Biomedical subjects

Manfred Dietel

Publications and source records attributed to Manfred Dietel.

At least 19 recordsLinked to original sources

PubMed2007

Taxol-resistance-associated gene-3 (TRAG-3/CSAG2) expression is predictive for clinical outcome in ovarian carcinoma patients.

An obstacle in chemotherapy of ovarian cancer is the development of drug resistance. Taxol (paclitaxel)-resistance-associated gene-3 (TRAG-3/CSAG2) was found to be overexpressed in a paclitaxel-resistant ovarian carcinoma cell line. However, clinical impact of TRAG-3 in ovarian carcinoma has not been demonstrated previously. For demonstration of potential clinical impact of TRAG-3, immunohistochemistry was applied to determine TRAG-3 protein expression in specimens obtained from ovarian carcinoma patients (n=37) who received a paclitaxel-based chemotherapy at two different time points, initial laparotomy before chemotherapy, and secondary cytoreduction after chemotherapy. The TRAG-3-specific immunohistochemical staining was correlated with clinical outcome. In ovarian carcinoma specimens obtained at the initial laparotomy, an advantage in overall (P < 0.001) and progression-free (P = 0.003) survival for patients with weak TRAG-3 expression could be demonstrated. Tumor specimens excised at secondary cytoreduction procedure were not predictive for clinical outcome. In summary, TRAG-3 was found to be a prognostic factor for the prediction of clinical outcome after the application of paclitaxel-based chemotherapy.

Adult↗

PubMed2006

ABCC2 (MRP2, cMOAT) can be localized in the nuclear membrane of ovarian carcinomas and correlates with resistance to cisplatin and clinical outcome.

PURPOSE: Cisplatin resistance is a major obstacle in the treatment of ovarian carcinoma. ABCC2 is commonly localized in apical cell membranes and could confer cisplatin resistance. Here, we show that ABCC2 can be localized in the cytoplasmic membrane as well as in the nuclear membrane of various human tissues including ovarian carcinoma cells. EXPERIMENTAL DESIGN: For the subcellular detection of ABCC2, immunohistochemistry was done using 41 Federation Internationale des Gynaecologistes et Obstetristes stage III ovarian carcinoma specimens prepared before treatment with cisplatin-based schemes and 35 specimens from the same group after chemotherapy. Furthermore, 11 ovarian carcinoma cell lines as well as tissue microarrays consisting of various human tissues were analyzed. RESULTS: Nuclear membranous localization of ABCC2 was associated with response to first-line chemotherapy at primary (P = 0.0013) and secondary surgery (P = 0.0060). Cases with relapse showed higher nuclear membrane expression at primary (P = 0.0003) and secondary surgery (P = 0.0024). Kaplan-Meier analyses showed that weak nuclear membrane ABCC2 expression before treatment was associated with significantly longer overall (P = 0.04) and progression-free survival (P = 0.001); following chemotherapy, it correlated with significantly longer progression-free survival (P = 0.038). Tissue microarrays confirmed nuclear membranous localization of ABCC2, in particular, in poorly differentiated cells. In ovarian carcinoma cells, it correlated with resistance against cisplatin, whereas localization in the cytoplasmic membrane did not. CONCLUSIONS: ABCC2 confers resistance to cisplatin of ovarian carcinoma in cell culture systems and in clinics when expressed in the nuclear membrane. Thus, ABCC2 localization can predict platinum therapy outcome. Furthermore, expression of ABCC2 in nuclear membranes in human tissues is specific for poorly differentiated cells including stem cells.

Antineoplastic Agents↗

PubMed2006

Mass spectrometry-based metabolic profiling reveals different metabolite patterns in invasive ovarian carcinomas and ovarian borderline tumors.

