DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Posted August 22, 2018

Arti Shukla, Ph.D., University of Vermont

Nelson J. Chao, M.D., Duke University, Idea Award with Special Focus, Cancers Related to Radiation Exposure

Arti Shukla, Ph.D.,
University of Vermont

Mesothelioma is a cancer that results from the malignant transformation of cells that line internal organs such as the lungs and abdomen. Over 80% of mesothelioma cases are due to environmental exposure to fibrous minerals such as asbestos. Service members and Veterans are at risk due to deployment locations in the developing world, where building regulations do not restrict the use of exposed asbestos, or assignments within the United States that may lead to encounters with asbestos hazards located in areas such as U.S. Navy shipyards. The time between exposure and detection of mesothelioma can be over 30 years. The early symptoms of mesothelioma are cough, chest pain, and shortness of breath, which are often mistaken for common illnesses. Therefore, mesothelioma is frequently not diagnosed until the disease is in an advanced stage. Surgery, radiation, and chemotherapy are generally ineffective at treating advanced mesothelioma cases; thus, patient prognosis is poor. Though a direct link between chronic asbestos exposure and mesothelioma has been established, the biological mechanisms that cause asbestos-induced disease are still debated. There is a need to understand the early cellular events in mesothelioma development, which could lead to the identification of biomarkers, the ability to diagnose mesothelioma earlier, and the development of effective therapies.

Dr. Arti Shukla, supported by a Fiscal Year 2013 Idea Award with Special Focus, has been studying the role of exosomes in the development of mesothelioma. Exosomes are tiny vesicles that are secreted from almost all types of cells as a means of sharing information (RNA, proteins, and lipids) between different cell types. There is growing evidence that exosomes contribute to tumorigenesis, metastasis, and chemoresistance. There is also hope that tumor exosomes in the blood could be used as biomarkers to identify cancer at an early stage of disease. Dr. Shukla hypothesized that, in response to asbestos exposure, epithelial cells and macrophages (a type of immune cell) secrete exosomes that are then taken up by mesothelial cells. These exosomes, Dr. Shukla theorized, may harbor proteins or genetic material that could enable development of malignant mesothelioma.

To address this hypothesis, cultured human lung epithelial cells and macrophages were treated with asbestos, then exosomes were isolated and their protein content was analyzed. Exosomes released from asbestos-exposed lung epithelial cells or macrophages have a differentially abundant proteomic signature compared with exosomes from cells that are not exposed to asbestos. These exosomes contain proteins known to be upregulated in mesothelioma or involved in cellular de-differentiation and inflammation. In the second part of the study, the asbestos-treated exosomes were then added to cultured mesothelial cells. The mesothelial cells were analyzed for gene expression changes involved in mesothelioma development. When mesothelial cells were targeted with asbestos exosomes, the cells downregulated genes that maintain cellular polarity and adhesion and overexpressed genetic regulators of cellular differentiation, cell-cycle machinery, and chromosomal instability. These changes in gene expression are characteristic of cancer initiation and therefore suggest that exosomes contribute to this process (4).

To confirm their in vitro findings, mice were exposed to asbestos, and exosomes from their blood were isolated and characterized. Exosomes from asbestos-treated mice contained significantly more proteins and also had a differentially abundant protein signature than exosomes from untreated mice. Several of the overly abundant proteins identified in exosomes had already been implicated in mesothelioma development, inflammation, and cellular migration. These initial results require further study, but confirm Dr. Shukla’s theory that exosomes in vivo have an altered protein signature after asbestos exposure (5).

These are the first reports describing the potential role of exosomes in mesothelioma development, and reveals an indirect mechanism for asbestos to target mesothelial cells. Dr. Shukla’s team plans to further validate these findings in animal models and human patients. Dr. Shukla’s ultimate goal is to identify biomarkers that can be detected in the blood of individuals with known asbestos exposure. The ability to detect and identify asbestos-related exosomes in blood samples could be a key step to diagnosis mesothelioma at earlier stages.

References:

1 https://www.cancer.gov/types/mesothelioma

2 https://www.cancer.gov/about-cancer/causes-prevention/risk/substances/asbestos

3 https://www.vets.gov/disability-benefits/conditions/exposure-to-hazardous-materials/asbestos/

4 Munson P, Lam YW, Dragon J, MacPherson M, Shukla A. 2018. “Exosomes from Asbestos-Exposed Cells Modulate Gene Expression in Mesothelial Cells.” FASEB. doi: 10.1096/fj.201701291RR.

5 Munson P, Lam YW, MacPherson M, Beuschel S, Shukla A. 2018. “Mouse Serum Exosomal Proteomic Signature in Response to Asbestos Exposure.” J Cell Biochem. 119(7):6266-6273. doi: 10.1002/jcb.26863.

Link:

Public and Technical Abstracts: Exosomes in Development and Therapy of Malignant Mesothelioma

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Last updated Wednesday, August 22, 2018