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Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice
Published on: December 21, 2019
Malignant mesothelioma-associated inflammatory microenvironment promotes tumor progression via GPNMB
Cristina Belgiovine1,2, Elisabeth Digifico3, Marco Erreni4,5
1IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano (Milan), Italy. Cristina.belgiovine@unipv.it.
Background:
Tumor-Associated Macrophages (TAMs) are the main immune component of the tumor stroma with heterogeneous functional activities, predominantly suppressing the immune response and promoting tumor progression, also via secretion of different factors. Among these, GPNMB (Glycoprotein non-metastatic B) is usually associated with disease progression in several tumor types. Malignant pleural mesothelioma (MPM) a severe neoplasia with poor prognosis, is characterized by an abundancy of TAMs, testifying the presence of a long-lasting inflammation which is pathogenetic of the disease. However, the role of GPNMB in MPM is unclear.
Methods:
Clinical samples from patients with MPM were used to measure RNA and protein levels of GPNMB. The functional role of GPNMB in vivo was studied in an orthotopic mouse model of mesothelioma using the murine cell lines AB1 and AB22. Experiments included in vivo tumor growth in wild type and in GPNMB-deficient mice and blocking of GPNMB-induced signaling with anti-CD44 antibodies.
Results:
We show that in human and murine MPM tissues the protein GPNMB is mainly produced by infiltrating TAMs. Gpnmb RNA levels in MPM patients from TCGA are significantly associated with lower survival. Using an orthotopic mouse model of mesothelioma we observed that in GPNMB-defective mice (DBA2/J mice) unable to produce the protein, tumors formed by AB1 and AB22 mesothelioma cells grow significantly less than in GPNMB-proficient mice (DBA2/J-Gpnmb+ mice), indicating that host GPNMB is involved in tumor progression. Likewise, the ectopic expression of GPNMB in AB1 and AB22 cells causes an acceleration of tumor growth in vivo, significantly different compared to mock-transduced cells. Treatment of tumor-bearing mice with blocking anti-CD44 (a major receptor for GPNMB) results in a significant reduction of tumor growth.
Conclusions:
Overall, these results indicate that the protein GPNMB, a product and marker gene of TAMs, is a driver of mesothelioma progression and may constitute a promising therapeutic target.
Insights
Tumor-associated macrophages (TAMs) promote malignant pleural mesothelioma (MPM) progression. Glycoprotein non-metastatic B (GPNMB), produced by TAMs, drives mesothelioma growth and may be a therapeutic target.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Tumor-associated macrophages (TAMs) are key immune cells in the tumor microenvironment, often promoting tumor progression.
- Glycoprotein non-metastatic B (GPNMB) is implicated in the progression of various cancers.
- Malignant pleural mesothelioma (MPM) is characterized by abundant TAMs, but the role of GPNMB in MPM remains unclear.
Purpose of the Study:
- To investigate the role of GPNMB in malignant pleural mesothelioma (MPM) progression.
- To determine if GPNMB, produced by TAMs, influences tumor growth in MPM.
- To evaluate GPNMB as a potential therapeutic target in MPM.
Main Methods:
- Analysis of GPNMB RNA and protein levels in human and murine MPM tissues.
- In vivo studies using an orthotopic mouse model of mesothelioma with GPNMB-deficient and proficient mice.
- Assessment of tumor growth following GPNMB ectopic expression and blockade of GPNMB signaling via anti-CD44 antibodies.
Main Results:
- GPNMB protein is primarily produced by TAMs infiltrating human and murine MPM.
- Higher GPNMB RNA levels in MPM patients correlate with reduced survival.
- Host GPNMB deficiency significantly reduces mesothelioma tumor growth in mice.
- Ectopic GPNMB expression accelerates tumor growth, and anti-CD44 antibody treatment inhibits it.
Conclusions:
- GPNMB, a marker of TAMs, drives mesothelioma progression.
- GPNMB represents a promising therapeutic target for malignant pleural mesothelioma.
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