Metabolites are the end products of cellular regulatory processes, and their levels can be regarded as the ultimate response of biological systems to genetic or environmental changes. We have used a metabolite profiling approach to test the hypothesis that quantitative signatures of primary metabolites can be used to characterize molecular changes in ovarian tumor tissues. Sixty-six invasive ovarian carcinomas and nine borderline tumors of the ovary were analyzed by gas chromatography/time-of-flight mass spectrometry (GC-TOF MS) using a novel contamination-free injector system. After automated mass spectral deconvolution, 291 metabolites were detected, of which 114 (39.1%) were annotated as known compounds. By t test statistics with P < 0.01, 51 metabolites were significantly different between borderline tumors and carcinomas, with a false discovery rate of 7.8%, estimated with repeated permutation analysis. Principal component analysis (PCA) revealed four principal components that were significantly different between both groups, with the highest significance found for the second component (P = 0.00000009). PCA as well as additional supervised predictive models allowed a separation of 88% of the borderline tumors from the carcinomas. Our study shows for the first time that large-scale metabolic profiling using GC-TOF MS is suitable for analysis of fresh frozen human tumor samples, and that there is a consistent and significant change in primary metabolism of ovarian tumors, which can be detected using multivariate statistical approaches. We conclude that metabolomics is a promising high-throughput, automated approach in addition to functional genomics and proteomics for analyses of molecular changes in malignant tumors.

Cluster Analysis↗

PubMed2006

ADAM8 expression in prostate cancer is associated with parameters of unfavorable prognosis.

Gene products of the A disintegrin and metalloprotease (ADAM) family are critically involved in carcinogenesis and tumor progression of various solid tumors. Little is known about ADAM8 in prostate cancer. In our quest for novel diagnostic tissue markers of prostate cancer, we aimed to evaluate the expression of ADAM8 in prostate cancer and to correlate it with clinicopathological parameters. One hundred twenty-eight clinicopathologically characterized prostate cancer patients, with available follow-up data, were immunostained for ADAM8. Additionally, ADAM8 mRNA expression was quantified by real-time reverse transcription polymerase chain reaction (n = 59). ADAM8 protein expression was significantly associated with higher pT status, positive nodal status, and higher Gleason scores. Still, a significant prognostic value for the prostate-specific antigen relapse-free survival of ADAM8 could not be demonstrated. The differentiality of ADAM8 expression on protein and on mRNA level was low and partially inconclusive. Therefore, despite of its significant association with conventional parameters of an unfavorable prognosis, ADAM8 adds only limited information to the conventional histopathological assessment of prostate cancer.

ADAM Proteins↗

PubMed2006

The diagnostic path, a useful visualisation tool in virtual microscopy.

BACKGROUND: The Virtual Microscopy based on completely digitalised histological slide. Concerning this digitalisation many new features in mircoscopy can be processed by the computer. New applications are possible or old, well known techniques of image analyses can be adapted for routine use. AIMS: A so called diagnostic path observes in the way of a professional sees through a histological virtual slide combined with the text information of the dictation process. This feature can be used for image retrieval, quality assurance or for educational purpose. MATERIALS AND METHODS: The diagnostic path implements a metadata structure of image information. It stores and processes the different images seen by a pathologist during his "slide viewing" and the obtained image sequence ("observation path"). Contemporary, the structural details of the pathology reports were analysed. The results were transferred into an XML structure. Based on this structure, a report editor and a search function were implemented. The report editor compiles the "diagnostic path", which is the connection from the image viewing sequence ("observation path") and the oral report sequence of the findings ("dictation path"). The time set ups of speech and image viewing serve for the link between the two sequences. The search tool uses the obtained diagnostic path. It allows the user to search for particular histological hallmarks in pathology reports and in the corresponding images. RESULTS: The new algorithm was tested on 50 pathology reports and 74 attached histological images. The creation of a new individual diagnostic path is automatically performed during the routine diagnostic process. The test prototype experienced an insignificant prolongation of the diagnosis procedure (oral case description and stated diagnosis by the pathologist) and a fast and reliable retrieval, especially useful for continuous education and quality control of case description and diagnostic work. DISCUSSION: The Digital Virtual Microscope has been designed to handle 1000 images per day in the daily routine work of a pathology institution. It implies the necessity of an automatic mechanism of image meta dating. The non - deterministic correlation between the oral statements (case report) and image information content guides the image meta dating. The presented software opens up new possibilities for a content oriented search in a virtual slide, and can successfully support medical education and diagnostic quality assurance.

Journal Article↗

PubMed2006

Peroxisome proliferator-activated receptor gamma is highly expressed in pancreatic cancer and is associated with shorter overall survival times.

