c-MET/phospho-MET expression and MET BISH positivity differed according to histological type. Among ADCs, c-MET expression and MET BISH positivity were more common in poorly differentiated cases. MET BISH positivity was an independent prognostic factor in nonsquamous NSCLCs.

RationaleAlveolar epithelial cell apoptosis and protease/antiprotease imbalance based proteolysis play central roles in the pathogenesis of pulmonary emphysema but molecular mechanisms underlying these two events are not yet clearly understood. Cell adhesion molecule 1 (CADM1) is a lung epithelial cell adhesion molecule in the immunoglobulin superfamily. It generates two membrane associated C terminal fragments (CTFs), αCTF and βCTF, through protease mediated ectodomain shedding.ObjectiveTo explore the hypothesis that more CADM1-CTFs are generated in emphysematous lungs through enhanced ectodomain shedding, and cause increased apoptosis of alveolar epithelial cells.Methods and resultsWestern blot analyses revealed that CADM1-CTFs increased in human emphysematous lungs in association with increased ectodomain shedding. Increased apoptosis of alveolar epithelial cells in emphysematous lungs was confirmed by terminal nucleotide nick end labelling (TUNEL) assays. NCI-H441 lung epithelial cells expressing mature CADM1 but not CTFs were induced to express αCTF both endogenously (by shedding inducers phorbol ester and trypsin) and exogenously (by transfection). Cell fractionation, immunofluorescence, mitochondrial membrane potentiometric JC-1 dye labelling and TUNEL assays revealed that CADM1-αCTF was localised to mitochondria where it decreased mitochondrial membrane potential and increased cell apoptosis. A mutation in the intracytoplasmic domain abrogated all three abilities of αCTF.ConclusionsCADM1 ectodomain shedding appeared to cause alveolar cell apoptosis in emphysematous lungs by producing αCTF that accumulated in mitochondria. These data link proteolysis to apoptosis, which are two landmark events in emphysema.

Myxofibrosarcoma is a common mesenchymal malignancy with complex genomics and heterogeneous clinical outcomes. Through gene-expression profiling of 64 primary high-grade myxofibrosarcomas, we defined an expression signature associated with clinical outcome. The gene most significantly associated with disease-specific death and distant metastasis was ITGA10 (integrin-α10). Functional studies revealed that myxofibrosarcoma cells strongly depended on integrin-α10, whereas normal mesenchymal cells did not. Integrin-α10 transmitted its tumor-specific signal via TRIO and RICTOR, two oncoproteins that are frequently co-overexpressed through gene amplification on chromosome 5p. TRIO and RICTOR activated RAC/PAK and AKT/mTOR to promote sarcoma cell survival. Inhibition of these proteins with EHop-016 (RAC inhibitor) and INK128 (mTOR inhibitor) had anti-tumor effects in tumor-derived cell lines and mouse xenografts, and combining the drugs enhanced the effects. Our results demonstrate the importance of integrin-α10/TRIO/RICTOR signaling for driving myxofibrosarcoma progression and provide the basis for promising targeted treatment strategies for patients with high-risk disease.

Background. As segmentectomy becomes widely used for lung cancer treatment, complex segmentectomy, which makes several, intricate intersegmental planes, remains controversial because of procedural complexity and risk of increased complications and incurability. Questions remain about mortality, morbidity, surgical margin, lymph nodes dissection, and postoperative pulmonary function. We evaluated operative and postoperative outcomes of complex compared with simple segmentectomy.Methods. We retrospectively reviewed patients with clinical stage I lung cancer who could tolerate lobectomy and underwent complex or simple segmentectomy between April 2007 and March 2017. Clinicopathologic, operative, and postoperative results of the complex (n [ 117) and simple (n [ 92) segmentectomy groups were compared.Results. No statistically significant differences were detected in age, sex, comorbidities, preoperative pulmonary function, tumor histology, and size. Although only median operative time (180 versus 143.5 minutes, p < 0.0001) was significantly longer in the complex group, 30-day mortality (0% versus 0%), overall complications (24.8% versus 22.8%), and prolonged air leakage (11.9% versus 10.9%) were nearly equivalent between the two groups, respectively. The complex group showed comparable results in median surgical margin distance (16.0 versus 17.5 mm) and number of dissected lymph nodes (6.0 versus 7.0 nodes). Margin relapse occurred in 2 patients in the simple group but none occurred in the complex group. Both groups also showed similar postoperative pulmonary functions.Conclusions. Complex segmentectomy is a safe option in the treatment of lung cancers with adequate operative outcomes.

No abstract

Pathologic invasive component size, as opposed to total tumor size, is associated more significantly with malignant behavior and prognosis and specifically should be considered before choosing candidates for adjuvant chemotherapy in pathologic stage I lung adenocarcinoma.

Purpose: Lung adenocarcinoma often manifests as tumors with mainly lepidic growth. The size of invasive foci determines a diagnosis of in situ, minimally invasive adenocarcinoma, or invasive types and suggests that some adenocarcinomas undergo malignant progression in that order. This study investigates how transcriptional aberrations in adenocarcinoma cells at the early stage define the clinical phenotypes of adenocarcinoma tumors at the advanced stage.Experimental Design: We comprehensively searched for differentially expressed genes between preinvasive and invasive cancer cells in one minimally invasive adenocarcinoma using laser capture microdissection and DNA microarrays. We screened expression of candidate genes in 11 minimally invasive adenocarcinomas by reverse transcriptase PCR and examined their involvement in preinvasive-to-invasive progression by transfection studies. We then immunohistochemically investigated the presence of candidate molecules in 64 samples of advanced adenocarcinoma and statistically analyzed the findings, together with clinicopathologic variables.Results: The transcription factors Notch2 and Six1 were upregulated in invasive cancer cells in all 11 minimally invasive adenocarcinomas. Exogenous Notch2 transactivated Six1 followed by Smad3, Smad4, and vimentin, and enlarged the nuclei of NCI-H441 lung epithelial cells. Immunochemical staining for the transcription factors was double positive in the invasive, but not in the lepidic growth component of a third of advanced Ads, and the disease-free survival rates were lower in such tumors.Conclusions: Paired upregulation of Notch2 and Six1 is a transcriptional aberration that contributes to preinvasive-to-invasive adenocarcinoma progression by inducing epithelial-mesenchymal transition and nuclear atypia. This aberration persisted in a considerable subset of advanced adenocarcinoma and conferred a more malignant phenotype on the subset. Clin Cancer Res; 18(4); 945-55. Ó2011 AACR.

Patients with small (≤20 mm) pathologic N0 solid or micropapillary predominant invasive adenocarcinoma might be possible candidates for adjuvant chemotherapy.