The aims of the present work were to evaluate the prognostic significance of the micropapillary pattern of lung adenocarcinoma and determine whether there are differences in the behavior of this type of tumor according to its immunohistochemical profile. A series of 191 consecutively resected pulmonary adenocarcinomas were divided into those with (n = 62) and those without (n = 129) micropapillary components. The disease was stage I in 38 and 54 patients, respectively. The 5-year survival rates of patients with and without micropapillary components were 54% and 77%, respectively (log rank P = .03). In multivariate survival analysis, the micropapillary component proved to be an independent prognostic factor (hazard ratio, 3.2). Five autopsy cases were used to investigate the immunohistochemical profile. The percentages of cases positive for various markers were 56.7 for p53, 94 for Ki67, 85.1 for c-myc, 2.9 for Bcl-2, 35.8 for epidermal growth factor receptor, 43.3 for cyclin D1, and 46.3 for Bax. The prognostic value was evaluated according to the expression of the different markers in micropapillary carcinomas in stage I. In univariate analysis, only cyclin D1 expression and Bax expression were associated with significantly worse survival (log rank P = .03 and P = .02, respectively). We conclude that it is important to recognize the micropapillary growth pattern in lung adenocarcinoma. Moreover, cyclin D1 and Bax seem to be markers of a poor prognosis.
"In non-tumor cells, the cyclin D1 gene senses the mitogenic potential of the microenvironment during cell-cycle entry from quiescence because its induction requires coordinated signaling from the extracellular matrix and soluble growth factors (Assoian and Klein, 2008). These controls can be lost during cellular transformation upon exposure to carcinogens or tumor promoters, resulting in the corresponding overexpression of cyclin D1 in a number of cancers, including those of the breast, liver, lung, and colon (Gillett et al., 1996; Yamamoto et al., 2006; Molenaar et al., 2008; Sanchez-Mora et al., 2008). Cyclin D1 levels can be regulated in a transcriptional and post-transcriptional manner (Zhang et al., 2012; Ouyang et al., 2005). "
[Show abstract][Hide abstract] ABSTRACT: Selective activation of Rho GTPase cascade requires the release of Rho from RhoGDI (GDP-dissociation inhibitors) complexes. Our previous studies identified RhoGDIα SUMOylation at Lys-138 and its function in the regulation of cancer cell invasion. In the current study, we demonstrate that RhoGDIα SUMOylation has a crucial role in the suppression of cancer cell anchorage-independent growth as well as the molecular mechanisms underlying this suppression. We found that ectopic expression of RhoGDIα resulted in marked inhibition of an anchorage-independent growth with induction of G0/G1 cell cycle arrest, while point mutation of RhoGDIα SUMOylation at residue Lys-138 (K138R) abrogated this growth suppression and G0/G1 cell cycle arrest in cancer cells. Further studies showed that SUMOylation at Lys-138 was critical for RhoGDIα down-regulation of cyclin D1 protein expression and that MEK1/2-Erk was a specific downstream target of SUMOylated RhoGDIα for its inhibition of C-Jun/AP-1 cascade, cyclin d1 transcription, and cell cycle progression. These results strongly demonstrate that SUMOylated RhoGDIα suppressed C-Jun/AP-1-dependent transactivation specifically via targeting MEK1/2-Erk, subsequently leading to the down-regulation of cyclin D1 expression and anti-cancer activity. Our results provide new mechanistic insights into the understanding of essential role of SUMOylation at Lys-138 in RhoGDIα's biological function.
"All the sides were independently assessed by two pathologists. The immunostained results of Notch-1 protein were semi-quantitated according to the criteria from published literatures [2,11]. Each section randomly selected 5 high-power fields, positive cells represented by the percentage of totally number of similar cells. "
[Show abstract][Hide abstract] ABSTRACT: According to the International Multidisciplinary Classification of Lung Adenocarcinoma (LAD) by International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) in 2011, the diagnosis of LAD is changing from simple morphology into a comprehensive multidisciplinary classification. The aim of this study is to detect the expression of Notch-1 and analyze its clinicopathological or prognostic significance in different histological subtypes of Lung Adenocarcinomas (LADs).
