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Results for “Tissue Array Analysis”

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PubMed2005

Application of novel tissue microarrays to investigate expression of tryptase, chymase and KIT protein in placental mast cells.

INTRODUCTION: Tissue microarrays comprise numerous small representative tissue samples from hundreds of different cases assembled on a single histologic slide, and therefore allow high throughput analysis of multiple specimens at the same time. Mast cells are paracrine cells found ubiquitously in connective tissue. Expression of the serine proteases tryptase and chymase, as well as KIT protein, the receptor for stem cell factor (SCF), has been demonstrated in mast cells. Because little is known about the role of mast cells in the placenta, we investigated the number and expression of chymase, tryptase, and KIT protein in placental mast cells using newly developed tissue microarrays. MATERIALS AND METHODS: Tissue microarrays were prepared from archival paraffin tissue blocks of 90 placentae, including 15 normal ones as a control group. Gestational age of the placentae ranged from 7 to 42 weeks. Sections of formalin-fixed paraffin-embedded material were prepared on chemically activated cover-slides. The slides were cut in 4-mm(2) squares containing representative areas, and transferred to a tissue microarray. Hematoxylin and eosin (H&E), chloroacetate esterase (CAE), toluidine blue, periodic acid--Schiff (PAS), and immunohistochemical staining were performed. The number of mast cells and expression of chymase, tryptase, and KIT protein were evaluated in each case. RESULTS: Mast cell numbers in placentae with inflammation/abortion exceeded that of normal placentae. Although statistically not significant, we furthermore observed an increase in chymase-positive mast cells in the group of placentae associated with fetal malformations/chromosomal aberrations compared with normal placentae. DISCUSSION: Novel tissue microarray technique has been introduced into placental research, and allows multiple placental tissue samples to be effectively analyzed simultaneously. This study indicated an increased number of chymase-positive mast cells in placentae with fetal malformation/chromosomal aberration. Activation of angiotensin II by chymase may play a role in fetal malformation. Moreover, it has been speculated that mast cells may only express chymase (MC(C)). Our findings denote the presence of placental MC(C). However, further studies are needed to elucidate more precisely the role of mast cell chymase in the placenta.

Adult↗

PubMedDate not supplied

IL-6, IL-10 and HSP-90 expression in tissue microarrays from human prostate cancer assessed by computer-assisted image analysis.

The interleukins (IL)-6 and -10 and heat shock proteins (HSP) have an important role in the host-tumor interaction and in tumor bulk. HSP-90 may have a regulatory role in cytokine biosynthesis and prognostic value in some tumors. To define the role of IL-6, IL-10 and HSP-90 in prostate cancer progression the immunohistochemical expressions of these proteins were analyzed in 168 prostatic carcinomas. IL-6, IL-10 and HSP-90 immunoreactivity was higher in prostatic carcinoma (CaP) and intra-epithelial prostatic neoplasia (PIN) than in normal prostatic tissue (NAP) adjacent to neoplasia. In the epithelium, IL-6, IL-10 and HSP-90 expressions increased from NAP to PIN to CaP. In the stroma, IL-6 and IL-10 expressions decreased significantly from NAP to PIN to CaP (p < 0.01 by Chi-square test), while HSP-90 expression increased. In the epithelium of PIN and CaP, IL-6 immunoreactivity was significantly lower than IL-10 and HSP-90. In neoplastic acini HSP-90 levels were significantly higher than those of IL-6 and IL-10 (p < 0.01 by Chi-square test). In the stroma of NAP and PIN, but not of CaP, HSP-90 immunoreactivity was significantly lower than that of IL-6 and IL-10 (p < 0.01). Our results indicate that the IL-6 and IL-10 cytokine balance differs in pathological and normal prostate, thus suggesting that certain cytokines are specific to the neoplastic prostate. Changes in the expressions of IL-6, IL-10 and HSP-90 in human prostate carcinoma samples could be used as a prognostic marker of disease progression.

Adenocarcinoma↗

PubMed2006

Expression profiling of transcription factors Pax-5, Oct-1, Oct-2, BOB.1, and PU.1 in Hodgkin's and non-Hodgkin's lymphomas: a comparative study using high throughput tissue microarrays.

