BRG1 and BRM, two core catalytic subunits in SWI ⁄ SNF chromatin remodeling complexes, have been suggested as tumor suppressors, yet their roles in carcinogenesis are unclear. Here, we present evidence that loss of BRG1 and BRM is involved in the progression of lung adenocarcinomas. Analysis of 15 lung cancer cell lines indicated that BRG1 mutations correlated with loss of BRG1 expression and that loss of BRG1 and BRM expression was frequent in E-cadherin-low and vimentin-high cell lines. Immunohistochemical analysis of 93 primary lung adenocarcinomas showed loss of BRG1 and BRM in 11 (12%) and 16 (17%) cases, respectively. Loss of expression of BRG1 and BRM was frequent in solid predominant adenocarcinomas and tumors with low thyroid transcription factor-1 (TTF-1, master regulator of lung) and low cytokeratin7 and E-cadherin (two markers for bronchial epithelial differentiation). Loss of BRG1 was correlated with the absence of lepidic growth patterns and was mutually exclusive of epidermal growth factor receptor (EGFR) mutations. In contrast, loss of BRM was found concomitant with lepidic growth patterns and EGFR mutations. Finally, we analyzed the publicly available dataset of 442 cases and found that loss of BRG1 and BRM was frequent in E-cadherin-low, TTF-1-low, and vimentin-high cases and correlated with poor prognosis. We conclude that loss of either or both BRG1 and BRM is involved in the progression of lung adenocarcinoma into solid predominant tumors with features of epithelial mesenchymal transition and loss of the bronchial epithelial phenotype. BRG1 loss was specifically involved in the progression of EGFR wild-type, but not EGFR-mutant tumors. (Cancer Sci 2013; 104: 266-273) L ung cancer is the leading cause of cancer death in many developed countries, including the United States and Japan. (1,2) The identification of genetic abnormalities, such as epidermal growth factor receptor (EGFR) mutations, KRAS mutations, EML4-ALK translocation, and MET amplifications has revolutionized our understanding of the molecular mechanisms in lung cancer development. (3) However, it has become increasingly apparent that epigenetic alternations play equally important roles in tumorigenesis, and among them, chromatin remodeling factors have attracted much attention recently. (4) Indeed, identification of mutations of chromatin remodeling factors in cancer has been a major hot topic in the past 2 years. (5)(6)(7)(8) BRG1 and BRM, two core catalytic ATPase subunits in human SWI ⁄ SNF chromatin remodeling enzymes, have now emerged as bona fide tumor suppressor genes. (9)(10)(11)(12) Inactivating mutations of BRG1 have been identified in 35% of non-small cell lung cancer cell lines and a subset of primary lung cancer. (9) In a mouse model of lung cancer, targeted knockout of BRG1 can affect tumor development. (10) In contrast to BRG1, mutations of BRM have rarely been identified and epigenetic silencing of BRM plays a contributory role in some cancers. (4,11) However, whether loss of BRG1 and BRM affects phenotype and...
In this study we explored the distribution of nestin-positive cells in extraneural human tissues with special reference to stromal myofibroblasts. Tissue microarrays were constructed from various tissues with normal histology and tissues with fibrosing disorders. Sections were immunostained for nestin, alpha-smooth muscle actin (alpha-SMA), desmin, vimentin, CD34, and other stromal markers. Nestin was expressed in the myoepithelium of the breast, podocytes of the renal glomerulus, and endothelial cells of most organs. Nestin was also expressed in the stroma of several organs, including the intestine, uterine cervix, and endometrium. Nestin-positive fibroblast-like cells appeared in the stroma of the kidney, pancreas, lung, and skin in fibrosing conditions. With the notable exception of endometrial stromal cells, most of these nestin-positive stromal cells were alpha-SMA-positive. Interestingly, we observed a concomitant appearance of nestin- and CD34-positive myofibroblasts under fibrosing conditions. Further investigation showed that nestin was expressed by stromal fibroblasts in cervical squamous cell carcinoma, but not in lung adenocarcinoma, pointing to heterogeneity of cancer stroma. In conclusion, nestin was expressed in variable proportions of stromal myofibroblasts in human tissues. The differential expression of nestin may indicate phenotypic and functional heterogeneity. Nestin-positive myofibroblast may represent a relatively immature subpopulation of cells with multipotentiality.
We performed an immunohistochemical analysis of the expression of zinc-finger E-box binding homeobox 1 (ZEB1), a master regulator of epithelial-mesenchymal transition (EMT), and determined its relationship with E-cadherin in 157 non-small cell lung carcinomas (93 adenocarcinomas, 36 squamous cell carcinomas, 18 large cell carcinomas, and 10 pleomorphic carcinomas). Although the expression of E-cadherin was low in the subset of adenocarcinomas (10%) and squamous cell carcinomas (11%), ZEB1 expression was only observed in one case of squamous cell carcinoma and none of the adenocarcinomas. In contrast, the low expression of E-cadherin (50% and 90%, respectively) and the positive expression of ZEB1 (11% and 50%, respectively) were more frequently observed in poorly differentiated carcinomas (large cell carcinomas and pleomorphic carcinomas). Overall, the expression of ZEB1 was inversely correlated with that of E-cadherin. Furthermore, the distribution of ZEB1-positive cancer cells was more restricted than in the area in which the expression of E-cadherin was lost, and the former was detected within the latter. We concluded that the expression of ZEB1 was not necessarily associated with the low expression of E-cadherin in lung adenocarcinomas and squamous cell carcinomas. The expression of ZEB1 correlated with an undifferentiated and/or sarcomatoid morphology that may occur in the late stage of EMT.
Systemic lupus erythematosus (SLE) is often complicated by pericarditis with effusion, which generally responds well to glucocorticoid. We report herein a Japanese patient with SLE who showed a sign of cardiac tamponade and severe chest and back pain because of massive intractable pericardial effusion. Pulse glucocorticoid and pulse cyclophosphamide gained marginal effects. Pericardial effusion accumulated again soon after ultrasound-guided pericardiocentesis and drainage. Pericardial fenestration performed surgically as a last resort, for draining pericardial fluid into the pleural space, was very effective, and only a much smaller amount of fluid was observed in the space thereafter in comparison with the volume before the surgery. Pathological examination of the retrieved pericardium unfolded intense hyperplasia of small vessels and capillaries. Levels of IL-6 and TNF-alpha in pericardial effusion were extremely higher than those in serum. Pericardial effusion with extensive capillary hyperplasia in SLE would be resistant to medical treatment and require surgical fenestration.
Based on colonoscopy findings, we made a preoperative diagnosis of primary mucinous cystadenocarcinoma of the appendix with features of a submucosal tumor (SMT) in the ascending colon. A 59-year-old woman who presented with right lower quadrant abdominal pain underwent colonoscopy, which revealed an SMT with three nodules covered with mucus in the ascending colon. Examination of colonoscopic biopsy specimens indicated "very" well-differentiated adenocarcinoma with mucus lakes. Abdominal computed tomography showed irregular wall thickness from the cecum to the ascending colon. The adjacent appendix had an enhanced wall and unclear border against the ascending colon. Thus, we performed right hemicolectomy, with good results. Histopathological examination revealed mucinous cystadenocarcinoma of the appendix, invading the ascending colon with fistula formation. Appendiceal tumors can manifest with a variety of colonoscopic features, and curative surgical resection should be attempted even if there is fistula formation.
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