Asbestos Fibers And Mesothelioma: Biological Mechanisms
Asbestos Fibers And Mesothelioma: Biological Mechanisms – Malignant pleural mesothelioma (MPM) is a rare but serious form of cancer, with an incidence that varies considerably in different countries and around the world. It develops in one to two people per million of the general population, causing thousands of deaths worldwide each year. To date, MPM is most associated with occupational exposure to asbestos. Asbestos is the most important etiological factor with well-documented occupational exposure to asbestos for approx. 70% of MPM cases with an average exposure time of more than 40 years. Environmental exposure to asbestos is increasingly recognized as a cause of mesothelioma, along with gene mutations. The possible roles of other cofactors, such as viral infections and radiation exposure, are still debated. MPM is a fatal tumor. This cancer occurs at an early stage without any clinical signs. As a result, its diagnosis occurs in advanced stages. Standard clinical therapeutic methods include surgery, chemotherapy, and radiation therapy. Preclinical and clinical research is making significant progress in this deadly disease, identifying new biomarkers and innovative therapeutic approaches. Among the newly identified markers and potential therapeutic targets, circulating microRNAs and the Notch pathway are promising avenues for early tumor detection and may lead to new therapeutic approaches.
Malignant pleural mesothelioma (MPM) accounts for about 80% of mesothelioma cases. MPM is a regional and very aggressive tumor that arises from the pleura on the pleural surface. Rarely, other serous membranes in the human body are also covered with mesothelium, such as the peritoneum (peritoneal mesothelioma), the pericardium (pericardial mesothelioma) and the tunica vaginalis (tunica vaginalis mesothelioma). Although this malignancy is rare, the incidence of MPM has increased significantly, with an estimated 40,000 deaths worldwide each year due to asbestos-related MPM (1, 2), due to the increased and widespread use of these carcinogenic mineral fibers (3) . , 4). Asbestos refers to a group of natural silicate mineral fibers with physical properties that cause disease (5). The International Agency for Research on Cancer has confirmed that all fibrous forms of asbestos (actinolite, amosite, anthophyllite, tremolite, crocidolite and chrysotile) are carcinogenic to humans and cause mesothelioma. So far, asbestos includes about 400 types of fibers known in nature, but among them, only the 6 types mentioned above are regulated due to their high commercial use. The World Health Organization estimates that 125 million people worldwide are exposed to asbestos each year, both at work and at home. Although scientific evidence provides a clear and strong link between asbestos and MPM (6-9), many Western countries and newly industrialized economies still use asbestos (10-12). In addition, asbestos is defined differently depending on its context (commercial, mineralogical, analytical and regulatory), and this definition has lost the carcinogenic properties of some minerals (5). Previous studies have reported cases of MPM in humans exposed to erionite, the most potent carcinogenic mineral fiber, but it is not regulated because it is not defined as asbestos (13).
Asbestos Fibers And Mesothelioma: Biological Mechanisms
An accepted view assumes that the first step to MPM is the interaction of asbestos fibers with human pleural mesothelial cells (HMCs). Presumably, asbestos fibers enter the pleura and, depending on the size, length of exposure and the type of deposition in different areas, cause inflammation (12), which activates nuclear factor-kappa B (NF-κB) signaling This activation. It increases the survival and proliferation of parietal HMC and induces changes in molecular signaling events, such as oncogene activation, tumor gene loss, and DNA damage, increasing the risk of developing MPM (14, 15). To date, the molecular mechanism(s) by which asbestos affects the selection of these HMC subpopulations is not yet fully understood (16).
Brca1 Haploinsufficiency Impairs Iron Metabolism To Promote Chrysotile‐induced Mesothelioma Via Ferroptosis Resistance
Several epidemiologic studies showed (17) an increased incidence of MPM cases among subjects with a low level or no history of occupational exposure to asbestos, including women (7). These studies indicate that there is para-occupational exposure to asbestos, i.e. exposure to asbestos in work clothes, commercial asbestos-containing products, asbestos-containing buildings and natural asbestos in the soil, indicating that asbestos is becoming an environmental contaminant that can cause Acts together with other cofactors in the initiation of MPM (18). Both para-occupational exposure and direct (occupational) exposure have been shown to increase the risk of mesothelioma (19, 20).