Analysis of B-cell-specific transcription factors is useful in understanding of the differentiation-linked phenotype in Hodgkin's as well as in non-Hodgkin's lymphomas. We analyzed the expression profiling of transcription factors Pax-5, Oct-1, Oct-2, BOB.1, and PU.1 in 109 cases, including non-Hodgkin's lymphomas of B- and T-lineage, classical Hodgkin's lymphomas, and nodular lymphocyte predominant Hodgkin's lymphomas. Our study revealed that all transcription factors were universally expressed in all cases of nodular lymphocyte predominant Hodgkin's and variably expressed in non-Hodgkin's lymphomas of B-lineage. Cases of classical Hodgkin's lymphoma variably expressed the Pax-5, Oct-1, Oct-2, and BOB.1. However, in contrast to nodular lymphocyte predominant Hodgkin's lymphoma, the transcription factor PU.1 was consistently absent in all cases of classical Hodgkin's lymphoma. Transcription factors Pax-5, BOB.1, and PU.1 were not detectable in cases of anaplastic large cell lymphoma. However, the Oct-1 was detected in all anaplastic large cells lymphoma cases, indicating that expression of this transcription factor was not restricted to B-lineage lymphoid malignancies. Our findings suggest that inclusion of the PU.1 antibody may prove useful in separating classical Hodgkin's lymphomas from nodular lymphocyte predominant Hodgkin's lymphomas in problematic cases.

Diagnosis, Differential↗

PubMed2006

High throughput tissue microarray analysis of FHIT expression in diffuse large cell B-cell lymphoma from Saudi Arabia.

Recent studies have suggested a potential prognostic role of alterations of the fragile histidine triad (FHIT) gene in diffuse large B-cell lymphoma. To evaluate possible mechanisms of FHIT inactivation and to further clarify its potential prognostic relevance, we analyzed a set of 114 diffuse large B-cell lymphoma with clinical follow-up information. Tissue microarrays were analyzed by immunohistochemistry for protein expression, and corresponding DNA samples were analyzed for FHIT promotor hypermethlyation. Reduced or absent FHIT expression was found in 75 of 114 diffuse large B-cell lymphoma (66%), but was unrelated to clinical tumor stage or patient prognosis. FHIT promotor hypermethylation was observed in 29 of 93 (23%) interpretable diffuse large B-cell lymphoma. Hypermethylation was not significantly correlated to protein expression loss, which could be explained by competing mechanisms for FHIT inactivation in a substantial fraction of non FHIT hypermethylated diffuse large B-cell lymphoma. Hypermethylation was significantly associated with poor prognosis of diffuse large B-cell lymphoma patients and predominantly seen in nongerminal center diffuse large B-cell lymphoma (27%), but less frequent (13%) in germinal center diffuse large B-cell lymphoma. In summary, these data suggest that promotor hypermethylation is responsible for reduced FHIT expression in a substantial subset of diffuse large B-cell lymphoma, which is primarily composed of nongerminal center subtype with poor patient prognosis.

Acid Anhydride Hydrolases↗

PubMed2006

M-CAM expression as marker of poor prognosis in epithelial ovarian cancer.

Currently available clinico-pathologic criteria provide an imperfect assessment of outcome for patients with advanced epithelial ovarian cancer (EOC). Identification of prognostic factors related to tumor biology might improve this assessment. We investigated the prognostic significance of the melanoma cell adhesion molecule (M-CAM) in EOC. Using the same antibody, M-CAM expression was tested by Western blotting in protein extracts and by immunohistochemestry in tissue microarrays generated from 133 consecutively resected, well characterized EOC samples. Fisher test, Kaplan-Meier method and Cox proportional hazards analysis were used to relate M-CAM expression to clinico-pathological variables and to time to progression (TTP) and overall survival (OS). In vitro biochemical analysis showed a progressively increased M-CAM expression from normal to malignant cells. M-CAM protein, detected immunohistochemically, was significantly associated with advanced tumor stage, serous and undifferentiated histotype, extent of residual disease and p53 accumulation. Presence or absence of M-CAM significantly divided patients according to their TTP (median, 22 vs. 79 months, respectively; log-rank p = 0.001) and OS (median, 42 vs. 131 months, respectively; log-rank p = 0.0003). In the subgroup of advanced stage patients who achieved complete response after front-line treatment, M-CAM expression and absence of residual disease were significantly associated with shorter TTP (p = 0.003, HR 5.25, 95% Cl 1.79-15.41 and p = 0.011, HR 3.77, 95% Cl 1.36-10.49 respectively) at the multivariate level. In the same sub-group of patients, M-CAM expression remained the only parameter significantly associated with OS (p = 0.005, HR 3.35, 95% Cl 1.42-6.88). M-CAM is a marker of early relapse and poorer outcome in EOC. In particular, M-CAM expression identifies a subgroup of front-line therapy-responding patients who undergo dramatic relapses, thus helping to better select patients who might benefit from new/alternative therapeutic modalities.

