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Find video protocols related to scientific articles indexed in Pubmed.
[Pathological diagnosis of renal tumors: up to date].
Rinsho Byori
PUBLISHED: 08-26-2014
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Renal cell carcinoma (RCC) is composed of heterogenous histological types, with different clinical features and molecular biological characteristics. The "General Rule for Clinical and Pathological Studies on RCC" was revised in 2011, according to the World Health Organization system (WHO) (2004). Although most RCC is clear cell RCC (approximately 70-80% of RCC), papillary and chromophobe RCCs are occasionally encountered (approximately 10 and 5%, respectively). Collecting duct carcinoma is a rare and highly aggressive adenocarcinoma derived from the collecting duct. Additionally, several histological types have been introduced, and "granular RCC" has been omitted as a diagnostic term. For precise diagnosis, careful gross and histological evaluations are required along with immunohistochemical and molecular biological analyses. Additionally, novel histological types have recently been emerging, i.e., 6p21 translocation-associated RCC, dialysis-associated RCC, and tubulocystic carcinoma. Furthermore, mimics of RCC are always considered as differential diagnostic candidates, i.e., metanephric adenoma, epithelioid angiomyolipoma, juxtaglomerular cell tumor, and carcinoid tumor.
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SIRT1 expression is associated with a poor prognosis, whereas DBC1 is associated with favorable outcomes in gastric cancer.
Cancer Med
PUBLISHED: 08-21-2014
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Clinical trials of histone deacetylase (HDAC) inhibitors as antitumor therapy have been conducted for gastric cancer. Expression of SIRT1, a class III HDAC, is related to poor prognosis in some malignancies. We investigated the correlation between SIRT1 expression and progression and prognosis of gastric cancers comparing with molecules linked to SIRT1 in order to better predict the efficacy of HDAC inhibitors in treating this disease. We evaluated SIRT1 expression by western blot in 51 cases and SIRT1, DBC1, acetylated H4K16 (H4K16Ac), acetylated H3K9 (H3K9Ac), and p53 by immunohistochemistry (IHC) in 557 cases of gastric cancer. Western blotting showed that SIRT1 high expression related with statistics to advanced tumor progression, positive lymphatic invasion, positive venous invasion, and advanced stage but not to poor prognosis. IHC revealed that SIRT1 high expression correlated with worse clinico-pathological prognostic factors as same as in western blotting and related poor prognosis both by univariate and multivariate analyses. By the contrast, DBC1 and H4K16Ac were related to favorable prognostic factors and linked to favorable prognosis by univariate analysis but not by multivariate analysis. H3K16Ac correlated only favorable prognostic factors. Results of p53 were very similar to those of SIRT1. We found that SIRT1 high expression closely correlates with progression and prognosis in gastric cancer patients. And it was also indicated that SIRT1 acts as an oncogene by the results of DBC1, H4K16Ac, and H3K9Ac and might be a target molecule of HDAC inhibitor treatment for gastric cancer patients.
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Establishment of successively transplantable rabbit VX2 cancer cells that express enhanced green fluorescent protein.
Med Mol Morphol
PUBLISHED: 01-15-2014
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Morphological detection of cancer cells in the rabbit VX2 allograft transplantation model is often difficult in a certain region such as serosal cavity where reactive mesothelial cells mimic cancer cells and both cells share common markers such as cytokeratins. Therefore, tagging VX2 cells with a specific and sensitive marker that easily distinguishes them from other cells would be advantageous. Thus, we tried to establish a successively transplantable, enhanced green fluorescent protein (EGFP)-expressing VX2 model. Cancer cells obtained from a conventional VX2-bearing rabbit were cultured in vitro and transfected with an EGFP-encoding vector, and then successively transplanted in Healthy Japanese White rabbits (HJWRs) (n = 8). Besides, conventional VX2 cells were transplanted in other HJWRs (n = 8). Clinicopathological comparison analyses were performed between the two groups. The success rate of transplantation was 100 % for both groups. The sensitivity and specificity of EGFP for immunohistochemical detection of VX2 cells were 84.3 and 100 %, respectively. No significant differences in cancer cell morphology, tumor size (P = 0.742), Ki-67 labeling index (P = 0.878), or survival rate (P = 0.592) were observed between the two. VX2 cells can be genetically altered, visualized by EGFP, and successively transplanted without significant alteration of morphological and biological properties compared to those of the conventional model.
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HER2 protein overexpression and gene amplification in upper urinary tract urothelial carcinoma-an analysis of 171 patients.
