It is known that an epidermal growth factor receptor (EGFR) gene mutation(s) is present in a percentage of non-small cell lung cancers (NSCLCs). Gefitinib, an inhibitor of the tyrosine kinase activity of EGFR, is effective on most of them. The EGFR mutation status alone cannot fully predict the response to gefitinib and the prognosis for the patients. We hypothesized that information on the expression levels of phosphorylated-EGFR and -Akt, and E-cadherin, alone or in combination with information on the EGFR mutation, may refine our ability of prediction. We investigated 24 NSCLCs that had recurred after surgery and were treated with gefitinib. Specimens resected by surgery were subjected to the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp reaction to determine the EGFR mutation status, and to immunohistochemical staining of phosphorylated-EGFR and -Akt, and E-cadherin to determine their expression levels. The EGFR mutation status was predictive of responsive disease (complete response: CR + partial response: PR) and controlled disease (CR + PR + stable disease: SD). Positive E-cadherin staining was predictive of longer time to progression (12.4 vs. 5.9 months, p<0.05) and overall survival (OS) (18.4 vs. 13.0 months, p<0.05). Together the patients with an EGFR mutation and the patients with positive E-cadherin staining defined a patient group with a median OS of 18.4 months and excluded the patient group with the median OS of 3.7 months. Neither p-Akt nor p-EGFR staining was associated with the response and survival. In patients with surgically resected NSCLC tumors, the EGFR mutation status and E-cadherin staining can select patients who will benefit from gefitinib therapy.
"Several hypotheses for this differential response have been proposed. As tumor cells dedifferentiate and take on a more mesenchymal phenotype, EMT mechanisms may be involved in modulating EGFR activation and signaling or in activating alternative downstream targets that do not rely exclusively on the EGFR pathway (such as AKT), resulting in a decreased response to EGFR inhibitors (Figure 4) [Voulgari and Pintzas, 2009; Miyanaga et al. 2008; Andle and Rustgi, 2006] Data suggest that E-cadherin expression (a reliable marker of EMT) may be responsible for inhibiting EGFR activity by decreasing receptor mobility and ligand affinity [Andle and Rustgi, 2006; Yauch et al. 2005; Fedor-Chaiken et al. 2003]. Immunohistochemical staining of E-cadherin and vimentin in 62 unselected primary NSCLCs revealed the frequency of the epithelial phenotype (E-cadherin positivity) to be significantly greater in people with EGFR mutations than in the wild-type EGFR tumors [Deng et al. 2009]. "
[Show abstract][Hide abstract] ABSTRACT: Pulmonary carcinosarcoma is a rare and aggressive neoplasm that has both epithelial and mesenchymal components. We report on a 63-year-old woman who was found to have a right upper-lobe pulmonary carcinosarcoma with metastases to the liver and gastric fundus. There are currently no published guidelines on the treatment of pulmonary sarcomatoid carcinomas. However, with our expanding knowledge of cancer metastasis, cases of carcinosarcoma illustrate our current understanding of epithelial-mesenchymal transition in action. Here, we discuss the development and treatment of these biphasic tumors and the possible role of epithelial-mesenchymal transition.
rapeutic Advances in Medical Oncology, The 01/2012; 4(1):31-7. DOI:10.1177/1758834011421949 · 2.83 Impact Factor
"Such a technique has been applied to search for K-Ras mutations in various tumour samples (Sun et al, 2002; Chen et al, 2004; Taback et al, 2004; Däbritz et al, 2005; Luo et al, 2006; Miyake et al, 2007). This method was also used to detect EGFR mutations in NSCLC (Nagai et al, 2005; Soh et al, 2006; Sutani et al, 2006; Tanaka et al, 2007; Miyanaga et al, 2008). As NSCLC, in particular adenocarcinoma, could often be mixed with normal cells, the aim of this study was to estimate the possibility to increase the sensitivity of the detection of K-Ras mutations on an EGFR-targeted naive NSCLC cohort, even in cases of low tumour cellularity and to evaluate its routine clinical usefulness. "
[Show abstract][Hide abstract] ABSTRACT: Non-small cell lung cancers (NSCLC), in particular adenocarcinoma, are often mixed with normal cells. Therefore, low sensitivity of direct sequencing used for K-Ras mutation analysis could be inadequate in some cases. Our study focused on the possibility to increase the detection of K-Ras mutations in cases of low tumour cellularity. Besides direct sequencing, we used wild-type hybridisation probes and peptide-nucleic-acid (PNA)-mediated PCR clamping to detect mutations at codons 12 and 13, in 114 routine consecutive NSCLC frozen surgical tumours untreated by targeted drugs. The sensitivity of the analysis without or with PNA was 10 and 1% of tumour DNA, respectively. Direct sequencing revealed K-Ras mutations in 11 out of 114 tumours (10%). Using PNA-mediated PCR clamping, 10 additional cases of K-Ras mutations were detected (21 out of 114, 18%, P<0.005), among which five in samples with low tumour cellularity. In adenocarcinoma, K-Ras mutation frequency increased from 7 out of 55 (13%) by direct sequencing to 15 out of 55 (27%) by clamped-PCR (P<0.005). K-Ras mutations detected by these sensitive techniques lost its prognostic value. In conclusion, a rapid and sensitive PCR-clamping test avoiding macro or micro dissection could be proposed in routine analysis especially for NSCLC samples with low percentage of tumour cells such as bronchial biopsies or after neoadjuvant chemotherapy.
British Journal of Cancer 03/2009; 100(6):985-92. DOI:10.1038/sj.bjc.6604925 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epithelial-to-mesenchymal transition is a process in which cells undergo a developmental switch from an epithelial to a mesenchymal phenotype. We investigated the role of this phenomenon in the pathogenesis and progression of adenocarcinoma and squamous cell carcinoma of the lung. Archived tissue from primary tumors (n=325), brain metastases (n=48) and adjacent bronchial epithelial specimens (n=192) were analyzed for immunohistochemical expression by image analysis of E-cadherin, N-cadherin, integrin-alpha v beta 6, vimentin, and matrix metalloproteinase-9. The findings were compared with the patients' clinicopathologic features. High expression of the epithelial-to-mesenchymal transition phenotype (low E-cadherin and high N-cadherin, integrin-alpha v beta 6, vimentin, and matrix metalloproteinase-9) was found in most lung tumors examined, and the expression pattern varied according to the tumor histologic type. Low E-cadherin membrane and high N-cadherin cytoplasmic expression were significantly more common in squamous cell carcinoma than in adenocarcinoma (P=0.002 and 0.005, respectively). Dysplastic lesions had significantly lower expression of the epithelial-to-mesenchymal transition phenotype than the squamous cell carcinomas, and integrin-alpha v beta 6 membrane expression increased stepwise according to the histopathologic severity. Brain metastases had decreased epithelial-to-mesenchymal transition expression compared with primary tumors. Brain metastases had significantly lower integrin-alpha v beta 6 membrane (P=0.04), N-cadherin membrane, and cytoplasm (P<0.0002) expression than the primary tumors. The epithelial-to-mesenchymal transition phenotype is commonly expressed in primary squamous cell carcinoma and adenocarcinoma of the lung; this expression occurs early in the pathogenesis of squamous cell carcinoma. Brain metastases showed characteristics of reversed mesenchymal-to-epithelial transition. Our findings suggest that epithelial-to-mesenchymal transition is a potential target for lung cancer chemoprevention and therapy.
Modern Pathology 03/2009; 22(5):668-78. DOI:10.1038/modpathol.2009.19 · 6.19 Impact Factor
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