Adult↗

PubMed2005

Immunohistochemical analysis of PTEN in endometrial carcinoma: a tissue microarray study with a comparison of four commercial antibodies in correlation with molecular abnormalities.

The tumor suppressor gene PTEN/MMAC1 is located on chromosome 10q23.3. Inactivation of PTEN, either by mutations, deletions, or promoter hypermethylation, has been identified in a wide variety of tumors. Inactivation of the two alleles of PTEN is required, because it is a tumor suppressor gene. Immunohistochemical staining may be an effective screening method to demonstrate the absence of the protein in tumors exhibiting PTEN inactivation. We studied a tissue microarray, constructed from paraffin-embedded blocks of 95 endometrial carcinomas, 38 of them previously evaluated for alterations in PTEN. We also studied cell blocks obtained from one PTEN-defective endometrial cancer cell line, after transfection with either a plasmid encoding wild-type PTEN or the empty vector. The tumor samples were tested with four different anti-PTEN commercial antibodies: a polyclonal antibody, the monoclonal antibody 28H6, the monoclonal antibody 10P03, and the monoclonal antibody 6.H2.1. Results were correlated with the presence of abnormalities in PTEN, as well as with the immunohistochemical expression of phosphorylated AKT. Antibody 28H6 produced a predominant nuclear staining, while the other three antibodies produced a predominant cytoplasmic staining. There was no significant correlation between the results obtained with the four antibodies. The monoclonal antibody 6.H2.1 was the only one that exhibited a correlation with the presence of molecular alterations in PTEN, and a statistically significant association with immunostaining for phosphorylated AKT (r=-0.249, P=0.037). The monoclonal antibody 10P03 exhibited an association with phospho-AKT that did not have statistical significance. Both 6.H2.1 and 10P03 antibodies stained PTEN-transfected cells, and were negative in the PTEN-deficient cell line blocks. The polyclonal antibody and the monoclonal antibody 28H6 produced positive staining in PTEN-deficient cell line blocks, suggesting nonspecific staining. The results indicate that monoclonal antibody 6.H2.1 may be a suitable alternative for tumors with inactivation of PTEN.

Antibodies, Monoclonal↗

PubMed2006

Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays.

In spite of the known function of polycomb group (PcG) genes in stem cell self-renewal, control of cellular proliferation and differentiation, its role in cancer pathogenesis is still poorly understood. We studied the expression by immunohistochemistry of several PcG-maintenance complex proteins (RING1, RNF2, BMI1, MEL18, HPH1 and RYBP) in nontumoral (154 samples) and tumoral (550 samples) human tissues using Tissue Microarrays. For selected genes (BMI1 and RING1) FISH analysis has been also carried out. PcG proteins had a tissue- and cell-type-specific expression pattern. Some of them were highly selectively expressed, such as HPH1, which was detected in germ cells in testis, pituitary and parathyroid glands and Langerhans islets, and RYBP, which was found in placenta, umbilical cord and thyroid gland. By contrast, RING1 was ubiquitously expressed in every normal tissue analyzed. Changes in expression associated with tumoral transformation have been found for BMI1 and RNF2, which exhibited increased expression in a large series of tumors, including gastrointestinal tumors, pituitary and parathyroid adenomas, and lymphomas, compared with their expression in normal-cell counterparts. The high level of expression of BMI1 protein observed in mantle-cell lymphomas and pituitary adenomas is associated in some cases with amplification of BMI1 locus. These findings imply that upregulation of BMI1 may constitute a malignancy marker in different types of cancer, mainly in lymphoid and endocrine tumors. RING1 was lost in a group of renal-cell carcinomas and testicular germ-cell tumors. Lastly, RYBP is anomalously expressed in Hodgkin's lymphomas and oligodendrogliomas, among others tumors. A significant finding of the study is the identification of unique PcG profiles for some tumors, such as testicular germ-cell tumors, which have high levels of HPH1 expression and loss of RING1 and/or BMI1; pituitary adenomas, which expressed every PcG protein analyzed; and clear-cell renal-cell carcinoma, which was the only tumor other than testicular germ-cell tumors that did not express RING1.