Int J Clin Exp Pathol
PUBLISHED: 01-01-2014
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Upper urinary tract urothelial carcinomas (UUTUC) are infrequent and show an occurrence of about 5-10% of all urothelial carcinomas. In this study, we investigated the HER2 status of 171 UUTUC patients with nephroureterectomy. The number of patients is the largest of any HER2 study. All 171 cases were analyzed for both HER2 overexpression using immunohistochemistry and HER2 gene amplification using dual-color in situ hybridization. The scoring system proposed by the ASCO/CAP and ToGA trials was used. Out of 171 patients, 140 patients had a HER2 score-0 or score-1 (81.9%), 17 a score-2 (9.9%), and 14 a score-3 (8.2%) with immunohistochemistry. HER2 gene amplification was observed in 31 out of 171 cases (18.1%). A good correlation was observed between protein overexpression and gene amplification (p<0.0001). Twenty-three UUTUC (13.5%) were determined as HER2-positive cancer according to ASCO/CAP and ToGA criteria. HER2 positivity in patients over 70 years old was higher than that of patients under 70 years old (p=0.0132). HER2 expression correlated to a high histological grade (p=0.0003) and the coexistence of a high grade carcinoma in situ (p=0.0089). No HER2-positive cancer was observed in patients with renal pelvic UUTUC (0 out of 76, p<0.0001). HER2-positive UUTUC showed a shorter recurrence time in the residual urinary bladder after nephroureterectomy with Kaplan-Meier analysis (p=0.0284) and multivariate analysis (p=0.0034). The results suggest that HER2 positivity in UUTUC is an independent predictive marker for early recurrence of urothelial carcinoma in the residual urinary bladder after surgery.
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Anti-interleukin-5 and multiple autoantibodies are associated with human atherosclerotic diseases and serum interleukin-5 levels.
FASEB J.
PUBLISHED: 05-22-2013
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Atherosclerotic diseases, such as coronary artery disease and peripheral artery disease, are systemic disorders and among the leading causes of mortality and morbidity throughout the world. However, the exact pathophysiological mechanisms underlying the development of atherosclerosis remain unknown; currently, atherosclerosis is thought to involve an inflammatory process. Systemic inflammatory reactions and accumulation of immune cells in atherosclerotic lesions in situ are considered essential. We have comprehensively analyzed autoantibodies in patients with atherosclerosis by means of a newly developed high-throughput autoantibody analysis system. A wide range of autoantibodies was found in sera from patients with atherosclerosis. After we statistically analyzed the titers of each autoantibody with conventional techniques, the results underwent text-mining analyses based on natural language processing. Combinatory analysis revealed a close association between anti-interleukin (IL)-5 antibody and atherosclerosis. Titers of anti-IL-5 antibodies and serum IL-5 concentrations were also closely associated with other risk factors, such as low-density lipoprotein cholesterol, serum creatinine, fasting plasma glucose, gender, and age, suggesting that suppressed IL-5 function mediated by autoantibodies in patients with atherosclerosis plays an important role in the disease process. To validate the clinical significance of these findings, we computed the specificity and sensitivity of titers of anti-IL-5 autoantibodies for human atherosclerosis. When antibody titers of 1.49 were assumed to predict the presence of atherosclerosis, the sensitivity was 95.0% and the specificity 91.0%, with an area under the curve of 0.940. Our results provide important clues to understanding the role of autoantibody-mediated immune reactions in human atherosclerosis and suggest novel therapeutic opportunities for management of the disease.
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SIRT1 expression is associated with good prognosis for head and neck squamous cell carcinoma patients.
Oral Surg Oral Med Oral Pathol Oral Radiol
PUBLISHED: 03-05-2013
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SIRT1, class III histone deacetylase, has been described to be up-regulated in various malignancies. However, the opposite results have been reported in other malignancies. Therefore, we investigated SIRT1 expression to clarify its biological behavior and identify its usefulness as a biomarker for head and neck squamous cell carcinoma (HNSCC).
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POU domain transcription factor BRN2 is crucial for expression of ASCL1, ND1 and neuroendocrine marker molecules and cell growth in small cell lung cancer.
Pathol. Int.
PUBLISHED: 02-09-2013
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BRN2 is a developmental neural cell-specific POU domain transcription factor and is crucial for cell lineage determination. We investigated the importance of BRN2 in the expression of the lineage-specific transcription factors (achaete-scute homolog-like 1 (ASCL1) and NeuroD1 (ND1)) and neural/neuroendocrine marker molecules (neural cell adhesion molecule 1 (NCAM1), synaptophysin (SYP) and chromogranin A (CHGA)) in small cell lung cancer (SCLC) using cultured lung cancer cells. All examined SCLC cell lines expressed BRN2, as well as ASCL1, ND1, NCAM1, SYP and CHGA. The expression levels of ASCL1, ND1, NCAM1, SYP and CHGA considerably decreased when BRN2 was knocked down in SCLC cells, and the addition of a BRN2 transgene into non-SCLC (NSCLC) cells induced the expression of ASCL1, ND1, NCAM1, SYP and CHGA. However, the BRN2 gene was not activated by the forced expression of ASCL1 or ND1 in NSCLC cells. The knockdown of BRN2 caused significant growth retardation with decrease of S to G2 phase population and mitotic cell rates and unaltered Ki-67-labeled or apoptotic cell rates in SCLC cells, indicating increase of G1 phase population. These findings suggest that BRN2 is a higher level regulator than ASCL1 and ND1 and BRN2 might be involved in aggressiveness of SCLC.
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Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer.
Lab. Invest.
