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PubMedDate not supplied

Expressions of MMP-2, MMP-9 and VEGF are closely linked to growth, invasion, metastasis and angiogenesis of gastric carcinoma.

BACKGROUND: Gastric carcinoma is still a major leading cause of cancer death in East Asia. Since angiogenesis is a necessary condition for invasion and metastasis, its regulation is of essential significance. MATERIALS AND METHODS: Expressions of MMP-2, MMP-9 and VEGF were examined with microarray of gastric carcinoma tissue samples (n = 249) by immunostaining. In addition, microvessel density (MVD) was assessed after labelling with the anti-CD34 antibody. Data were cross-compared with clinicopathological parameters of tumors, including PTEN expression. RESULTS: Expressions of MMP-2, MMP-9 and VEGF were positively correlated with tumour size, depth of invasion, lymphatic and venous invasion, lymph node metastasis, UICC staging and MVD of gastric carcinomas (p < 0.05).VEGF expression was positively linked with levels of MMP-2 and MMP-9 (p < 0.05), but negatively with PTEN (p < 0.05). The latter was also inversely associated with the MVD in gastric carcinomas (p < 0.05). CONCLUSION: MMP-2, MMP-9 and VEGF largely contribute to the angiogenesis and progression of gastric carcinomas. PTEN might inhibit the processes by down-regulating VEGF expression. These parameters should be regarded as good markers to indicate pathobiological behaviours of gastric carcinomas.

Adenocarcinoma↗
PubMed2006

[The clinical significance of expression and amplification of FGF3 in bladder transitional cell carcinoma].

OBJECTIVE: To investigate the amplification and expression of FGF3 in bladder transitional cell carcinoma (BTCC) and its clinical significance. METHODS: Immunohistochemistry (IHC) and Fluorescence In Situ Hybridization (FISH) methods were used to examine the protein expression and amplification of FGF3 in a tissue microarray (TMA) of 100 BTCCs and 30 adjacent normal bladder mucosas, so as to analyze their correlation and association with patient's clinico-pathological features. RESULTS: In this study, none of the normal bladder mucosas were detected FGF3 positivity, while in 89 informative BTCCs, 20 (22%) cases were observed positive expression of FGF3 protein, and it was significantly more frequently to occur in BTCCs of poor-differentiation (Grade 3), later clinical stage (T2-4) and tumor in >or= 3 cm in diameter (P < 0.05). In FISH study, 10 of the 63 (16%) informative BTCCs were observed amplification of FGF3 and it was significantly associated with BTCC's tumor size and clinical stage (P < 0.05). In addition, 10 BTCCs with amplification of FGF3 in this study were all detected positive expression of FGF3 protein, while in the remaining 53 BTCCs without amplification of FGF3, only 3 (6%) cases were observed FGF3 protein positivity. CONCLUSION: The up-regulated expression of FGF3 in BTCC was associated closely with tumor's malignant clinical phenotypes, and it might be involved in the malignant progression of parts of BTCC. The amplification of FGF3 gene might be a predominant mechanism of increased expression of FGF3 protein in BTCC.

Carcinoma, Transitional Cell↗
PubMed1999

[Use of high-density filters ("DNA arrays") for gene expression analysis in human tissues].

Most technical strategies for the analysis of gene expression in tissues are able to study only one protein or RNA product at the same time. A new recent method referred to as < > or < > is able to analyze simultaneously several hundreds of different genes. The DNA array is a nylon membrane on which are spotted equal amounts of cDNAs corresponding to different genes. This filter is hybridized with a < > probe synthesized with mRNA derived from the tissue analyzed. The result gives a global profile of gene expression within the tissue and allows quantitative and comparative analysis between different tissues or cell types.

DNA, Complementary↗
PubMed2006

Evaluation of the prognostic value of cellular inhibitor of apoptosis protein in epithelial ovarian cancer using automated quantitative protein analysis.