Carrier Proteins↗

PubMed2006

Proteomic analysis of mitochondria-to-nucleus retrograde response in human cancer.

All tumors examined to date contain mutations in mitochondrial DNA (mtDNA). In addition, depletion of mtDNA is reported in a variety of tumors. Mitochondrial dysfunction resulting from changes in mtDNA invokes mitochondria-to-nucleus retrograde response in human cells. To identify proteins involved in retrograde response and their potential role in tumorigenesis, we carried out a comparative proteomic analysis using a cell line in which the mitochondrial genome was completely depleted (rho(0) cells lacking all mtDNA-encoded protein subunits), a cybrid cell line in which mtDNA was restored, and the parental cell line. Our comparative proteomic approach revealed marked changes in the cellular proteome and led us to identify quantitative changes in expression of several proteins. We found that subunits of complex I and complex III, molecular chaperones, and a protein involved in cell cycle control were downregulated and Inosine 5'-monophosphate dehydrogenase type 2 (IMPDH2) involved in nucleotide biosynthesis was upregulated in rho(0) cells. Our findings demonstrate that the expression of proteins is restored to wild type level by transfer of wild type mitochondria to rho(0) cells, suggesting that these proteins play key roles in retrograde response. To determine a potential role for identified retrograde responsive proteins in tumorigenesis, we analyzed the expression of UQCRC1 gene (encoding ubiquinol cytochrome-c reductase core protein I) in breast and ovarian tumors. We found that (1) UQCRC1 was highly expressed in breast (74%) and ovarian tumors (34%) and (2) the expression positively correlated with cytochrome c-oxidase (COXII) encoded by mtDNA. Our study opens an avenue for identification of retrograde proteins as potential tumor suppressors or oncogenes involved in carcinogenesis.

Adenocarcinoma↗

PubMed2005

Loss of maspin is a helpful prognosticator in colorectal cancer: a tissue microarray analysis.

Mammary serpin (Maspin) belongs to the serine protease inhibitor (serpin) superfamily and has been identified as a tumor suppressor. In addition, a p53-dependent regulatory pathway of maspin in human cancer has been indicated. The role of maspin in the tumorigenesis and progression of colorectal cancer is still unclear. Therefore, the first aim of the present study was to determine the prognostic value of maspin protein expression for the recurrence-free and overall survival of patients with colorectal carcinoma undergoing left- or right-sided colectomy. Secondly, maspin expression was correlated with p53 protein expression to gain additional information about a possible regulatory influence of the wild-type p53 protein on maspin; it was also correlated with further patient and tumor characteristics (age, sex, TNM, disease stage, tumor localization, and grading). An immunohistochemical study was performed on 280 carcinoma specimens using the tissue microarray technique. In addition, 80 colorectal adenomas and 60 tumor-free tissues were investigated. Maspin protein expression was detectable in 88-100% of the adenomas and non-tumorous tissues and in 193 out of 280 carcinoma patients (69%; maspin-positive). After a median follow-up of 102 months (23-140 months), the median recurrence-free survival was 80 months for maspin-positive cases (M +) and 42 months for maspin-negative cases (M-) (p = 0.02). The median long-term survival was 98 months for M + and 57 months for M- (p = 0.03). After 5 years, M + and M- patients had a total survival of 69% and 38%, and, after 10 years, 45% and 9%, respectively. Mutant type p53 expression was detectable in 178 colorectal carcinomas (64%). Mt p53 was positive in 91 out of 193 M + (47%) compared with 87 of 87 M- (100%, p<0.001). This study showed that loss of maspin protein correlates with p53 protein activity, with a higher likelihood for the development of tumor relapse, and with a decreased recurrence-free and overall survival in colorectal carcinomas. The determination of the immunohistochemical expression status of maspin might be a helpful independent prognosticator and an applicable tool for the development of therapeutic strategies for patients with this disease.

