Exploring the Biology of Mesothelioma: What Research Tells Us

A deeper understanding of the anatomy and mechanisms of mesothelioma tumors has helped the effort to develop new treatments.

Recent research into the biology of mesothelioma is shedding light on how this aggressive cancer develops and spreads. By understanding the cellular and molecular mechanisms at play, scientists hope to develop more effective treatments and, eventually, a cure. 

The Basics of Mesothelioma

Mesothelioma arises from mesothelial cells, which form the lining (or mesothelium) of several cavities in the body. The mesothelium produces a lubricating fluid that allows organs to move smoothly against each other, such as during respiration. In pleural mesothelioma, the most common form of the disease, cancer forms in the pleural lining that encases the lungs. Peritoneal mesothelioma, another common form, affects the abdominal lining.

Exposure to asbestos fibers is the primary cause of mesothelioma. When these tiny, sharp fibers are inhaled or ingested, they can become embedded in the mesothelial lining, causing inflammation and cellular damage over time. The body’s immune response to these fibers can inadvertently lead to genetic mutations, which disrupt normal cell regulation. As a result, mesothelial cells begin to divide uncontrollably, forming tumors. Mesothelioma is particularly insidious because of its long latency period, often taking 20 to 50 years after asbestos exposure to develop.

Understanding the Cellular Mechanisms

At its core, mesothelioma is driven by mutations at the cellular level, which cause normal mesothelial cells to transform into cancer cells. These mutations interfere with key cellular processes like growth regulation, apoptosis (programmed cell death), and DNA repair. Several key pathways and genetic alterations have been identified as playing significant roles in the development of mesothelioma.

Genetic Mutations and Chromosomal Alterations

One of the most critical factors in the development of mesothelioma is genetic mutation. Mutations in tumor suppressor genes, such as BAP1 (BRCA-associated protein 1), have been found in a significant number of mesothelioma cases. BAP1 is involved in regulating cell growth and DNA repair, and its inactivation allows damaged cells to proliferate without control. Research suggests that individuals with inherited BAP1 mutations may be at a higher risk for developing mesothelioma, especially if they have been exposed to asbestos.

In addition to BAP1, other genetic mutations associated with mesothelioma include changes in NF2, CDKN2A, and TP53. These genes also play roles in controlling cell growth and apoptosis, and their alteration can lead to unchecked cell proliferation. Genetic studies have revealed that mesothelioma tumors often show complex chromosomal changes, including deletions and duplications of certain gene regions, contributing to the cancer’s progression.

Signaling Pathways: mTOR and Hippo

Research has also identified several critical signaling pathways involved in the growth and spread of mesothelioma cells. Among the most significant are the mTOR (mechanistic target of rapamycin) and Hippo pathways. These pathways are involved in cell growth, survival, and proliferation.

Inflammation and Immune Evasion

Chronic inflammation is a key factor in mesothelioma development. Asbestos fibers lodged in the mesothelium cause persistent irritation and inflammation, which can lead to DNA damage in mesothelial cells. Over time, the repeated inflammatory response creates a favorable environment for tumor development. The body’s immune system attempts to clear the asbestos fibers, but this ongoing immune response often backfires, promoting cancerous mutations instead.

One of the hallmarks of mesothelioma is its ability to evade the immune system. Cancer cells in mesothelioma can suppress the immune response, allowing them to grow unchecked. For instance, mesothelioma tumors often express high levels of PD-L1, a protein that inhibits T-cell activity and helps cancer cells avoid immune detection. This discovery has led to the development of immunotherapy treatments, such as checkpoint inhibitors, which aim to restore the immune system’s ability to recognize and attack mesothelioma cells.

Metastasis: How Mesothelioma Spreads

Mesothelioma is known for its aggressive spread, particularly within the chest and abdomen. Metastasis, or the spread of cancer to other parts of the body, occurs when cancer cells detach from the primary tumor and invade surrounding tissues or enter the bloodstream and lymphatic system.

Epithelial-to-Mesenchymal Transition (EMT)

One of the key processes involved in metastasis is epithelial-to-mesenchymal transition (EMT). In this process, cancer cells change from an epithelial state, in which they are more stationary and cohesive, to a mesenchymal state, where they become more mobile and invasive. Research has shown that EMT is driven by several molecular pathways, including the TGF-β (transforming growth factor-beta) signaling pathway. Understanding EMT may provide opportunities to develop treatments that prevent mesothelioma cells from becoming invasive and metastatic.

Lymphatic and Hematogenous Spread

Mesothelioma often spreads through the lymphatic system, a network of vessels and nodes that helps the body fight infection. Once mesothelioma cells enter the lymphatic system, they can spread to lymph nodes and distant organs. Similarly, hematogenous spread occurs when cancer cells enter the bloodstream, allowing them to travel to other parts of the body. Research into the mechanisms of both lymphatic and hematogenous spread is ongoing, with the aim of finding ways to prevent or slow metastasis.

Emerging Research and Therapeutic Targets

Advances in mesothelioma research are identifying new therapeutic targets and approaches that may improve outcomes for patients. Researchers are investigating targeted therapies, immunotherapies, and gene-editing techniques to combat the disease.

Targeted Therapies

Targeted therapies are drugs designed to specifically inhibit molecular pathways or genetic mutations that drive cancer growth. In mesothelioma, targeted therapies aimed at pathways like EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) are being explored. While these therapies have shown success in other cancers, more research is needed to determine their effectiveness in mesothelioma.

Immunotherapy

Immunotherapy, which harnesses the body’s immune system to fight cancer, has shown promise in mesothelioma treatment. Checkpoint inhibitors, such as pembrolizumab and nivolumab, block proteins like PD-1 and PD-L1 that cancer cells use to evade the immune system. Clinical trials are ongoing to evaluate the effectiveness of these drugs in mesothelioma patients, with some showing positive results in slowing tumor progression.

Gene Therapy and CRISPR

Gene-editing technologies like CRISPR-Cas9 are being explored as potential treatments for mesothelioma. These techniques allow scientists to directly target and repair genetic mutations that contribute to cancer development. While still in its early stages, gene therapy holds promise for the future of mesothelioma treatment.

Conclusion

Research into the biology of mesothelioma is rapidly advancing our understanding of how this aggressive cancer develops and spreads. By uncovering the genetic mutations, signaling pathways, and immune evasion strategies that drive mesothelioma, scientists are identifying new therapeutic targets and strategies to combat the disease. Although mesothelioma remains difficult to treat, these discoveries offer hope for more effective treatments and, ultimately, a cure.