Pleural mesothelioma (PMe): The evolving molecular knowledge of a rare and aggressive cancer

Abstract

Mesothelioma is a type of late-onset cancer that develops in cells covering the outer surface of organs. Although it can affect the peritoneum, heart, or testicles, it mainly targets the lining of the lungs, making pleural mesothelioma (PMe) the most common and widely studied mesothelioma type. PMe is caused by exposure to fibres of asbestos, which when inhaled leads to inflammation and scarring of the pleura. Despite the ban on asbestos by most Western countries, the incidence of PMe is on the rise, also facilitated by a lack of specific symptomatology and diagnostic methods. Therapeutic options are also limited to mainly palliative care, making this disease untreatable. Here we present an overview of biological aspects underlying PMe by listing genetic and molecular mechanisms behind its onset, aggressive nature, and fast-paced progression. To this end, we report on the role of deubiquitinase BRCA1-associated protein-1 (BAP1), a tumour suppressor gene with a widely acknowledged role in the corrupted signalling and metabolism of PMe. This review aims to enhance our understanding of this devastating malignancy and propel efforts for its investigation.

Keywords: BAP1 and therapy; asbestos; mesothelioma.

Fig. 1

Tissues affected by mesothelioma. Representation of the most common tissues of origin for the mesothelioma pathology. Source: www.asbestos.com/mesothelioma. Created with Biorender.com.

Fig. 2

Mesothelioma cell types. Illustration of the three possible cell types involved in mesothelioma. Created with Biorender.com.

Fig. 3

Possible mechanisms of carcinogenesis caused by asbestos. Representation of the proposed mechanisms of action of asbestos fibres in mesothelioma progression. (A) DNA damage caused by ROS produced by macrophages after asbestos phagocytosis. (B) Abnormal cell cycle due to asbestos fibres entangling chromosomes during mitosis. (C) Activation of receptors localised on the cell surface by asbestos fibres. (D) Transport of cancerous chemical compounds inside the cell carried on the surface of the fibres. Created with Biorender.com.

Fig. 4

Schematic representation of the genes and protein most commonly deregulated in PMe. Representation of a PMe cell with dysregulated pathways and molecular mediator differently expressed or regulated during the onset of the pathology indicated. Created with Biorender.com.

Fig. 5

Schematic representation of BAP1 sequence, domains, and binding sites. Representation of BAP1 illustrating the functional domains and known binding sites to other proteins and complexes. UCH, ubiquitin carboxyl‐terminal hydrolase domain; ULD, UCH37‐like domain; NLS, nuclear localization sequence.

Fig. 6

Scheme of the different BAP1 functions in the cell. BAP1 is a tumour‐suppressor protein that exerts its role via the coordination of several different cellular mechanisms. In the nucleus, it is involved in gene expression regulation, DNA damage repair, and chromatin remodelling, while in the cytosol it can stabilise the calcium channel IP3R3. The downstream effects on a cell include the regulation of cell death via apoptosis and ferroptosis. Created with Biorender.com.