Adenocarcinoma↗

PubMed2005

Chromogenic in situ hybridization-detected hotspot MYCN amplification associates with Ki-67 expression and inversely with nestin expression in neuroblastomas.

Since neuroblastomas are intratumorally heterogeneous, the analysis of genetic and biologic features of randomly selected tumor specimen spots may lead to erroneous conclusions. Our purpose was therefore to construct an easily assessable and strictly defined strategy to unify the detection of various molecular markers in paraffin-embedded neuroblastoma samples. We selected tumor specimen spots of highest proliferation activity, that is, hotspots, for the analysis of MYCN amplification status and proliferation-associated molecular markers, such as nestin, which role in neuroblastoma specimens was evaluated for the first time. Using a chromogenic in situ hybridization (CISH) technique, we showed that patients with a MYCN copy number higher than six in anti-Ki-67-detected hotspots have significantly worse overall survival prognosis than patients with low MYCN copy numbers (P = 0.0006). The chosen cutoff value of six was shown to dichotomize MYCN-amplified neuroblastomas at least as specifically as Southern blot hybridization, in which amplification was defined by a copy number of > or = 10. Interestingly, we also detected without difficulty MYCN-amplified neuroblastic cells in bone marrow samples using the CISH technique. The proliferation activity, assessed with an anti-Ki-67-based proliferation index, was significantly higher in MYCN-amplified than in nonamplified hotspots. The proliferation indices of the hotspots had also a significant correlation with the prognosis (International Classification) and histological type, whereas the proliferation accelerator Id2 did not associate with any of the mentioned parameters. The expression of nestin associated inversely with MYCN amplification (P = 0.018), which challenges a previously suggested role of nestin in neuroblastomas. In summary, hotspot focusing provides a means of analyzing proliferation-associated markers in neuroblastomas, and together with the CISH detection of the MYCN copy number enables an easy and reliable examination of MYCN status in neuroblastomas.

Antibodies, Antinuclear↗

PubMed2006

[Quantitative study of thyroid transcription factor-1 protein expression in lung carcinoma cell nucleus by tissue microarray].

OBJECTIVE: To investigate thyroid transcription factor-1 (TTF-1) expression in normal human adult type II alveolar epithelial cells, embryonic pneumocytes, lung carcinoma cells and lymph node metastases of lung cancer. METHODS: Lung carcinoma tissue microarray was constructed containing 765 cores of 20 normal adult lung tissues, 15 embryonic lung tissues, 100 lung carcinomas and 55 corresponding lymph node metastases. TTF-1 protein expression on the microarray was detected by immunohistochemical SP method using TTF-1 monoclonal antibody and assessed quantitatively with Leica Q500MC image analysis system. RESULTS: The number TTF-1 positive units (PU) was smaller in the nuclei of embryonic pneumocytes than in those of normal adult type II alveolar epithelial cells (P<0.001). The nuclei of lung carcinoma cells had smaller TTF-1 PU than normal adult type II alveolar epithelial cells and embryonic pneumocyte nuclei (P<0.001). The lung adenocarcinoma and small cell lung carcinoma cell nuclei had greater TTF-1 PU than squamous cell carcinoma and large cell lung carcinoma cell nuclei (P<0.001). TTF-1 PU was greater in squamous cell carcinoma cell nuclei than in large cell lung carcinoma cell nuclei (P<0.001). In lung adenocarcinoma, squamous cell lung carcinoma and large cell lung carcinoma, TTF-1 PU was greater in the cancerous cell nuclei of lymph node metastases than in the corresponding primary carcinoma cell nuclei (P<0.001, P<0.001, and P<0.05, respectively). In small cell lung carcinoma, TTF-1 PU of the cancerous cell nuclei of lymph node metastases was similar to that of primary carcinomas (P>0.05). TTF-1 PU was greater in lung carcinoma with lymph node metastases than in those without metastalsis (P<0.001). TTF-1 PU of the cell nuclei was not associated with the tumor growth pattern, differentiation and patients' gender (P>0.05), but was greater in TNM stage II-IV than in stage I (P<0.001). CONCLUSIONS: The amount of TTF-1 in the cell nuclei decreases in the order of normal adult type II alveolar epithelial cells, embryonic pneumocytes and lung carcinoma cells. TTF-1 expression is higher in adenocarcinoma and small cell carcinoma and lower in squamous carcinoma and large cell carcinoma. Stronger TTF-1 expression is associated with greater likeliness of lung carcinoma metastatie, and can be an important hallmark for metastasis potential of lung adenocarcinoma, squamous cell carcinoma and large cell carcinoma.