PURPOSE: The cellular inhibitor of apoptosis protein (cIAP) is regarded as an important prognostic biomarker in cancer. Here, we sought to determine the prognostic value of cIAP protein levels in epithelial ovarian cancer using a novel method of compartmentalized in situ protein analysis. METHODS: A tissue array composed of 150 advanced-stage ovarian cancers, treated with surgical debulking followed by platinum/paclitaxel-based combination chemotherapy, was constructed. For evaluation of protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis. RESULTS: The mean follow-up time for the entire cohort was 34.4 months. Patients with tumors bearing high cIAP membranous expression had a 3-year survival rate of 31% compared with 73% for patients with low cIAP expressing tumors (P = 0.0020). In multivariable analysis, adjusting for well-characterized prognostic variables, low membranous cIAP expression level was the only significant prognostic factor for overall survival. CONCLUSIONS: Our results indicate that cIAP protein levels have prognostic value in ovarian cancer patients. Modulation of cIAP levels may improve clinical outcome in ovarian cancer.

Automation↗
PubMed2005

[Immunohistochemical characterization of salivary gland tumors with tissue micro-arrays].

Systematic analysis of gene expression in salivary gland tumors is necessary to identify genes associated with specific tumor types. From the salivary gland register of the University Hospital Hamburg-Eppendorf sufficient samples of various tumors were available to generate Tissue Micro-Arrays (TMA). In light of the considerable heterogeneity of salivary gland tumors, this study was aimed at evaluating the suitability of TMA in salivary gland diagnostics and research. Epithelial antigens are not sufficient for a tumor-type-specific characterization. Myoepithelial markers are suitable for distinguishing biphasic tumor types from purely epithelial tumors. The detection of amylase in acinic cell carcinomas, and the detection of steroid hormone receptors in these and other malignant salivary gland tumors particularly in combination with the expression of transcription factors, oncogenes and proliferation associated antigens result in characteristic expression profiles. These may prove to be valuable for further investigations, especially on the molecular level.

Biomarkers, Tumor↗
PubMed2005

Microsatellite instability and gene mutations in transforming growth factor-beta type II receptor are absent in small bowel carcinoid tumors.

BACKGROUND: Microsatellite instability (MSI) with concomitant mutations in the coding region of transforming growth factor-beta type II receptor (TGFbetaRII) results in an aberrant growth-regulatory phenotype in colorectal carcinomas. The authors postulated that a similar mechanism occurred during the malignant evolution of small bowel carcinoid tumors. METHODS: Mutational analysis of two coding regions in the TGFbetaRII gene associated with MSI and BAT-26 within intron 5 of the mismatch repair gene, hMSH2, was undertaken in small bowel carcinoids (n = 14), lymph node metasasis (n = 1) and liver metastases (n = 5). Quantitative PCR analysis [TAQMAN, Applied Biosystems, Foster City, CA] was then undertaken to examine gene alterations in mismatch repair genes (hMLH1 and hMSH2) in small bowel carcinoids (n = 7) and matched normal mucosa (n = 5). Staining was then analyzed using quantitative tissue array profiling (AQUA analysis) in a small bowel EC carcinoid tissue microarray (n = 55 tumors) with immunostaining against TGFbetaRII and MSH2. RESULTS: Mutational examination of the TFGbetaRII gene and BAT-26 demonstrated that MSI was not present in any carcinoid material. Q RT-PCR analysis demonstrated statistically significant increased message levels of hMSH2 but not hMLH1 in carcinoid tumors. Quantitative analysis of membrane TGFbetaRII immunostaining using AQUA demonstrated that TGFbetaRII expression was down-regulated (P < 0.0002) in thirty-three primary small bowel carcinoids that exhibited lymph node and liver metastases compared to normal mucosa. AQUA analysis of nuclear MSH2 immunostaining demonstrated no differences for MSH2 between normal tissue and carcinoid tumor metastasis. Small bowel carcinoids characterized by variable expression of TGFbetaRII, did not exhibit MSI and had no differences in MSH2 expression. CONCLUSIONS: The molecular events leading to the formation of carcinoid tumors in the small bowel were different from those resulting in epithelial carcinomas. The usually slow-growing and relatively nonaggressive carcinoid tumors had variable expression of TGFbetaRII but were associated with the retention of mismatch repair protein function and a microsatellite-stable phenotype.