PUBLISHED: 01-28-2013
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Thyroid transcription factor 1 (TTF1) plays crucial roles in thyroid, lung, and developing brain morphogenesis. Because TTF1-expressing neoplasms are generated from organs and tissues that normally express TTF1, such as the thyroid follicular epithelium and peripheral lung airway epithelium, TTF1 is widely used as a cell lineage-specific and diagnostic marker for thyroid carcinomas and for lung adenocarcinomas with terminal respiratory unit (TRU) differentiation. However, among lung neuroendocrine tumors, small-cell carcinomas (small-cell lung cancers (SCLCs)), most of which are generated from the central airway, also frequently express TTF1 at high levels. To clarify how SCLCs express TTF1, we investigated the molecular mechanisms of its expression using cultivated lung cancer cells and focusing upon neural cell-specific transcription factors. Both SCLC cells and lung adenocarcinoma cells predominantly expressed isoform 2 of TTF1, and TTF1 promoter assays in SCLC cells revealed that the crucial region for activation of the promoter, which is adjacent to the transcription start site of TTF1 isoform 2, has potent FOX-, LHX-, and BRN2-binding sites. Transfection experiments using expression vectors for FOXA1, FOXA2, LHX2, LHX6, and BRN2 showed that BRN2 substantially upregulated TTF1 expression, whereas FOXA1/2 weakly upregulated TTF1 expression. BRN2 and FOXA1/2 binding to the TTF1 promoter was confirmed through chromatin immunoprecipitation experiments, and TTF1 expression in SCLC cells was considerably downregulated after BRN2 knockdown. Furthermore, the TTF1 promoter in SCLC cells was scarcely methylated, and immunohistochemical examinations using a series of primary lung tumors indicated that TTF1 and BRN2 were coexpressed only in SCLC cells. These findings suggest that TTF1 expression in SCLC is a cell lineage-specific phenomenon that involves the developing neural cell-specific homeoprotein BRN2.
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Pathology of asthma.
Front Microbiol
PUBLISHED: 01-01-2013
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Asthma is a serious health and socioeconomic issue all over the world, affecting more than 300 million individuals. The disease is considered as an inflammatory disease in the airway, leading to airway hyperresponsiveness, obstruction, mucus hyper-production and airway wall remodeling. The presence of airway inflammation in asthmatic patients has been found in the nineteenth century. As the information in patients with asthma increase, paradigm change in immunology and molecular biology have resulted in an extensive evaluation of inflammatory cells and mediators involved in the pathophysiology of asthma. Moreover, it is recognized that airway remodeling into detail, characterized by thickening of the airway wall, can be profound consequences on the mechanics of airway narrowing and contribute to the chronic progression of the disease. Epithelial to mesenchymal transition plays an important role in airway remodeling. These epithelial and mesenchymal cells cause persistence of the inflammatory infiltration and induce histological changes in the airway wall, increasing thickness of the basement membrane, collagen deposition and smooth muscle hypertrophy and hyperplasia. Resulting of airway inflammation, airway remodeling leads to the airway wall thickening and induces increased airway smooth muscle mass, which generate asthmatic symptoms. Asthma is classically recognized as the typical Th2 disease, with increased IgE levels and eosinophilic inflammation in the airway. Emerging Th2 cytokines modulates the airway inflammation, which induces airway remodeling. Biological agents, which have specific molecular targets for these Th2 cytokines, are available and clinical trials for asthma are ongoing. However, the relatively simple paradigm has been doubted because of the realization that strategies designed to suppress Th2 function are not effective enough for all patients in the clinical trials. In the future, it is required to understand more details for phenotypes of asthma.
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Coexpression of aPKC?/? and IL-6 in prostate cancer tissue correlates with biochemical recurrence.
Cancer Sci.
PUBLISHED: 06-02-2011
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Atypical protein kinase C ?/? (aPKC?/?) and interleukin-6 (IL-6) have been implicated in prostate cancer progression, the mechanisms of which have been demonstrated both in vitro and in vivo. However, the clinical significance of the correlation between the expressions of these factors remains to be clarified. In the present study, we report a significant correlation between aPKC?/? and IL-6 proteins in prostate cancer tissue by immunohistochemical staining. We evaluated the association of both proteins by analyzing clinicopathological parameters using chi-square test, Kaplan-Meier with log-rank test, and a Cox proportional hazard regression model in univariate and multivariate analyses. The results again showed that the expression of aPKC?/? and IL-6 correlates in prostate cancer tissue (P < 0.001). Atypical protein kinase C ?/? was also found to correlate with the Gleason score (P < 0.001) and with biochemical recurrence after prostatectomy (P = 0.02). Furthermore, aPKC?/? correlated with biochemical recurrence in a Kaplan-Meier and log-rank test (P = 0.01) and Cox analysis (P = 0.02 in the univariate analysis, P = 0.02 in the multivariate analysis). The coexpression of aPKC?/? and IL-6 also correlated with biochemical recurrence by Kaplan-Meier and log-rank test (P = 0.005) and Cox analysis (P = 0.01 in the univariate analysis, P = 0.03 in the multivariate analysis). These results indicate a strong correlation between aPKC?/? and IL-6 in prostate tumors, and that the aPKC?/?-IL-6 axis is a reliable prognostic factor for the biochemical recurrence of this cancer.