In addition to exposure to asbestos, other environmental interactions may increase the risk of developing MPM. In vitro and in vivo studies, along with detection of viral gene sequences in human samples, have shown an association between MPM and oncogenic virus 40 (SV40) (21-24), suggesting a synergistic transformative effect between asbestos fibers and SV40. (25). Furthermore, recent immunological studies have demonstrated a higher prevalence of SV40 antibodies in sera from MPM patients compared to healthy blood donors. These data strengthen the association between MPM and SV40 (26, 27). Genetic predisposition and radiation exposure appear to play a role as etiologic factors that may contribute to the development of MPM with asbestos alone or with asbestos (17, 28, 29).
One of the characteristics of MPM is the long-term latency period between asbestos exposure and tumor onset (approximately 25 to 70 years), with a poor prognosis and survival of less than one year from diagnosis (30, 31). Most affected patients are 60 years of age at presentation, with age-specific incidence peaks at 80–84 years for men and 75–79 years for women (32). In the case of occupational exposure to asbestos, the prevalence is higher among men than among women (male-female ratio approx. 4:1-8:1) (7, 33).
Asbestos And Bile Duct Cancer
Malignant pleural mesothelioma is heterogeneous in its histological features (34). In fact, it can be distinguished into three main histological subtypes (35), according to the primary cellular component and the different biological behavior. Epithelioid mesothelioma, the most common form (50-70% of cases), has polygonal, oval, or cubic cells that resemble carcinomas; sarcomatoid type (10–20%), with fusion cell morphology similar to sarcoma; while mixed or biphasic (30%), it is composed of epithelioid and sarcomatoid forms, in different proportions, within the same tumor (36). Cytological diagnosis of MPM supported by immunohistochemistry shows that median survival varied significantly between histological subtypes. The epithelioid subtype is more aggressive than the sarcomatoid subtype. It is highly sensitive and responds better to chemotherapy, resulting in longer survival than the sarcomatoid or biphasic subtypes of MPM (37, 38).
The correct identification of the histological subtype of MPM facilitates the differential diagnosis, which affects the subsequent prognosis and therapeutic decisions of this disease. However, MPM is still fatal and a great deal of effort is being made in clinical and basic research in an attempt to find a cure for this tumor.
The purpose of this review is to describe currently available therapies and to discuss novel therapeutic targets and/or early detection markers that may be developed based on dissection of the underlying molecular mechanisms involved in the onset and progression of MPM.
Update Of In Vitro, In Vivo And Ex Vivo Fluoro‑edenite Effects On Malignant Mesothelioma: A Systematic Review (review)
Numerous studies over the past 20 years have led to the identification of dysregulated biological processes that may play an important role in the development of MPM. These studies have shown that MPM increases cell proliferation (downregulation of tumor suppressor genes, overexpression of oncogenes), inhibition of apoptosis (39, 40) and alteration of intracellular Ca.
Homeostasis (41, 42). There is evidence that some of these molecular changes, such as overexpression of the adenosine A3 receptor (43), purinergic P2X7 receptor (40), and dysregulation of cellular microRNAs (44) and circulating miRNAs (miRNAs) (27, 45) can be used for diagnosis. and hinder MPM growth. In the following, the literature related to the most frequently found change in MPM will be reviewed with particular focus on the opportunities that can be exploited for early diagnosis and treatment of MPM in the future.
Antitumor genes play a key role in cell cycle regulation. Deactivation and/or loss of function is one of the most important events in tumor development. Loss of heterozygosity, which usually leads to the discovery of a somatic mutation in a tumor mutagen through loss of the wild-type allele, appears to be a pervasive feature of MPM. Recent breakthrough studies have identified a mutation/inactivation of BAP1 (BRCA1-related protein 1), a tumor suppressor gene located on chromosome 3p21.3 in families with a genetic predisposition to develop MPM (46, 47). BAP1 is a deubiquitinating hydrolase that binds the RING finger domain of the BRCA1 protein, which is thought to be a regulator of many cancer-related pathways (48). Previous studies reported that BAP1 was involved in several biological processes, including cell cycle regulation, DNA damage response, and chromatin dynamics ( 49 ). BAP1 is ubiquitously expressed and interacts with tissue- and cell-type-specific proteins to mediate the metabolic stress response (50) and to promote survival associated with its deubiquitinating activity (51). A recently published study has shown that heterozygous BAP1 mutations (BAP1+/-) cause metabolic changes in cells associated with increased aerobic glycolysis, leading to reprogramming of activities that create an environment favorable for carcinogenesis and tumor growth (52) . Germline BAP1 gene mutations result in an abnormally short BAP1 protein that is likely to be cleaved prematurely. These mutations have come together
Systemic Treatments For Unresectable Pleural Mesothelioma: A Review Of The Literature
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