Adenocarcinoma↗

PubMed2004

Overexpression of G1-S cyclins and cyclin-dependent kinases during multistage human pancreatic duct cell carcinogenesis.

PURPOSE: Molecular analysis of pancreatic intraepithelial neoplasia lesions and ductal adenocarcinoma suggested a multistage paradigm for pancreatic duct cell carcinogenesis. This study investigated the molecular basis for the neoplastic duct cells in this pancreatic intraepithelial neoplasia-carcinoma sequence to acquire progressive enhancement of their proliferative potential. EXPERIMENTAL DESIGN: Using tissue microarray blocks containing 15 to 40 pancreatic intraepithelial neoplasia lesions and ductal adenocarcinoma of pancreas, we studied by immunohistochemistry the expression profiles of cyclins and cyclin dependent kinases (CDKs) that regulate the G1-S cell cycle checkpoints. The role of cyclins D3 and D1 in three pancreatic cancer cell lines was investigated using specific short interfering RNA technique. RESULTS: Cyclin D3 overexpression was noted the earliest in pancreatic intraepithelial neoplasia-1A and was prevalent in 90% to 100% of high-grade pancreatic intraepithelial neoplasias and ductal cancer. Cyclin A overexpression was also noted early and reached 50% to 100% of high-grade pancreatic intraepithelial neoplasias and cancer, but the percentage of abnormal duct cells showing overexpression of cyclin A was significantly lower than cyclin D3. Cyclin E overexpression occurred in 20% to 25% of high-grade pancreatic intraepithelial neoplasias and in 75% of ductal carcinoma. Cyclin D1 demonstrated the lowest frequency of overexpression that occurred late. CDK2 and CDK4 overexpression was also noted in early pancreatic intraepithelial neoplasias and progressively increased to reach 60% to 75% in carcinoma. The down-regulation of cyclin D3 mRNA and protein levels using specific short interfering RNA resulted in growth inhibition of pancreatic cancer cell lines. CONCLUSION: The results provide additional insight into the mechanism of G1-S cell cycle checkpoints deregulation during stepwise pancreatic duct cell carcinogenesis, and suggest a p16-independent role for cyclin D3 in deregulating the G1 cell cycle checkpoints during early stages of pancreatic duct cell carcinogenesis.

Blotting, Western↗

PubMed2006

Differential expression of claudin 1, 3, and 4 during normal mammary gland development in the mouse.