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Identification of phosphorylated proteins involved in the oncogenesis of prostate cancer via Pin1-proteomic analysis.
Prostate
PUBLISHED: 03-21-2011
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The peptidyl-prolyl isomerase Pin1 regulates a subset of phosphorylated proteins by catalyzing the cis-trans isomerization of their specific phosphorylated Ser/Thr-Pro motifs. Although Pin1 has been shown to be involved in cell transformation and the maintenance of the malignant phenotype in prostate cancer, its specific substrates during these processes have not yet been determined.
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Differential expression patterns of CXCR3 variants and corresponding CXC chemokines in clear cell ovarian cancers and endometriosis.
Gynecol. Oncol.
PUBLISHED: 03-15-2011
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Carcinogenesis of the ovary is often associated with endometriosis. We previously demonstrated that antitumor chemokine receptor CXCR3 was upregulated both in endometriosis and ovarian cancers. Currently, little is known about the roles of CXCR3 variants in these ovarian diseases. In this study, we investigated the expression of CXCR3 variants and their corresponding ligands in endometriosis and ovarian cancers.
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Disrupted balance of angiogenic and antiangiogenic signalings in preeclampsia.
J Pregnancy
PUBLISHED: 01-12-2011
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The placenta plays a central role in governing local circulatory system that mediates maternal condition and fetal growth. In early gestational phases, the placenta exerts properties of invasion and neovascularization for successful placentation. Extravillous invasive trophoblasts replace uterine endometrial vasculature and establish local blood pathway to obtain oxygen and nutrients from the mother. In later phases, the placenta promotes villous angiogenesis and vascular maturation that are finely controlled by angiogenic and antiangiogenic molecules. Among various molecules involved in placental neovascularization, vascular endothelial growth factor receptors (VEGFRs) and angiotensin II receptor type 1 (AT1) mediate important signaling pathways for maternal circulatory system and fetal growth. VEGFR1 and VEGFR2 are functional receptors for placental growth factor (PlGF) and VEGF, respectively, and PlGF-VEGFR1 and VEGF-VEGFR2 interactions are disturbed in many preeclamptic patients by excess amount of soluble form of VEGFR1 (also named sFlt1), a natural PlGF/VEGF antagonist. Recent studies have disclosed that excessive sFlt1 production in the placenta and aberrant AT1 signaling in the mother are closely associated with the pathology of preeclampsia and intrauterine growth restriction (IUGR). In this paper, neovascularization of the placenta and pathological events associated with disrupted balance between angiogenic and antiangiogenic signaling in preeclampsia are discussed.
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Complexity of tumor vasculature and molecular targeting therapies.
Front Biosci (Elite Ed)
PUBLISHED: 01-04-2011
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Malignant solid tumors require blood supply for their uncontrollable progression. Angiogenic blood vessels generally sprout from preexisting vascular cells. In addition, various types of precursor cells also participate in tumor neovascularization. They include endothelial progenitor cells, hematopoietic stem cells and mesenchymal stem cells that are stimulated and attracted into tumor lesion, in which a wide variety of proinflammatory factors are involved. Among key molecules, vascular endothelial growth factor (VEGF) works as a mastermind regulator. Humanized monoclonal antibodies targeting VEGF-mediated signaling pathways are currently used as the most pervasive drugs in several types of progressive tumors. Adverse effects of these drugs include hypertension and proteinuria. Such symptoms are widely observed in preeclamptic patients whose blood contain high amount of natural VEGF antagonist. Vasoactive G protein-coupled receptors (GPCRs)-mediated signalings such as renin-angiotensin system and chemokine axes are also noticed that they may become effective therapeutic targets. In this review, we discuss general view of angiogenic microenvironment in solid tumors, and highlight several key signaling molecules and inhibitory effects of them on the whole system.
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Possible involvement of peptidylprolyl isomerase Pin1 in rheumatoid arthritis.
Pathol. Int.
PUBLISHED: 12-28-2010
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The peptidylprolyl isomerase Pin1 is over-expressed in some human diseases including malignancies and chronic inflammatory diseases, this suggests that it contributes to the constitutive activation of certain intracellular signaling pathways that promote cell proliferation and cell invasion. Here, we investigate the possible role of Pin1 in rheumatoid arthritis (RA). Pin1 expression was immunohistochemically analyzed in synovial tissue (ST) obtained from patients with RA and osteoarthritis (OA). To investigate the correlation between Pin1 and motility and proliferation of synovial cells, Pin1 localization was immunohistochemically compared with matrix metalloproteinase (MMP)-1, MMP-3, and proliferating cell nuclear antigen (PCNA). Double immunofluorescent staining for Pin1 and p65 was performed to determine whether Pin1 is involved in nuclear factor ?B (NF-?B) activation in RA-ST. Results showed Pin1 expression was significantly higher in RA-ST than in OA-ST. The expression of MMP-1, MMP-3, and PCNA was also significantly elevated in RA-ST. Double immunofluorescent staining revealed colocalization of Pin1 and p65 in the nuclei of RA-ST. These results suggest that Pin1 may be involved in the pathogenesis of RA binding with p65 to activate the proteins MMP-1, MMP-3, and PCNA. Therefore, Pin1 may play a pivotal role in the pathogenesis of RA.