PURPOSE: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor that has been implicated in carcinogenesis and progression of various solid tumors, including pancreatic carcinoma. We aimed to clarify the expression patterns of PPARgamma in pancreatic ductal carcinomas and to correlate these to clinicopathologic variables, including patient survival. EXPERIMENTAL DESIGN: Array-based expression profiling of 19 microdissected carcinomas and 14 normal ductal epithelia was conducted. Additionally, Western blots of pancreatic cancer cell lines and paraffinized tissue of 129 pancreatic carcinomas were immunostained for PPARgamma. For statistical analysis, Fisher's exact test, chi2 test for trends, correlation analysis, Kaplan-Meier analysis, and Cox's regression were applied. RESULTS: Expression profiles showed a strong overexpression of PPARgamma mRNA (change fold, 6.9; P=0.04). Immunohistochemically, PPARgamma expression was seen in 71.3% of pancreatic cancer cases. PPARgamma expression correlated positively to higher pT stages and higher tumor grade. Survival analysis showed a significant prognostic value for PPARgamma, which was found to be independent in the clinically important subgroup of node-negative tumors. CONCLUSIONS: PPARgamma is commonly up-regulated in pancreatic ductal adenocarcinoma and might be a prognostic marker in this disease. Both findings corroborate the importance of PPARgamma in tumor progression of pancreatic cancer.

Adult↗

PubMed2006

Anaplastic large-cell non-Hodgkin's lymphoma of the breast in periprosthetic localisation 32 years after treatment for primary breast cancer--a case report.

Primary, as well as secondary, lymphomas of the breast are rare diseases and might, in some cases, be misdiagnosed as breast cancer on routine hematoxylin/eosin stainings. We report a case of an anaplastic large cell lymphoma in a 72-year-old woman with a history of breast cancer treated with breast-ablative surgery and a subsequent silicon implant 32 years ago. Clinically, she presented with an ulceration of the skin, which had developed within a few months. On conventional histology, the tumor cells were mimicking poorly differentiated invasive ductal carcinoma with a prominent leukocytic infiltrate. The immunoprofile of the tumor showed negativity for cytokeratins and led to the diagnosis of a CD30-positive anaplastic large cell lymphoma.

Aged↗

PubMed2006

Expression of the ELAV-like protein HuR in human colon cancer: association with tumor stage and cyclooxygenase-2.

There is growing body of evidence that post-translational events contribute-in addition to genetic changes-to the progression of malignant tumors. These post-translational alterations may provide targets for new therapeutic approaches. The ELAV-like protein HuR stabilizes a group of cellular mRNAs which contain AU-rich elements in their 3' untranslated region. To investigate a possible contribution of post-translational changes to the progression of colon cancer and to overexpression of COX-2, we studied expression of HuR and COX-2 a cohort of colorectal adenocarcinomas and in colon cancer cell lines. All cell lines showed an expression of HuR mRNA and protein. In tumor tissue of colon carcinomas we observed two different staining patterns of HuR: A nuclear expression in 98% as well as an additional cytoplasmic expression in 53% of cases. COX-2 was expressed in 63% of carcinomas. Cytoplasmic expression of HuR was significantly associated with increased COX-2 expression as well as with high tumor stage. In univariate Kaplan-Meier analysis, grading, tumor stage and nodal status but not HuR or COX-2 expression were prognostic factors for overall survival. Our results suggest that the overexpression of HuR in colon cancer may be part of a regulatory pathway that controls the mRNA stability of cyclooxygenase-2 and provides an interesting example for a contribution of a dysregulation of mRNA stability to the progression of colorectal cancer. Based on our results, further studies are necessary to investigate whether HuR might be a potential target for a molecular tumor therapy.

Adenocarcinoma, Mucinous↗

PubMed2006

Personalized medicine and development of targeted therapies: The upcoming challenge for diagnostic molecular pathology. A review.

