation by the gC1qR blocking 60.11 antibody. This inhibition was specific for targeting the C1q binding domain of gC1qR at aa 76-93, as a separate monoclonal antibody 74.5.2, directed against amino acids 204-218, had no discernable effect. In vivo studies, using a murine orthotopic xenotransplant model, demonstrated an even greater reduction in MSTO tumor growth (50% inhibition) in mice treated with the 60.11 antibody compared to controls. Immunohistochemical studies of resected tumors revealed increased cellular apoptosis by caspase 3 and TUNEL staining, in 60.11 treated tumors compared to controls, as well as impaired angiogenesis by decreased CD31 staining. Taken together, these data identify gC1qR as a potential new therapeutic target against mesothelioma with both antiproliferative and antiangiogenic properties.

Copyright © 2020 Peerschke, Stier, Li, Kandov, de Stanchina, Chang, Xiong, Manova-Todorova, Fan, Barlas, Ghebrehiwet and Adusumilli.

In plain English

This was a laboratory and mouse study. It did not investigate asbestos exposure. The authors tested whether blocking gC1qR, a protein found on mesothelioma cells, with a lab-made antibody called 60.11 slowed tumor growth. They used a human biphasic mesothelioma cell line, MSTO-211H, grown in dishes and placed in the chest cavity of 20 female mice: 10 received the antibody and 10 received vehicle only. In dishes, 60.11 reduced cell growth by 25.3%. A second antibody aimed at another part of the protein had a negligible effect (2.9%). Treated mice had roughly 50% less tumor than controls. At week 2, imaging signal averaged 34.6 in treated mice versus 61.1 in controls (units of 10 million photons per second). Treated tumors showed more markers of cell death and less staining for blood vessels. Treated mice did not lose weight but had lower white blood cell counts. The protein was found in 10 of 22 pleural fluid samples from patients with malignant pleural mesothelioma. The authors called this an exploratory proof of concept, limited by using one cell line and one targeting strategy.

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 and an animal experiment in an orthotopic mouse model of pleural mesothelioma, plus measurement of a protein in stored patient pleural fluid samples
• Who was studied: The human biphasic mesothelioma cell line MSTO-211H. Female NSG immunodeficient mice, 6 to 8 weeks old, given intrapleural tumor cells and split into vehicle (n = 10) and 60.11 antibody (n = 10) groups. 22 deidentified pleural fluid samples from patients with advanced malignant pleural mesothelioma, at Memorial Sloan Kettering.
• Exposure: Asbestos exposure was not investigated. The treatment tested was monoclonal antibody 60.11, directed against the C1q binding domain of gC1qR (amino acids 76 to 93). Cells received 10 µg/ml. Mice received 100 mg/kg by intraperitoneal injection twice weekly, starting on day 8 after tumor implantation. A second antibody, 74.5.2 (amino acids 204 to 218), was used for comparison in cell culture.
• Main results:
  • In cell culture, antibody 60.11 reduced MSTO cell proliferation by 25.3 ± 1.8% (n = 4).
  • In cell culture, antibody 74.5.2, directed against amino acids 204 to 218, had a negligible effect (2.9 ± 2.2% inhibition).
  • In mice, those treated with 60.11 showed an approximately 50% reduction in tumor development compared with vehicle controls.
  • Tumor burden (bioluminescence total flux, ×10^7) in vehicle controls versus 60.11-treated mice: baseline 2.1 ± 1.0 vs 2.4 ± 1.4 (p = 0.635); week 1 18.8 ± 6.1 vs 9.6 ± 3.6 (p = 0.0006); week 2 61.1 ± 25.6 vs 34.6 ± 19.6 (p = 0.018).
  • Tumors from 60.11-treated mice showed increased early and late apoptosis markers (cleaved caspase 3 and TUNEL) compared with controls. They showed decreased CD31 staining, which the authors took to suggest decreased angiogenesis. There was no difference in the proliferation index (Ki67).
  • Treated tumors were macroscopically smaller, but H&E staining showed no histologic differences between groups.
  • 60.11-treated mice showed no weight loss (23.5 ± 1.08 g vs 23.0 ± 1.16 g in vehicle mice). They had a modest decrease in white blood cells (3.65 ± 1.02 vs 5.02 ± 1.05 ×10^3/µl), mainly neutrophils (3.24 ± 0.91 vs 4.57 ± 0.92 ×10^3/µl).
  • Soluble gC1qR was found in 10 of 22 pleural fluids from patients with malignant pleural mesothelioma, at a mean concentration of 1.11 ± 0.57 ng/ml among the 10 positive samples.
  • In culture, soluble and immobilized gC1qR enhanced MSTO cell adhesion.
• The authors' conclusion: The authors concluded that this exploratory study gives the first in vivo proof of concept that targeting gC1qR at the C1q binding site can reduce mesothelioma tumor burden, by increasing tumor cell apoptosis and decreasing tumor angiogenesis. They said gC1qR deserves further study as a potential new therapeutic target.
• Limitations the authors state:
  • The study used only a single cell line and a single anti-gC1qR targeting strategy.
  • Lymphocyte counts in this mouse strain are extremely low, so differences between groups are difficult to interpret.
  • Soluble gC1qR levels previously found in blood and body fluids, and those in pleural effusions from patients with malignant pleural mesothelioma, were significantly lower than the levels found to enhance cell proliferation in the dish. The authors said this needs further study, though concentrations next to the tumor are likely different.
  • Cell growth in a dish is not directly comparable to tumor growth in a living animal.
  • The therapeutic potential and toxicity of 60.11 need further exploration.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Prognosis, Chemotherapy, Angiogenesis, Monoclonal Antibody, Biphasic Mesothelioma, Apoptosis.

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