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Thymic alterations in GM2 gangliosidoses model mice.
PLoS ONE
PUBLISHED: 07-13-2010
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Sandhoff disease is a lysosomal storage disorder characterized by the absence of ?-hexosaminidase and storage of GM2 ganglioside and related glycolipids. We have previously found that the progressive neurologic disease induced in Hexb(-/-) mice, an animal model for Sandhoff disease, is associated with the production of pathogenic anti-glycolipid autoantibodies.
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A novel method for isolating podocytes using magnetic activated cell sorting.
Nephrol. Dial. Transplant.
PUBLISHED: 06-08-2010
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A large body of accumulated data has now revealed that podocytes play a major role in the development of proteinuria. However, the mechanisms of podocyte injury, leading to foot process effacement and proteinuria, are still unclear partly due to the current lack of an appropriate strategy for preparing podocytes. In this study, we have developed a novel method of rapid isolation of podocytes from mice using magnetic activated cell sorting with an anti-nephrin antibody.
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The topoisomerase II alpha gene status in primary breast cancer is a predictive marker of the response to anthracycline-based neoadjuvant chemotherapy.
Pathol. Res. Pract.
PUBLISHED: 01-20-2010
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This study aimed at evaluating the usefulness of topoisomerase II alpha (TOP2A) for predicting the effect of anthracycline-based neoadjuvant chemotherapy in breast cancer. The TOP2A status was examined using fluorescent in situ hybridization (FISH) in 14 pre-chemotherapeutic breast cancer tissues, and was also assessed by immunohistochemistry (IHC) in 14 pairs of pre- and post-chemotherapeutic breast cancer specimens. TOP2A gene aberration by IHC tended to show a correlation with pathological responses but this was not statistically significant (p=0.060). On the other hand, the low TOP2A/CEP17 ratio correlated with good pathological responses (p=0.012). TOP2A overexpression was not significantly associated with response (p=0.580). Our results thus suggest that the TOP2A/CEP17 ratio may be a useful predictor of the effects of anthracycline-based neoadjuvant chemotherapy in breast cancer.
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Lung cysts in Birt-Hogg-Dubé syndrome: histopathological characteristics and aberrant sequence repeats.
Pathol. Int.
PUBLISHED: 10-01-2009
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Birt-Hogg-Dubé (BHD) syndrome is a rare disorder inherited in an autosomal dominant manner. The affected patients are predisposed to cutaneous fibrofolliculomas, renal cell tumors and lung cysts with recurrent pneumothorax. Contrary to neoplastic events in the skin and the kidney, the lung cysts have frequently been confused with non-neoplastic changes such as blebs or bullae. Herein is reported a case of multiple lung cysts associated with BHD syndrome. Detailed histopathological characteristics of the lesion are also given. The lung cysts were closely associated with the peripheral interlobular septum, visceral pleura or septal-pleural junctional region. These cysts were partly abutting alveolar structures, and lined by a layer of alveolar epithelium. These unique microscopic features supported the notion that the BHD lung lesions are distinct from other types of bullous changes. Genomic DNA analysis indicated an aberrant sequence repeat that caused frameshift mutation. Immunohistochemistry showed the localization of folliculin, the BHD gene-encoding protein, in macrophages and epithelial cells in the patients and normal controls lungs. Haploinsufficiency of folliculin may cause deranged alveolar development, leading to the aberrant cystic alveolar formation. The unique mutation patterns of abnormal sequence repeats in patients with BHD syndrome are also reviewed.
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Identification of NPC2 protein as interaction molecule with C2 domain of human Nedd4L.
Biochem. Biophys. Res. Commun.
PUBLISHED: 07-28-2009
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Epithelial sodium channels (ENaC) located along the aldosterone-sensitive distal nephron (ASDN) play a pivotal role in the homeostasis of sodium balance. Among various modulating proteins, E3 ubiquitin ligase, Nedd4L, binds the PY motif of ENaC COOH terminals and catalyzes ubiquitination of the NH(2) terminal of the protein for subsequent degradation. One of the isoforms of human Nedd4L with evolutionarily new C2 domain was reported to play a significant role for degradating cell surface ENaC with interfering with wild isoforms by us previously. We focused the current analyses on isolating the binding molecules with C2 domain using yeast two-hybrid screening to elucidate further molecular interactions between ENaC and Nedd4L. We found NPC2, also known as HE-1, bind C2 domain of human Nedd4L and express along ASDN colocalized with Nedd4L. Additionally, in experiments using a model of salt-sensitive hypertension in Dahl rats, we provided evidence suggesting that transcriptional regulation and activation of NPC2 protein depends on sodium intake. NPC2 might regulate sodium reabsorption in the terminal nephron by interacting with ENaC-Nedd4L system.
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High expression of atypical protein kinase C lambda/iota in gastric cancer as a prognostic factor for recurrence.