Due to continuous technical developments and new insights into the high complexity of many diseases, molecular pathology is a rapidly growing field gaining center stage in the clinical management of tumors as well as in the pharmaceutical development of new anti-cancer drugs. The application of novel compounds in clinical trials has revealed promising results; however, the current diagnostic procedures available for determining which patients will primarily benefit from rational tumor therapy are insufficient. To read a patient's tissue as "deeply" as possible, in the future, gaining information on the morphology and on genetic, proteomic, and epigenetic alterations will be the upcoming task of surgical pathologists experienced in molecular diagnostics to provide the clinicians with information relevant for an individualized medicine. Among the different high-throughput technologies, DNA microarrays are now the first array approach close to enter routine diagnostics. Technically advanced and well-established microarray platforms can nowadays be evaluated by distinct bioinformatic tools capable of identifying both novel genes associated with disease development and clusters of genes predicting clinical outcome of an individual tumor. The automatic, highly parallel analysis of proteins and complex proteins lysates for early detection of cancers such as breast, prostate and ovary as proteomic patterns in the serum also appears at the horizon. In addition, an improved analysis of tumor samples via antibody or reverse-phase protein arrays is likely to provide the pathologist in the future with information about activated oncogenic signaling pathways and other cell functions, such as drug response or the potential to metastasize. While expression microarrays and proteomic analysis rely on relatively unstable material incompatible with paraffin-embedded tissue samples, an investigation of DNA methylation using specialized high-throughput platforms has revealed the potential of being used in future diagnostics. Each of these approaches on its own might not suffice to extract all information required for an efficient individualized diagnostics. Therefore, a "multiplex approach" combining the different biological levels DNA, RNA, and protein, may be necessary to functionally classify malignant tumors. This appears to become a major challenge for diagnostic pathologists.

Drug Design↗

PubMed2006

Specific inhibition of AKT2 by RNA interference results in reduction of ovarian cancer cell proliferation: increased expression of AKT in advanced ovarian cancer.

The protein kinase AKT is involved in several signaling pathways that are important for tumor development and progression, suggesting that AKT might be an interesting target for a molecular tumor therapy. In this study, we investigated the AKT expression in ovarian carcinomas and the role of the AKT isoforms to ovarian cancer cell proliferation. We observed an increased AKT expression in 58% of the primary ovarian carcinomas as compared to normal ovaries by immunohistochemistry. AKT expression was significantly associated with positive lymph node status (P=0.002) and advanced FIGO stage (P=0.009). In western blot analysis, total AKT was expressed in all ovarian cancer cell lines and HOSE cells, while phosphorylated AKT was only observed in OVCAR-3 and SKOV-3 cells. The isoforms AKT1 and AKT2 were expressed at the mRNA level in all cell lines, while no relevant AKT3 mRNA levels were detected by conventional and quantitative RT-PCR. To determine the effects on cell proliferation, we used the unselective PI3K-inhibitor LY294002 as well as RNA interference to selectively inhibit the AKT isoforms. Treatment with LY294002 and the AKT2 siRNA reduced proliferation of OVCAR-3 cells. Our results show that AKT is expressed in a subpopulation of advanced ovarian carcinomas suggesting a role for this protein in the progression of this entity. Deactivation of AKT, especially AKT2 can result in reduction of cell growth. Accordingly, AKT is an interesting target for therapeutic intervention in ovarian cancer.

Adult↗

PubMed2006

Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations.

Cancer patients with tumors of similar grading, staging and histogenesis can have markedly different treatment responses to different chemotherapy agents. So far, individual markers have failed to correctly predict resistance against anticancer agents. We tested 30 cancer cell lines for sensitivity to 5-fluorouracil, cisplatin, cyclophosphamide, doxorubicin, etoposide, methotrexate, mitomycin C, mitoxantrone, paclitaxel, topotecan and vinblastine at drug concentrations that can be systemically achieved in patients. The resistance index was determined to designate the cell lines as sensitive or resistant, and then, the subset of resistant vs. sensitive cell lines for each drug was compared. Gene expression signatures for all cell lines were obtained by interrogating Affymetrix U133A arrays. Prediction Analysis of Microarrays was applied for feature selection. An individual prediction profile for the resistance against each chemotherapy agent was constructed, containing 42-297 genes. The overall accuracy of the predictions in a leave-one-out cross validation was 86%. A list of the top 67 multidrug resistance candidate genes that were associated with the resistance against at least 4 anticancer agents was identified. Moreover, the differential expressions of 46 selected genes were also measured by quantitative RT-PCR using a TaqMan micro fluidic card system. As a single gene can be correlated with resistance against several agents, associations with resistance were detected all together for 76 genes and resistance phenotypes, respectively. This study focuses on the resistance at the in vivo concentrations, making future clinical cancer response prediction feasible. The TaqMan-validated gene expression patterns provide new gene candidates for multidrug resistance.

Antineoplastic Agents↗

PubMed2006

Prognostic relevance of AGR2 expression in breast cancer.