The claudins are a family of tight junction proteins that display varied tissue distribution and preferential specificity. We recently identified by microarray analysis, members of this family, particularly claudin 1 (cldn1), as highly upregulated genes in the mouse mammary gland during early involution. Gene expression was confirmed by immunohistochemistry and real-time PCR. We then examined gene and protein expression throughout normal mammary gland development. The cldn3 gene showed a steady increase in expression from pregnancy to involution, while cldn1 and cldn4 gene expression increased during pregnancy, but decreased sharply by D10 of lactation, and once again was significantly increased by D1 of involution (P < 0.001 for both genes). The different patterns of gene expression observed between cldn3, and cldn1, and 4 suggest that different family members may be functionally important at different times during mouse mammary gland development. All three genes exhibited a high level of expression at day 1 (D1) of involution, followed by a dramatic decrease in gene expression to day 10 of involution. Immunostaining with the cldn3 antibody showed intense staining of epithelial cells; however, a lesser degree of staining was evident with the cldn1 antibody. In addition to the lateral staining of epithelial cells, basal staining was evident at D1 and D2 of involution and cytoplasmic staining was evident during lactation. Since claudins are known to play a role as tight junction proteins, lateral and basal staining may suggest a role in other functions such as vesicle trafficking or remodeling of tight junctions at different stages of mammary gland development. Cldn1 and 3 antibodies also stained epithelial cells in mouse mammary tumors. In summary, cldn1, 3, and 4 are differentially expressed in the mammary gland during pregnancy, lactation, and involution, suggesting different roles for these proteins at different stages of mammary gland function. In addition, cldn1 and cldn3 are detected in mammary tumors and the wide distribution of cldn3 in particular, suggest specific roles for these proteins in mammary tumorigenesis.

Animals↗

PubMed2006

Co-overexpression of fibroblast growth factor 3 and epidermal growth factor receptor is correlated with the development of nonsmall cell lung carcinoma.

BACKGROUND: Lung cancer is a prevalent cancer with a poor prognosis. To develop a useful in vitro cell model, a cell line of lung squamous cell carcinoma (SCC-35) was established. METHODS: The SCC-35 cell was characterized by comparative genomic hybridization (CGH) and spectral karyotyping (SKY). Chromosome microdissection, fluorescence in situ hybridization (FISH), and Southern and Northern blots analyses were used to study target genes. RESULTS: Two amplicons were found at chromosomes 7p12 and 11q13. Amplification and overexpression of epidermal growth factor receptor (EGFR) at 7p12 and fibroblast growth factor 3 (FGF3) at 11q13 were found. To understand the correlation between these two genes in nonsmall cell lung carcinoma (NSCLC) more comprehensively, overexpression of FGF3 and EGFR was investigated by immunohistochemistry with a tissue microarray containing 406 NSCLC samples. Cytoplasmic overexpression of FGF3 and EGFR was detected in 61% and 69% NSCLC cases, respectively. More interestingly, a significant correlation between overexpression of FGF3 and EGFR was found in NSCLC. CONCLUSION: These results suggest that co-overexpression of FGF3 and EGFR may play an important role in the pathogenesis of lung carcinoma.

Carcinoma, Non-Small-Cell Lung↗

PubMed2007

Annexin-I as a potential target for green tea extract induced actin remodeling.

Using a multistep human urothelial model, we previously showed that green tea extract (GTE) selectively modulates actin remodeling in transformed cells (MC-T11), which resulted in increased cell adhesion and reduced cell motility (Lu et al., Clin Cancer Res 2005;11:1675-83). This study further analyzed which actin binding proteins (ABPs) might be involved in this process. Proteomic profiles of GTE treated and untreated MC-T11 cells using two-dimensional gel electrophoresis coupled with liquid chromatography tandem mass spectrometry (LC/MS/MS) and matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) identified 20 GTE-induced proteins. Among them, 3 were ABPs (tropomodulin, cofilin and annexin-I), and only annexin-I showed a dose- and time-dependent expression. The increased annexin-I correlated with actin remodeling, and was the result of transcription level up-regulation, as determined by RT-PCR, pull-down immunoblot and siRNA analyses. 5-Azacytidine, a DNA methylation inhibitor, exhibited no effect on annexin-I expression when used alone, but had an additive effect for GTE-induced annexin-I expression. Immunohistochemistry of bladder cancer tissue array showed a decrease of annexin-I expression in carcinoma in situ and low grade papillary carcinoma (n = 32, 0% positive) compared to nontumor urothelium (n = 18, 89% positive) (p < 0.001 by Fisher exact test), but increased in some (6 of 15, 40%) high-grade tumors. Together, GTE induced annexin-I expression plays a role in regulating actin remodeling and decreased annexin-I expression is a common event in early stage of bladder cancer development.

Actins↗

PubMed2007

HPV integration begins in the tonsillar crypt and leads to the alteration of p16, EGFR and c-myc during tumor formation.