Ann. Surg. Oncol.
PUBLISHED: 07-22-2009
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The atypical protein kinase C lambda/iota (aPKClambda/iota) is involved in several signal transduction pathways that influence cell growth, apoptosis, and the establishment and maintenance of epithelial cell polarity. Overexpression of aPKClambda/iota has been reported in several cancers and been shown to be associated with oncogenesis. However, the expression and role of aPKClambda/iota in gastric cancer, one of the commonest cancers in Asia, have not so far been investigated. This study aimed to clarify the relationship between aPKClambda/iota expression and the clinicopathological features of gastric cancer.
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III. Angiogenesis: complexity of tumor vasculature and microenvironment.
Curr. Pharm. Des.
PUBLISHED: 06-13-2009
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Vascular system plays critical roles in tumor progression and metastasis. Tumor vessels generally sprout from preexisting vascular cells. In addition, pluripotent progenitor cells also participate in tumor neovascularization. The latter populations include endothelial progenitor cells, hematopoietic stem cells and mesenchymal stem cells that are stimulated and attracted into the lesion. Recent studies on tumor microenvironment have disclosed that BM (bone marrow)-derived progenitor cells contain unique subpopulations that do not become fully-differentiated vascular constituents; instead, they show the nature of immature myeloid or mesenchymal lineage, and they enhance tumor angiogenic milieu in close contact with tumor vessels. BM-derived cells also migrate into pre-metastatic niche and stimulate vascular beds of distant organ for attracting circulating tumor cells. Currently, several antiangiogenic molecules are under clinical trials and they are expected to improve overall prognosis. Humanized monoclonal antibody bevacizumab specifically targeting VEGF (vascular endothelial growth factor), and several tyrosine kinase inhibitors targeting VEGF receptors-mediated pathways are the most widely studied agents in several types of advanced cancers. It is obvious that VEGF contributes to tumor neovascularization as a mastermind molecule. On the other hand, the mechanism has also been elucidated how tumors evade VEGF targeting therapies. To establish safer and more effective antiangiogenic therapies, it is important to understand the cross-communication between tumors and hosts in proinflammatory milieu. In this review, we discuss features of tumor angiogenic vessels and their microenvironment. Recent topics on the contribution of BM-derived cells, complexities of VEGF-targeting approaches, and chemoattractants that activate tumor vascular beds are summarized.
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Requirement for microtubule integrity in the SOCS1-mediated intracellular dynamics of HIV-1 Gag.
FEBS Lett.
PUBLISHED: 03-16-2009
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Suppressor of cytokine signaling 1 (SOCS1) is a recently identified host factor that positively regulates the intracellular trafficking and stability of HIV-1 Gag. We here examine the molecular mechanism by which SOCS1 regulates intercellular Gag trafficking and virus particle production. We find that SOCS1 colocalizes with Gag along the microtubule network and promotes microtubule stability. SOCS1 also increases the amount of Gag associated with microtubules. Both nocodazole treatment and the expression of the microtubule-destabilizing protein, stathmin, inhibit the enhancement of HIV-1 particle production by SOCS1. SOCS1 facilitates Gag ubiquitination and the co-expression of a dominant-negative ubiquitin significantly inhibits the association of Gag with microtubules. We thus propose that the microtubule network plays a role in SOCS1-mediated HIV-1 Gag transport and virus particle formation.
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Specificity of splenopancreatic field abnormality in trisomy 13 syndrome: macroscopic and histological analysis in 21 autopsy cases.
Pathol. Int.
PUBLISHED: 03-06-2009
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Splenopancreatic field abnormalities were carefully examined macroscopically and microscopically in 21 trisomy 13 (TR13) subjects, and the results were compared with those of non-TR13 control cases. Of the 21 TR13 subjects, 12 had intrapancreatic splenic tissue (IPST) and 17 had fusion of the pancreatic tail and splenic hilus and/or accessory spleen (FPS/FPAS). All 21 had IPST and/or FPS/FPAS. Five of 1060 controls (non-TR13) had IPST, while two had FPS/FPAS. On histology the pancreata of TR13 subjects had intralobular ducts, with goblet cells (ILDGC) and microcysts (MC) in 17 and 18 subjects, respectively. All 21 TR13 subjects had ILDGC and/or MC. Two of 360 age-matched controls (stillbirths and neonates) had ILDGC and nine had MC. IPST, FPS/FPAS, ILDGC, and MC were considered to be highly specific for TR13, and could therefore be useful in differentiating TR13 from other malformation diseases.
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Epithelioid angiomyolipoma of the kidney.
Pathol. Int.
