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

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.

A Complement-Related Gene Signature for Predicting Overall Survival and Immunotherapy Efficacy in Sarcoma Patients

“…C1QBP interacts with gC1q of C1q, and is involved in the regulation of T cell immunity and regulation of cytokines ( Ricklin et al, 2010 ). C1QBP was found to be closely related to tumorigenesis or metastasis of various cancers ( Bai et al, 2019 ; Xie et al, 2019 ; Peerschke et al, 2020 ; Egusquiza-Alvarez et al, 2021 ; Xie et al, 2021 ). C1S was also observed to promote tumor growth and survival in renal cancer and cutaneous squamous cell carcinoma ( Riihila et al, 2020 ; Daugan et al, 2021 ).…”

Heterozygous P32/C1QBP/HABP1 Polymorphism rs56014026 Reduces Mitochondrial Oxidative Phosphorylation and Is Expressed in Low-grade Colorectal Carcinomas

“…As protein synthesis of p32 is not affected by the SNP rs56014026 and mitochondrial import of p.T130M mutated p32 is impaired without concomitant increase in cytosolic protein, the question where the remaining extramitochondrial p32 is located instead awaits further investigation. Considering recent studies reporting different cancer cell lines to shed p32 into the extracellular compartment ( 46 , 47 ), one could hypothesize that p.T130M mutated p32 may be increasingly secreted into the extracellular milieu.…”

gC1qR: A New Target for Cancer Immunotherapy

“…As gC1qR was overexpressed in malignant pleural mesothelioma and mesothelioma (MSTO) cells lines, thus the antitumor efficacy gC1qR monoclonal antibody 60.11 was also assessed in MSTO mice models. The results indicated that gC1qR monoclonal antibody 60.11 reduced mesothelioma tumor volume via increasing apoptosis and reducing neovascularization ( 19 ). Additionally, the gC1qR-neutralizing antibody 3D9 could prevent the cells migration of plenty of cancer cell lines, including A549, MCF7 and MDA-MB-231.…”

“…It binds to a plethora of proteins found in plasma, on the cell surface and on pathogenic microorganisms. In contrast, in cancer conditions, gC1qR played a vital role in cancer progression and correlated with patient prognosis ( 19 ). gC1qR could reshape the tumor microenvironment (TME) by modulating immune cells and cancer cells, resulting in poor anti-tumor efficacy.…”