One of the most difficult aspects of a mesothelioma diagnosis for the patient and his or her family is coming to terms with the disease’s median survival figure, which states that the average life expectancy after diagnosis is only between 8 and 14 months long. Less than 10% of patients will survive for three or more years. While more precise surgical techniques and more effective chemotherapy regimens have had a positive effect on life expectancy, the overall successes have been limited and the survival differences compared to previous techniques are ones of degree, not of kind. For reasons still unknown, the great successes that medicine has had in treating other forms of cancer have not been replicated in the treatment of mesothelioma.

Many doctors feel that the key to more effective management of the disease is to better understand its molecular and genetic behavior. To this end, there are a number of research programs being conducted internationally that are attempting to uncover this information. A team of researches from Austria has recently released the results of a study that compared differences in protein expression and the role of signaling pathways between long-term and short-term survivors of pleural mesothelioma. Their results indicate that mesothelioma acts differently with long-term survivors than it does short-term survivors.

Introduction to the Study

To investigate the role played by the different signaling pathways, the researchers identified tissue samples from 70 previous cases of malignant pleura mesothelioma. Of these 70 samples, 48 were identified as epitheloid mesothelioma and included in the study. These samples were selected because the 10% of mesothelioma patients who survive longer than three years exclusively present with epitheloid mesothelioma. There were 26 cases of long-term survivors (LTS) and 22 cases of short-term survivors (STS). The median survival figure of the LTS group was 50.7 months, while the median survival figure of the STS group was only 9.1 months.

The initial samples were taken from tissue surgically-resected through a biopsy or a pleurectomy and then combined into a tissue microarray for immunohistochemical analysis, which revealed significant differences in protein expression between the LTS group and the STS group.

LTS Group

The LTS group showed overexpression of EGFR (epidermal growth factor receptor), which is the receptor for members of the epidermal growth factor family of extracellular protein ligands. EGFR overexpression has been implicated as a causative factor in a number of other cancers. In the LTS group, EGFR overexpression was the primary signaling pathway at work, which led to a specific protein expression profile that was not replicated in the STS group.

Previous research on EGFR signaling in mesothelioma concluded that EGFR blocking therapies were only valuable for a distinct minority of mesothelioma patients and the researchers here hypothesize that it is the same minority of patients who end up as long-term survivors that would be the principal beneficiaries of EGFR blocking.

STS Group

In the STS group, the researchers found that protein expression was more highly correlated with PDGFR (Platelet Derived Growth Factor Receptor) than it was EGFR. While both groups expressed similar levels of EGFR and PDGFR, and in some cases, even activation of the same proteins, in the case of the STS group, actual protein expression was driven by PDGFR signaling, while in the LTS group it was driven by EGFR signaling.

Protein Expression Between LTS and STS

Even though some of the same proteins were expressed in both groups, the overall expression profile was quite different. Both groups did show significant up-regulation of TIE2/Tek—which had not previously been discussed in relation to mesothelioma, but has been implicated with other cancers. In the LTS group, TIE2 up-regulation correlated with EGFR expression, while in the STS group it correlated with PDGFR expression.

The STS group also showed a much higher expression of survivin, which is a protein that inhibits apoptosis. Survivin overexpression has been identified in previous mesothelioma research as a primary reason for the disease’s poor response to chemotherapy and radiation. The researchers hypothesize that survivin up-regulation is induced by STAT1 expression, which was a surprise because previous research had concluded that STAT1 was a tumor suppressor and its siblings STAT3 and STAT5 were the oncogenes (a gene that can transform a healthy cell into a cancerous one). These findings indicate that in pleural mesothelioma STAT1 seems to act like an oncogene. Previous research on STAT1 expression has shown it can provide resistance to cisplatin and to radiation, which are often seen in mesothelioma.

Survivin and STAT1 expression did not play a significant role in the LTS group, although STAT3 was overexpressed in this group.

Conclusion

This paper was the first to compare signaling pathways and protein expression between a short-term group of mesothelioma survivors and a long-term group and the analysis indicates significant differences in signaling systems and protein expression. The hope, as in all cases of mesothelioma treatment research, is that these findings will lead to the development of important new treatment modalities. However, the researchers are quick to note that their paper only offers a number of hypotheses and that much more research needs to be completed before definitive conclusions can be drawn from their research.

Labels: mesothelioma