PUBLISHED: 01-06-2009
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Epithelioid angiomyolipoma (eAMLoma) is an uncommon renal mesenchymal tumor with malignant potential and is frequently associated with tuberous sclerosis (TSC). It is composed of polygonal large-sized tumor cells arranged in an epithelioid manner. Differential diagnosis from renal cell carcinoma (RCC) is often challenging because of its epithelioid morphology. Herein is reported three cases of eAMLoma, involving one in a 28-year-old man with TSC and two in women without TSC (34 and 62 years of age, respectively). The male TSC patient had microscopic conventional AMLomas in the same kidney. All patients were positive for melanoma (reactive with HMB45 antibody, and positive for melan A, tyrosinase and microphthalmia transcription factor) and smooth muscle markers (positive for alpha-smooth muscle-specific actin), but not for epithelial markers (cytokeratin, epithelial membrane antigen). In particular, the translocation RCC is an important differential diagnostic candidate, in terms of the positive reaction with HMB45 and morphological similarity. The present tumor samples did not show any reactivity for transcription factor binding to IGHM enhancer 3 or transcription factor EB, which excluded the possibility of translocation RCC. The possibility of eAMLoma should be evaluated as a diagnostic candidate, especially in cases of renal tumors (i) in young patients; (ii) associated with TSC; or (iii) with an epithelioid morphology and a high nuclear grade.
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Akt1 promotes focal adhesion disassembly and cell motility through phosphorylation of FAK in growth factor-stimulated cells.
J. Cell. Sci.
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The crosstalk between spatial adhesion signals and temporal soluble signals is key in regulating cellular responses such as cell migration. Here we show that soluble growth factors enhance integrin signaling through Akt phosphorylation of FAK at Ser695 and Thr700. PDGF treatment or overexpression of active Akt1 in fibroblasts increased autophosphorylation of FAK at Tyr397, an essential event for integrin turnover and cell migration. Phosphorylation-defective mutants of FAK (S695A and T700A) underwent autophosphorylation at Tyr397 and promoted cell migration in response to the integrin ligand fibronectin, but importantly, not in response to PDGF. This study has unveiled a novel function of Akt as an ignition kinase of FAK in growth factor signaling and may shed light on the mechanism by which growth factors regulate integrin signaling.
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Identification of miR-30d as a novel prognostic maker of prostate cancer.
Oncotarget
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Prostate cancer (PCa) is the most common malignant carcinoma that develops in men in Western countries. MicroRNA (miRNA) have the potential to be used as biomarkers and therapeutic targets for the treatment of various cancers. We found significantly higher expression of miR-30d in 3 PCa cell lines (PC3, DU145 and LNCaP) compared with 2 normal prostate cell lines (RWPE-1 and PrSc) using miRNA microarrays and qPCR. Clinicopathological study revealed that miR-30d expression levels were significantly higher in cancer tissue samples than in the paired normal controls (P = 0.03). Furthermore, the miR-30d-high group had shorter time to biochemical recurrence (P = 0.026). MiR-30d overexpressed PCa cells promoted proliferation and invasion in vitro. Inoculation of miR-30d depleted PCa cells dramatically reduced tumor volumes in vivo. Using reporter gene assay, we identified miR-30d as a downregulator of SOCS1 expression by directly binding to 3-UTR of SOCS1. MiR-30d regulated the expression of phospho-STAT3, MMP-2 and MMP-9 through the downregulation of SOCS1. The levels of SOCS1 mRNA and protein were significantly down-regulated in prostate cancer tissues. Consistently, miR-30d expression was inversely correlated with SOCS1 expression (P = 0.03). The miR-30d-high/SOCS1-low group was associated with an increased risk of early biochemical recurrence (P = 0.0057). Taken together, miR-30d appears to be a novel independent prognostic marker of PCa progression that allows clinicians to identify patients who need more intensive treatments.
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Impaired CXCL4 expression in tumor-associated macrophages (TAMs) of ovarian cancers arising in endometriosis.
Cancer Biol. Ther.
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Inflammatory cells play important roles in progression of solid neoplasms including ovarian cancers. Tumor-associated macrophages (TAMs) contribute to angiogenesis and immune suppression by modulating microenvironment. Ovarian cancer develops occasionally on the bases of endometriosis, a chronic inflammatory disease. We have recently demonstrated differential expressions of CXCR3 variants in endometriosis and ovarian cancers. In this study, we showed impaired CXCL4 expression in TAMs of ovarian cancers arising in endometriosis. The expressions of CXCL4 and its variant CXCL4L1 were investigated among normal ovaries (n = 26), endometriosis (n = 18) and endometriosis-associated ovarian cancers (EAOCs) composed of clear cell (n = 13) and endometrioid (n = 11) types. In addition, four cases of EAOCs that contained both benign and cancer lesions contiguously in single cysts were investigated in the study. Western blot and quantitative RT-PCR analyses revealed significant downregulation of CXCL4 and CXCL4L1 in EAOCs compared with those in endometriosis. In all EAOCs coexisting with endometriosis in the single cyst, the expression levels of CXCL4 and CXCL4L1 were significantly lower in cancer lesions than in corresponding endometriosis. Histopathological study revealed that CXCL4 was strongly expressed in CD68 (+) infiltrating macrophages of endometriosis. In microscopically transitional zone between endometriosis and EAOC, CD68 (+) macrophages often demonstrated CXCL4 (-) pattern. The majority of CD68 (+) TAMs in overt cancer lesions were negative for CXCL4. Collective data indicate that that CXCL4 insufficiency may be involved in specific inflammatory microenvironment of ovarian cancers arising in endometriosis. Suppression of CXCL4 in cancer lesions is likely to be attributable to TAMs in part.
