Neuroendocrine tumors of the lung include diverse entities ranging from highly aggressive small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC), to relatively indolent carcinoid tumors. SCLC accounts for 16% of lung cancers, while the other two are relatively rare, together comprising 2–3% of lung cancers.1
They are designated as neuroendocrine tumors because many have so-called “neuroendocrine” features in regards to histology, electron microscopy and immunohistochemistry, such as organoid, trabecular, palisading, or rosettes growth patterns, finely granular chromatin, dense-core neurosecretory granules, and expression of neuroendocrine markers.2, 3
However, there are many exceptions, and each type of tumor has its own distinct morphological features that allow histopathological diagnosis in most cases. Their biological behaviors are also different. While SCLC and LCNEC are characterized by aggressive course and poor prognosis, carcinoids are typically indolent and have favorable prognosis. An intermediate category, atypical carcinoid (AC), is used to designate tumors with features between those of typical carcinoids (TC) and high grade neuroendocrine carcinomas (SCLC and LCNEC).4
The tyrosine kinase receptor c-Met is normally activated by its ligand hepatocyte growth factor (HGF), and plays an important role in the tumorigenesis of various cancers including lung cancers. Activating mutations of c-Met in SCLC were first identified by Ma et al,5
and were subsequently documented in non-small cell lung cancer (NSCLC) as well.6
Expression of c-Met was detected in nearly all NSCLC and SCLC cases, and strong expression was present in more than half of the tumors. Amplification of MET gene has also been identified and appeared to be one of the mechanisms causing acquired resistance to gefitinib in NSCLC.7
These findings prompted studies on various c-Met inhibitors, including small interfering RNA and small molecules such as SU11274. These inhibitors were shown to decrease the growth rate of lung cancer cells, further supporting the role of c-Met in lung cancers and giving hopes that c-Met might be used as a therapeutic target.6, 8
Multiple clinical trials are currently underway to evaluate the therapeutic value of a number of c-Met inhibitors.8
The significance of c-Met in lung carcinoid tumors has not been well characterized, although its strong expression was reported in a large proportion of these tumors.6
In SCLC, the expression level of c-Met did not appear to correlate with the presence of activating mutations.5
The expression regulation of c-Met in the setting of lung cancers may provide further insights to understanding its role in tumorigenesis. PAX5, a transcription factor essential for B cell development, was strongly expressed in most SCLC cases and appeared to upregulate c-Met transcription. This may be unique for SCLC because PAX5 expression was not detected in NSCLC and several other cancers studied.9
Activated c-Met produces its biological effects through a number of downstream proteins in the HGF/c-Met pathway. One of them is paxillin, a key focal adhesion protein that is essential for cell-matrix adhesion, cell motility and migration. HGF/c-Met signaling can induce paxillin phosphorylation at its tyrosine residue, which in turn promotes tumor progression by enhancing tumor cell migration and spread.10
Activating c-Met mutations have been shown to increase paxillin phosphorylation in SCLC.5
In addition, paxillin has been shown to be highly expressed, and its gene sometimes amplified or mutated in NSCLC 11
. The role of paxillin in LCNEC and carcinoid has not been well studied.
The goal of this study was to evaluate the expression patterns of these three functionally related proteins, PAX5, c-Met and paxillin, in the setting of neuroendocrine tumors of the lung. We were particularly interested in possible correlation and coexpression between these markers.