Adult↗
PubMed2003

Combined array comparative genomic hybridization and tissue microarray analysis suggest PAK1 at 11q13.5-q14 as a critical oncogene target in ovarian carcinoma.

Amplification of chromosomal regions leads to an increase of DNA copy numbers and expression of oncogenes in many human tumors. The identification of tumor-specific oncogene targets has potential diagnostic and therapeutic implications. To identify distinct spectra of oncogenic alterations in ovarian carcinoma, metaphase comparative genomic hybridization (mCGH), array CGH (aCGH), and ovarian tumor tissue microarrays were used in this study. Twenty-six primary ovarian carcinomas and three ovarian carcinoma cell lines were analyzed by mCGH. Frequent chromosomal overrepresentation was observed on 2q (31%), 3q (38%), 5p (38%), 8q (52%), 11q (21%), 12p (21%), 17q (21%), and 20q (52%). The role of oncogenes residing in gained chromosomal loci was determined by aCGH with 59 genetic loci commonly amplified in human tumors. DNA copy number gains were most frequently observed for PIK3CA on 3q (66%), PAK1 on 11q (59%), KRAS2 on 12p (55%), and STK15 on 20q (55%). The 11q13-q14 amplicon, represented by six oncogenes (CCND1, FGF4, FGF3, EMS1, GARP, and PAK1) revealed preferential gene copy number gains of PAK1, which is located at 11q13.5-q14. Amplification and protein expression status of both PAK1 and CCND1 were further examined by fluorescence in situ hybridization and immunohistochemistry using a tissue microarray consisting of 268 primary ovarian tumors. PAK1 copy number gains were observed in 30% of the ovarian carcinomas and PAK1 protein was expressed in 85% of the tumors. PAK1 gains were associated with high grade (P < 0.05). In contrast, CCND1 gene alterations and protein expression were less frequent (10.6% and 25%, respectively), suggesting that the critical oncogene target of amplicon 11q13-14 lies distal to CCND1. This study demonstrates that aCGH facilitates further characterization of oncogene candidates residing in amplicons defined by mCGH.

Carcinoma↗
PubMed2003

Methylation target array for rapid analysis of CpG island hypermethylation in multiple tissue genomes.

Hypermethylation of multiple CpG islands is a common event in cancer. To assess the prognostic values of this epigenetic alteration, we developed Methylation Target Array (MTA), derived from the concept of tissue microarray, for simultaneous analysis of DNA hypermethylation in hundreds of tissue genomes. In MTA, linker-ligated CpG island fragments were digested with methylation-sensitive endonucleases and amplified with flanking primers. A panel of 468 MTA amplicons, which represented the whole repertoire of methylated CpG islands in 93 breast tumors, 20 normal breast tissues, and 4 breast cancer cell lines, were arrayed on nylon membrane for probe hybridization. Positive hybridization signals detected in tumor amplicons, but not in normal amplicons, were indicative of aberrant hypermethylation in tumor samples. This is attributed to aberrant sites that were protected from methylation-sensitive restriction and were amplified by PCR in tumor samples, while the same sites were restricted and could not be amplified in normal samples. Hypermethylation frequencies of the 10 genes tested in breast tumors and cancer cell lines were 60% for GPC3, 58% for RASSF1A, 32% for 3OST3B, 30% for HOXA5, 28% for uPA, 25% for WT1, 23% for BRCA1, 9% for DAPK1, and 0% for KL. Furthermore, hypermethylation of 5 to 7 loci of these genes was significantly correlated with hormone receptor status, clinical stages, and ages at diagnosis of the patients analyzed. This novel approach thus provides an additional avenue for assessing clinicopathological consequences of DNA hypermethylation in breast cancer.