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Expression of angiotensin II receptor-like 1 in the placentas of pregnancy-induced hypertension.
Int. J. Gynecol. Pathol.
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Angiotensin II receptor-like 1 (APJ), a G protein-coupled receptor that was identified as a homologue of angiotensin II type 1 (AT1) receptor, exerts antagonistic effects on AT1-mediated vasoconstriction. Studies on pregnancy-induced hypertension (PIH) revealed aberrant activation of AT1 downstream signaling. In contrast, little is known about APJ in the pathophysiology of human pregnancy. In this study, we investigated APJ expression in normal human and PIH placentas. mRNAs were extracted from 50 placental villous tissues of 18 cases with severe PIH (8 late-onset, 4 early-onset, and 6 superimposed PIH) and 32 control pregnancies (including 6 preterm cases). Histopathologic studies were conducted using paraffin-embedded placental tissues from 12 control placentas (from 23 to 39 wk) and 23 PIH placentas (from 24 to 41 wk). Reverse transcriptase-polymerase chain reaction showed that APJ was cooperatively expressed with its ligand apelin and AT1 in controls and in late-onset PIH placentas but was significantly downregulated in early-onset PIH placentas with poor fetal growth. Quantitative reverse transcriptase-polymerase chain reaction analysis revealed upregulated APJ in late-onset PIH placentas but significantly downregulated APJ in early-onset PIH. In immunohistochemical staining, APJ was detected strongly in villous capillary endothelial cells and trophoblasts of late-onset PIH placentas. In contrast, APJ was poorly stained in endothelial cells of hypoplastic villi of early-onset PIH placentas. Collective data indicate that the apelin-APJ system is involved in fetoplacental circulation during human pregnancy. Impaired APJ expression in early-onset PIH placentas may reflect an aggravated placental condition with poor fetal growth.
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Differences of molecular expression mechanisms among neural cell adhesion molecule 1, synaptophysin, and chromogranin A in lung cancer cells.
Pathol. Int.
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Neural cell adhesion molecule 1 (NCAM1), synaptophysin (SYPT), and chromogranin A (CGA) are immunohistochemical markers for diagnosing lung neuroendocrine tumors (LNETs). However, the precise expression mechanisms have not been studied in enough detail. The purpose of the present study is to define the molecular mechanisms of NCAM1, SYPT, and CGA gene expressions, using cultivated lung cancer cells and focusing upon NeuroD1 (ND1), achaete-scute homolog-like 1 (ASCL1), and known transcription factors, repressor element 1 (RE1)-silencing transcription factor (REST) and c-AMP responsive element-binding protein (CREB). Promoter assays, chromatin immunoprecipitation, and transfection experiments revealed that ND1 activated NCAM1, that ASCL1 weakly upregulated SYPT expression, and that CGA expression was not regulated by ND1 or ASCL1. REST expression was restricted in non-small cell lung cancer (NSCLC) cells, and knockdown of REST could cause as much SYPT expression as in SCLC cells and weak CGA expression in NSCLC cells. However, CGA gene upregulation via CREB activation was not found in REST-lacking NSCLC cells, indicating the requirement of some additional mechanism for sufficient expression. These results suggest that NCAM1, SYPT and CGA expressions are differently regulated by neuroendocrine phenotype-specific transcription factors and provide a reason why NCAM1 and SYPT are frequently expressed in LNETs, irrespective of malignancy grade.
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Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families.
Am. J. Surg. Pathol.
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Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by fibrofolliculomas, renal tumors, and pulmonary cysts with recurrent pneumothorax. Multiple pulmonary cysts and pneumothorax are the key signs for diagnosing BHD syndrome. The pathologic features of BHD pulmonary cysts, however, are poorly understood. This disorder is caused by mutations in the gene that encodes folliculin (FLCN). FLCN is regarded as a tumor suppressor; it mediates cellular activities by interacting with the mammalian target of rapamycin (mTOR). In this study, we investigated the lungs of 11 patients from 9 BHD families. The majority of patients consulting doctors were women between 30 and 60 years of age who had pulmonary cysts and repeated pneumothoraces. Genomic DNA testing revealed 5 different mutation patterns. Histopathologic examination found that the inner surface of cysts was lined by epithelial cells, sometimes with a predominance of type II pneumocyte-like cuboidal cells. The cysts occasionally contained internal septa consisting of alveolar walls or showed an "alveoli within an alveolus" pattern. The cells constituting the cysts stained positive for phospho-S6 ribosomal protein expression, suggesting activation of the mTOR pathway. Although BHD pulmonary cysts are frequently misdiagnosed as nonspecific cystic diseases, they are distinctly different in histopathology from other bullous changes. Mechanical stress such as rupture and postrupture remodeling allows mesothelial invagination and fibrosis. Such modified BHD pulmonary cysts are virtually indistinguishable from nonspecific blebs and bullae. We propose a new insight, namely, that the BHD syndrome-associated pulmonary cyst may be considered a hamartoma-like cystic alveolar formation associated with deranged mTOR signaling.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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