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Malignant Mesothelioma Resistance to Apoptosis: Recent Discoveries and their Implication for Effective Therapeutic Strategies

Thursday, June 12, 2008

Source: Current Medicinal Chemistry

Mesothelioma is a complex cancer that remains difficult to treat effectively. There is no cure for the disease and the standard therapies, even in the best of cases, can only extend life. Because of this, investigations into the basic physical processes responsible for its development make-up a significant proportion of contemporary research. An understanding of the precise genetic changes and cellular activities that lead to mesothelioma genesis is thought to be the best way to create more effective treatments for patients with pleural mesothelioma, peritoneal mesothelioma and the other forms of the disease.

One of the therapeutic targets this research has identified is mesothelioma’s resistance to apoptosis, which is the process by which damaged or malformed cells are killed off and removed from the cell cycle. The research seems to indicate that one of the reasons mesothelioma may be so difficult to treat, as well as why it acts so aggressively, is the number of ways in which it resists apoptosis. Previous studies have identified some of these processes, but a review of the available literature on mesothelioma and apoptosis has not been completed until recently, when Italian researchers published their review of these previous studies. In their article, published in the journal Current Medicinal Chemistry, the researchers provide detailed information on the various apoptotic inhibitors that have been identified and, where possible, have noted treatment strategies that are either under active investigation or have been proposed for treatment.

Introduction to Apoptosis

Apoptosis is an important part of the regulatory processes that keep the body healthy, so significant apoptotic dysfunction raises the possibility of cancer genesis and subsequent spread due to the continued replication of damaged cells. The process can be activated from signals received outside of the cell, via its extrinsic pathway or from signals generated within the cell itself, via its intrinsic pathway. Apoptosis is triggered via the extrinsic pathway when a specific extracellular ligand, known as a death ligand, binds to its receptor on the cell’s outer surface, known here as the cell’s death receptor, which responds by activating an intracellular enzyme family (the caspases) that is responsible for the processes that lead to the actual termination of the cell. Apoptotic signaling via the intrinsic pathway is triggered in response to the cell’s experience of some form of stress and leads to a similar activation of the caspases.

The entire process is normally tightly regulated, but it can be undermined in a number of ways: by the over-expression of specific proteins and/or growth factors that lead to an inhibition of apoptotic behavior, by an under-expression of other proteins that normally demonstrate pro-apoptotic behavior, as well as combinations of all of these.

Mesothelioma and Apoptosis

The researchers have reviewed the available literature on mesothelioma and apoptosis and they describe a number of the processes that have been shown to inhibit apoptosis in affected cells. Some of these involve basic signaling structures, while others involve more complex situations where growth factor overexpression leads to an up-regulation of proteins which exhibit their own anti-apoptotic behavior. As an example of the former situation, researchers have shown that mesothelioma appears to be less responsive overall to particular signaling structures, such as the binding of TNF-related apoptosis-inducing ligand (TRAIL) to DR4 and DR5 death receptors, as compared to normal cells. The reasons for this are still unclear, but they do note a number of proposed therapies to overcome this lack of responsiveness.

Most of the article, though, is a description of the various proteins and growth factors that have been identified as possible agents in mesothelioma’s resistance to apoptosis. They note two particular protein families that have been especially implicated in this process: the inhibitor of apoptosis proteins (IAPs), a family of proteins that bind with and inhibit certain members of the caspases enzymes so apoptosis cannot occur, and the Bcl-2 family of proteins, whose members actually exhibit both pro- and anti-apoptotic features, but which mesothelioma cells tend to express only those members that promote anti-apoptotic behavior. The authors note that a number of treatments specific to these protein families are under investigation.

The authors also describe the ways in which growth factor overexpression can lead to cancer genesis and the inhibition of apoptosis. Growth factors are special proteins that serve important roles in the regulation of cellular processes and functions, so their misregulation can be especially problematic for long-term health. The authors then describe the roles that Epidermal Growth Factor (EGF), Hepatocyte Growth Factor/Scatter Factor (HGF/SF), Vascular Endothelial Growth Factor (VEGF), Insulin-Like Growth Factors (IGFs) and misregulation of the Wnt signaling pathway may play in mesothelioma’s resistance to treatment.

Each of these growth factors play an essential role in a well-regulated body, but their overexpression has been implicated in mesothelioma and in other forms of cancer as well. For example, EGF plays a vital role in promoting cell survival, but is over-expressed in a number of epithelial cancers and is thought to up-regulate other proteins involved with the inhibition of apoptosis. VEGF is essential for angiogenesis, which is the process by which new blood vessels are formed from existing tissue structures, but is over-expressed in most forms of cancer, including mesothelioma. Both of these examples show how misregulation of the body’s essential functions can lead to serious health-related issues.

Conclusion

The authors conclude their article by noting that the understanding of mesothelioma's resistance to apoptosis is a recent discovery and they express hope that therapies specific to the identified processes will lead to more effective treatments for patients with the disease.

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posted by Belluck & Fox at 4:16 PM
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