Breast Neoplasms↗
PubMed2002

Analysis of microdissected prostate tissue with ProteinChip arrays--a way to new insights into carcinogenesis and to diagnostic tools.

Prostate carcinomas are one of the most common malignancies in western societies. The pathogenesis of this tumor is still poorly understood. These tumors present with two characteristic features: epithelial-mesenchymal interactions, which play a pivotal role for tumor development and most of clinically manifest cancers arise in prostate proper compared to a minority of tumors which develop in the transitional zone. Deciphering the epithelial-mesenchymal cross talk and identification of molecular pecularities of the sub-populations of cells in different zones can therefore help understanding carcinogenesis and development of new, non-invasive tools for the diagnosis and prognosis of prostate carcinomas which has remained a challenge until today. A ProteinChip array technology (SELDI = surface enhanced laser desorption ionization) has been developed recently by Ciphergen Biosystems enabling analysis and profiling of complex protein mixtures from a few cells. This study describes the analysis of approximately 500-1000 freshly obtained prostate cells by SELDI-TOF-MS (surface enhanced laser desorption ionization time-of-flight mass spectrometry). Pure cell populations of stroma, epithelium and tumor cells were selected by laser assisted microdissection. Multiple specific protein patterns were reproducibly detected in the range from 1.5 to 30 kDa in 28 sub-populations of 4 tumorous prostates and 1 control. A specific 4.3 kDa peak was increased in the prostate tumor stroma compared to normal prostate proper and transitional zone stroma and increased in prostate tumor glands compared to normal prostate proper and transitional zone glands. Coupling laser assisted microdissection with SELDI provides tremendous opportunities to identify cell and tumor specific proteins to understand molecular events underlying prostate carcinoma development. It underlines the vast potential of this technology to better understand pathogenesis and identify potential candidates for new specific biomarkers in general which could help to screen for and distinguish disease entities, i.e. between clinically significant and insignificant carcinomas of the prostate.

Aged↗
PubMed2003

[Bladder tumors and molecular markers. Current status and perspectives].

With 15,000 new cases each year, bladder tumors are the second leading urological cancer in France, after prostate carcinoma. In spite of advances in surgical techniques and therapeutic protocols based on trans-urethral resection associated with additive treatment (immunotherapy or endovesical chemotherapy), the natural course of superficial bladder tumors remains marked by two risks: recurrence and progression. In spite of the impressive efforts developed by molecular biologists searching for new specific markers, none of the markers can currently replace histological features such as stage and grade. Although detection of microsatellite instability is a promising approach, numerous difficulties limit the use of these markers and prevent their application in routine practice. Let us hope that the new techniques for tissue analysis such as DNA or tissue-arrays developed for simultaneous analysis of hundreds or even thousands of tumors will allow identification and validation of biological and even therapeutic markers. Among the various biological markers, only the proliferative index given by the expression of Ki67, the expression of p53 and EGFR have been examined in comparative studies. Ki67 seems to be the best marker for progression, its expression and the interpretation of results being more reproducible than for p53.

Biomarkers, Tumor↗
PubMed2001

Acoustic nonlinearity parameter tomography for biological tissues via parametric array from a circular piston source--theoretical analysis and computer simulations.