Western blot and Semi-quantitative Reverse transcription-polymerase chain reaction (RT-PCR) assays, as well as immunohisitochemistry, were performed to detect the expression of Notch-1 in LAD cells and tissue samples. Kaplan-Meier and multivariate Cox regression analyses were performed to evaluate the correlation of Notch-1 expression with clinicopathological factors and prognosis of LAD patients.
The expression level of Notch-1 protein in LAD cell lines or tissues was significantly lower than that in normal human bronchial epithelial cell line (16HBE) or nontumor tissues (P < 0.05). By statistical analyses, it was observed that negative Notch-1 expression was significantly associated with advanced clinical stage (P = 0.001) and lymph node metastasis (P = 0.026) in LAD patients. Also, the recurrence rate of Notch-1-positive group was higher than the Notch-1-negative group (P = 0.001), and patients with positive Notch-1 expression have a prolonged progression of overall survival (P = 0.033). More interestingly, the expression of Notch-1 protein was often observed to be negative in solid predominant adenocarcinoma (SPA) tissues, but highly expressed in papillary predominant adenocarcinoma (PPA) and micropapillary predominant adenocarcinoma (MPA) tissues. Kaplan-Meier survival analysis showed that patients with positive Notch-1 expression had a prolonged progression of overall survival compared with those with negative Notch-1 expression (P = 0.033). The median survival time of Notch-1-positive or negative patients was 64.6 months (95% CI: 31.497-97.703 months) or 36.0 months (95% CI: 12.132-59.868 months).
Notch-1 could be used as a predictable biomarker to be detected in different pathological and histological subtypes in LAD for diagnosis or prognosis.
Journal of Experimental & Clinical Cancer Research 10/2013; 32(1):84. DOI:10.1186/1756-9966-32-84 · 4.43 Impact Factor
"Prognosis of lung adenocarcinoma with MPC has been reported to be worse and have the potential for high malignancy [17,18], but no studies have separately evaluated SMPC and AMPC. We showed that SMPC(+) tumors as well as AMPC(+) tumors are associated with several biological factors including tumor size, lymph node metastasis, advanced stage disease, and pleural and lymphovascular invasion. "
[Show abstract][Hide abstract] ABSTRACT: Pulmonary adenocarcinomas with a micropapillary component having small papillary tufts and lacking a central fibrovascular core are thought to result in poor prognosis. However, the component consists of tumor cells often floating within alveolar spaces (aerogenous micropapillary component [AMPC]) rather than invading fibrotic stroma observed in other organs like breast (stromal invasive micropapillary component [SMPC]). We previously observed cases of lung adenocarcinoma with predominant SMPC that was associated with micropapillary growth of tumors in fibrotic stroma observed in other organs. We evaluated the incidence and clinicopathological characteristics of SMPC in lung adenocarcinoma cases.
We investigated the clinicopathological characteristics and prognostic significance of SMPC in lung adenocarcinoma cases by reviewing 559 patients who had undergone surgical resection. We examined the SMPC by performing immunohistochemical analysis with 17 antibodies and by genetic analysis with epidermal growth factor receptor (EGFR) and KRAS mutations.
SMPC-positive (SMPC(+)) tumors were observed in 19 cases (3.4%). The presence of SMPC was significantly associated with tumor size, advanced-stage disease, lymph node metastasis, pleural invasion, lymphatic invasion, and vascular invasion. Patients with SMPC(+) tumors had significantly poorer outcomes than those with SMPC-negative tumors. Multivariate analysis revealed that SMPC was a significant independent prognostic factor of lung adenocarcinoma, especially for disease-free survival of pathological stage I patients (p = 0.035). SMPC showed significantly higher expression of E-cadherin and lower expression of CD44 than the corresponding expression levels shown by AMPC and showed lower surfactant apoprotein A and phospho-c-Met expression level than corresponding expression levels shown by tumor cell components without a micropapillary component. Fourteen cases with SMPC(+) tumors (74%) showed EGFR mutations, and none of them showed KRAS mutations.
SMPC(+) tumors are rare, but they may be associated with a poor prognosis and have different phenotypic and genotypic characteristics from those of AMPC(+) tumors.
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