The prevalence of human papillomavirus (HPV) infection is high in the oropharyngeal mucosal regions, of which the tonsil is the most commonly affected. There may be a link between HPV and the pathogenesis of tonsillar cancer (TC), because of common anatomical characteristics between cervical and tonsillar cancer. We aimed to clarify whether HPV directly affects the oncogenesis and biologic behavior of TC by making a comparison between infection prevalence, physical status and viral loading numbers, and clinicopathologic prognostic factors. To compare HPV-related molecules between TC and tonsillitis (CFT), p16, survivin, HIF-1alpha, skp-1, cyclin A, cyclin B1, c-myc and EGFR were investigated. We observed a significant difference in HPV prevalence between 52 TCs and 69 CFTs (73.1% vs. 11.6%), and most of the HPVs were type 16 (87.2%) and nonepisomal (94.1%). Most TCs associated with HPV arose from the tonsillar crypts, and tended to be inverted and poorly differentiated. Compared with HPV-negative TC, HPV-positive TC showed a strong association with p16 overexpression (p<0.0001), and an inverse association with EGFR amplification (p=0.0478). HPV-16 integration status was strongly associated with c-myc amplification (p=0.034) and HIF-1alpha overexpression (p=0.022). HPV-16 integration could be directly related to tonsillar carcinogenesis initially in tonsillar crypts, followed by cell cycle aberration such as p16 overexpression related to the G1-S phase.

Carcinoma, Squamous Cell↗

PubMed2005

Mesorectal spread and micrometastasis of rectal cancer studied with large slice technique and tissue microarray.

BACKGROUND AND OBJECTIVES: Mesorectal tissue seems to be an ideal substrate for the spreading of tumors. The aim was to study the distribution of mesorectal neoplastic foci, examine occurrence of circumferential margin involvement and investigate micrometastasis of the lymph nodes. METHODS: A large slice technique, combined with tissue microarray, was used in the pathologic study of 31 specimens operated on following the principles of total mesorectal excision (TME). RESULTS: Three hundred and forty-nine mesorectal neoplastic foci were examined from 18 specimens. Almost one third of them were in the outer layer of mesorectum. Concerning position of primary tumor, ipsolateral neoplastic foci were significantly more than contralateral neoplstic foci. Twelve specimens were diagnosed to have circumferential margin involved. Nine hundred and ninety-two lymph nodes were harvested with 148 involved by tumor. No significant difference in occurrence of micrometastasis was observed among tumors of different stage. CONCLUSION: Combination of large slice and tissue microarray provided a more detailed method in studying the spread of rectal cancer. Complete excision of the mesorectum with fascia propria circumferentially intact is essential since there is an outer scattering and lateral discrepancy for neoplastic foci distribution. Circumferential margin involvement and micrometastasis observed suggested adoption of preoperative and/or postoperative radiochemotherapy.

Adult↗

PubMed2005

Targeting NAD(P)H:quinone oxidoreductase (NQO1) in pancreatic cancer.

NAD(P)H:quinone oxidoreductase (NQO1) functions as an important part of cellular antioxidant defense by detoxifying quinones, thus preventing the formation of reactive oxygen species (ROS). The aim of our study was to determine if NQO1 is elevated in pancreatic cancer specimens and pancreatic cancer cell lines and if so, would compounds previously demonstrated to redox cycle with NQO1 be effective in killing pancreatic cancer cells. Immunohistochemistry of resected pancreatic specimens demonstrated an increased immunoreactivity for NQO1 in pancreatic cancer and pancreatic intraepithelial neoplasia (PanIN) specimens versus normal human pancreas. Immunocytochemistry and Western immunoblots demonstrated increased immunoreactivity in pancreatic cancer cells when compared to a near normal immortalized human pancreatic ductal epithelial cell line and a colonic epithelial cell line. Streptonigrin, a compound known to cause redox cycling in the presence of NQO1, decreased clonogenic survival and decreased anchorage-independent growth in soft agar. Streptonigrin had little effect on cell lines with absent or reduced levels of NQO1. The effects of streptonigrin were reversed in pancreatic cancer cells pretreated with dicumarol, a known inhibitor of NQO1. NQO1 may be a therapeutic target in pancreatic cancer where survival is measured in months.

Agar↗