The acoustic nonlinearity parameter B/A describes the nonlinear features of a medium and may become a novel parameter for ultrasonic tissue characterization. This paper presents a theoretical analysis for acoustic nonlinear parameter tomography via a parametric array. As two primary waves of different frequencies are radiated simultaneously from a circular piston source, a secondary wave at the difference frequency is generated due to the nonlinear interaction of the primary waves. The axial and radial distributions of sound pressure amplitude for the generated difference frequency wave in the near field are calculated by a superposition of Gaussian beams. The calculated results indicated that the difference frequency component of the parametric array grows linearly with distance from the piston source. It therefore provides a better source to do the acoustic nonlinearity parameter tomography because the fundamental and second harmonic signals both have a near field that goes through many oscillations due to diffraction. By using a finite-amplitude insert substitution method and a filtered convolution algorithm, a computer simulation for B/A tomography from the calculated sound pressure of the difference frequency wave is studied. For biological tissues, the sound attenuation is considered and compensated in the image reconstruction. Nonlinear parameter computed tomography (CT) images for several biological sample models are obtained with quite good quality in this study.

Journal Article↗
PubMed2005

Subcellular localization and protein levels of cyclin-dependent kinase inhibitor p27 independently predict for survival in epithelial ovarian cancer.

PURPOSE: p27 protein is regarded as a valuable prognostic biomarker in cancer with a potential use as a molecular target. However, different methods of immunohistochemical assessment have yielded conflicting results. Here, we sought to determine the prognostic value of p27 in ovarian cancer using a novel method of compartmentalized in situ protein analysis. EXPERIMENTAL DESIGN: A tissue array composed of 150 advanced stage ovarian cancers uniformly treated, with surgical debulking followed by platinum-paclitaxel combination chemotherapy, was constructed. For evaluation of p27 protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis [automated quantitative analysis (AQUA)]. RESULTS: The mean follow-up time of the patients was 34.3 months. Patients with low Fédération Internationale des Gynaecologistes et Obstetristes stage were more likely to have low nuclear p27 expression (P = 0.008). Low nuclear p27 expression was associated with improved 3-year overall survival (66% versus 20%, P = 0.0047) and disease-free survival (27% versus 12%, P = 0.022). In multivariable analysis, adjusting for well-characterized prognostic variables, low nuclear p27 expression level was the most significant prognostic factor for both disease-free and overall survival. CONCLUSIONS: Our results indicate that quantitative assessment of nuclear p27 expression level by automated in situ quantitative analysis is a strong predictor for outcome in ovarian cancer.

Adult↗
PubMed2005

Evolution of microarray analysis.

Reddy's very thorough review of the history of gene expression analysis of neurodegenerative disease made me think about the early days of microarrays, so I want to reminisce a little before commenting on the evolution of the technology and some issues that I think still continue to plague us.

Alzheimer Disease↗
PubMed2003

Increased C-CRK proto-oncogene expression is associated with an aggressive phenotype in lung adenocarcinomas.

The C-CRK gene, cellular homolog of the avian v-crk oncogene, encodes two alternatively spliced adaptor signaling proteins, CRKI (28 kDa) and CRKII (40 kDa). Both CRKI and CRKII have been shown to activate kinase signaling and anchorage-independent growth in vitro and CRKI transformed cells readily form tumors in nude mice. Affymetrix oligonucleotide arrays were used to analyse 86 lung adenocarcinomas and 10 uninvolved lung tissues. C-CRK mRNA expression was increased in more advanced (stage III versus stage I), larger (T(2-4) versus T(1)), and poorly differentiated tumors and in tumors from patients demonstrating poor survival (P=0.00034). An overlapping series of 93 lung adenocarcinomas (64 stage I and 29 stage III) and 10 uninvolved lung specimens were measured for quantitative differences in CRKI and CRKII protein levels using 2-D PAGE. CRK protein spots were identified using mass spectrometry and 2-D Western blotting. A significant increase in levels of the CRKI oncoprotein and the phosphorylated isoform of CRKII was observed in tumors (P<0.05). No difference in protein level was evident between stages. Concordant with mRNA expression, CRKI and CRKII were increased in poorly differentiated tumors (P<0.05). CRK immunohistochemical analysis of tumor tissue arrays using the same tumor series also demonstrated increased abundance of nuclear and cytoplasmic CRK in more proliferative tumors (P<0.05). This study provides the first quantitative analysis of discrete CRKI and CRKII protein isoforms in human lung tumors and provides evidence that the C-CRK proto-oncogene may foment a more aggressive phenotype in lung cancers.

