Malignant mesothelioma is an aggressive, treatment-resistant tumor, arising from transformed mesothelial cells lining the pleura, peritoneum and pericardium. Athough relatively a rare disease, its incidence rate is increasing throughout the world [1, 2]. Its major risk factor is asbestos exposure, besides it can also be caused by ionizing radiation, erionite exposure, chest injuries, and presumably SV40 virus . Patients with malignant pleural mesothelioma (MPM) usually present with shortness of breath and chest pain with pleural effusions. Patients are diagnosed with cytopathology of mesothelioma effusions or fine-needle aspirations, and histopathology is often required to establish the diagnosis . Despite the current regimen of surgical resection, chemotherapy, and radiation therapy for treating MPM, the prognosis remains dismal, with median survival being 9–12 months from diagnosis . Therefore developing new molecular targeted therapies may pose promise for this devastating illness.
The pathogenic mechanisms underlying mesothelioma involve deregulation of multiple signaling pathways, including activation of multiple receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) family and MET, and subsequent deregulations of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT signaling cascades, the TNF-α / NF-κB survival pathway, Wnt signaling, and loss of tumor suppressors such as Neurofibromatosis type 2(NF2), p16INK4A, and p14ARF–. Understanding mechanisms of the dysregulated signaling pathways allows strategies for development of targeted new therapies against this devastating disease.
It has been recently reported that sonic hedgehog (Hh) signaling, another important pathway during development and tumorigenesis, is aberrantly activated in MPM, and inhibition of hedgehog signaling suppresses tumor growth . Deregulated Hedgehog (Hh) pathway activation has been implicated in several human cancers including glioma, basal cell carcinoma, medulloblastoma, lung, breast, pancreatic and gastric cancers –. The Hh family of proteins controls multiple fundamental cellular functions, including cell proliferation and survival, body patterning and organ morphogenesis during embryonic development , –. Hh signaling is orchestrated by two trans-membrane receptors, Patched (Ptch1) and Smoothened (SMO). In the absence of the Hh ligand, PTCH1 inhibits SMO, causing cleavage of GLI1 to the N-terminal repressor form. Once Hh binds to PTCH1, the inhibitory effect on SMO is released, causing active full-length GLI1 to transport into the nucleus and activate transcription of the Hh target genes in a context- and cell-type specific manner, including GLI1, PTCH1, HHIP and C-MYC –. Targeted inhibition of aberrant Hh signaling leads to suppression of cancer stem cells awakened and propelled by inappropriate Hh signaling [10, 11, 16].
We propose that the Hh signaling pathway may play an essential role during pathogenesis of MPM. To test this hypothesis, we measured SMO and SHH expression levels in MPM tissue specimens, and studied the relation of those expression levels with regard to overall survival. We also examined multiple mesothelioma cell lines for SMO expression and their cell proliferation responses to a specific SMO inhibitor. We therefore aim to better elucidate the role of Hh signaling in the tumorigenesis of MPM, and such finding may lead to development of improved molecular targeted therapies against this fatal disease.