Adenocarcinoma↗
PubMed2006

Deconstructing language by comparative gene expression: from neurobiology to microarray.

Language is a defining characteristic of our species that has emerged quite recently on an evolutionary timescale. Understanding the neurobiological substrates and genetic underpinnings of language constitutes a basic challenge for both neuroscience and genetics. The functional localization of language in the brain has been progressively refined over the last century through studies of aphasics and more recently through neuroimaging. Concurrently, structural specializations in these brain regions have been identified by virtue of their lateralization in humans and also through comparisons with homologous brain regions in non-human primate species. Comparative genomics has revealed the genome of our closest living relative, the chimpanzee, to be astonishingly similar to our own. To explore the role that changes in the regulation of gene expression have had in recent human evolution, several groups have used microarrays to compare expression levels for thousands of genes in the brain between humans and chimpanzees. By applying this approach to the increasingly refined peri-sylvian network of brain regions involved in language, it may be possible to discern functionally significant changes in gene expression that are universal among humans but unique to our species, thus casting light on the molecular basis of language in the brain.

Animals↗
PubMed2002

Analysis of gene expression in human colorectal cancer tissues by cDNA array.

BACKGROUND: The development and progression of cancer are accompanied by complex changes in patterns of gene expression. The purpose of this study was to clarify the relevance of macroarray analysis of human colorectal cancer tissues. METHODS: Hybridization of cDNA macroarray filters on which 550 genes had been spotted was performed with biotin-labeled cDNA targets that were prepared from mRNA extracted from 20 pairs of colorectal cancer and corresponding noncancerous tissues. Expression of differentially expressed genes was further studied by semiquantitative RT-PCR. RESULTS: Fourteen (2.5%) of the 550 genes were differentially expressed and up- or downregulated in cancer tissues by at least threefold compared with matched noncancerous tissues in 10 or more of the 20 patients. The genes that were upregulated in cancer tissues were associated with transcription, cell cycle, growth factor receptor, cell adhesion, extracellular matrix-degrading enzymes, and angiogenesis, and the downregulated genes were those involved in apoptosis and immune recognition. Semiquantitative RT-PCR analysis of these differentially expressed genes gave results consistent with those by cDNA array analysis. CONCLUSIONS: Although the macroarray used in this study contained only a small number of genes, our results support the feasibility and usefulness of this approach to study variation in gene expression patterns in human colorectal cancer tissues. The results also suggest the possibility of a diagnostic application of cDNA macroarrays in daily clinical settings.

Biopsy, Needle↗
PubMed2001

Identification of a prostate-specific G-protein coupled receptor in prostate cancer.

Membrane receptors coupled to heterotrimeric G-proteins play an essential role in the transmission of signals from the extracellular environment to the cytoplasm of the cell. A wide variety of external stimuli, including neurotransmitters, hormones, phospholipids, photons, odorants, taste ligands, and growth factors, can activate specific members of the G-protein coupled receptors (GPCRs). Besides essential functions in fully differentiated cells and tissues, GPCRs are also involved in embryogenesis, tissue regeneration, cell growth stimulation, and cell proliferation. In this study, we identified a novel prostate-specific G-protein coupled receptor that interacts with Galpha(12) in our yeast two-hybrid assays. The expression of the receptor protein is highly restricted to human prostate tissues using multiple-tissue Northern blot analysis, and tissue expression array. Furthermore, the expression of prostate-specific receptor is increased significantly in prostate tumors in comparison with the matched normal prostate tissues using PCR and Southern blot analysis, suggesting a potential role of this tissue-specific G-protein coupled receptor in prostate cancer development.

Amino Acid Sequence↗