PURPOSE: We aimed to evaluate the expression of the human anterior gradient-2 (AGR2) in breast cancer on RNA and protein level and to correlate it with clinicopathologic data, including patient survival. EXPERIMENTAL DESIGN: AGR2 mRNA expression was assessed by reverse transcription-PCR in 25 breast cancer samples and normal tissues. A polyclonal rabbit AGR antiserum was used for immunohistochemistry on 155 clinicopathologically characterized cases. Statistical analyses were applied to test for prognostic and diagnostic associations. RESULTS: Immunohistochemical detection of AGR2 was statistically significantly associated with positive estrogen receptor status and lower tumor grade. AGR2-positive tumors showed significantly longer overall survival times in univariate analyses. For the subgroup of nodal-negative tumors, an independent prognostic value of AGR2 was found. CONCLUSIONS: The expression of AGR2 in breast cancer is strongly associated with markers of tumor differentiation (estrogen receptor positivity, lower tumor grade). A prognostic effect of AGR2 for overall survival could be shown, which became independently significant for the group of nodal-negative tumors.

Breast↗

PubMed2006

Chromosomal alterations in lung metastases of colorectal carcinomas: associations with tissue specific tumor dissemination.

Comparative genomic hybridization was used to screen colorectal carcinomas for chromosomal aberrations that are associated with the metastatic phenotype of the lung. Specimens of 13 lung metastases, 6 primary tumors, 1 lymph node metastasis, 1 liver metastasis, and 1 ovarian metastasis were investigated and added to our CGH colon cancer tumor collective, comprising 85 tumor specimens from 56 patients (see CGH online tumor database at http://amba.charite.de/cgh). Lung metastases showed more alterations than liver metastases, particularly more deletions at 1p, 3p, 9q, 12q, 17q, 19p and 22q and gains at 2q, 5p, and chromosome 6. Comparing lung metastases with their corresponding primary tumors, particularly more deletions at 3p, 8p, 12q, 17q, and 21q21 and gains at 5p were observed. Based on our results, we wish to suggest a metastatic progression model. Specific subpopulations of metastatic cells have a distinct metastatic potential, which is reflected by a non-random accumulation of chromosomal alterations. Distinct alterations already exist within the primary tumor and this "ready to go package" gives the cells the metastatic potential to achieve the complex series of events needed for metastasis.

Chromosome Aberrations↗

PubMed2006

Analysis of gene expression profiles in melanoma cells with acquired resistance against antineoplastic drugs.

Resistance to various antineoplastic agents is common in the clinical management of malignant melanoma. The biological mechanisms conferring these different drug-resistant phenotypes are still unclear. To identify potential factors mediating drug resistance to melanoma cells, the mRNA expression profiles of the parental drug-sensitive human melanoma cell line MeWo and four derived drug-resistant sublines with acquired resistance against four commonly used drugs for melanoma treatment (cisplatin, etoposide, fotemustine and vindesine) were analysed. We investigated cDNA arrays with 43,000 cDNA clones ( approximately 30,000 unique genes) to study the expression patterns of these cell lines. We were able to simultaneously extract new candidate genes associated with drug resistance in malignant melanoma and to correlate the present findings with previously described resistance-associated genes. Using hierarchical clustering and analysing the overlap of genes with altered expression, we detected similarities between the expression signatures related to cisplatin and fotemustine resistance. The resistance against vindesine required a minimal set of changes in gene expression relative to the parental MeWo cell line. Our study provides new data that may be used to obtain further insight into the resistance characteristics of malignant melanoma.

Cell Line, Tumor↗

PubMed2006

Tissue pretreatment with formic acid might lower HercepTest scores in breast cancer.

Creutzfeldt-Jakob disease and other prion diseases are diseases with yet not well-defined routes of transmission and infection. The safe processing of potentially contaminated tissue material remains a challenge for histologic laboratories. Formic acid pretreatment is considered to be effective in prion inactivation. We evaluated the c-erbB2 and the hormone receptor-status in potentially prion infectious breast cancer tissue after pretreatment with formic acid. Paired breast cancer tissue samples were immunostained with commercially available antibodies against c-erbB2, estrogen receptor, and progesterone receptor with 1 tissue sample of each pair being pretreated with 98% formic acid. Staining was evaluated either according to the HercepTest score or using an immunoreactive score. Additionally, fluorescence in situ hybridization (FISH) analyses were performed for 7 of these cases. Untreated tissues showed strong circumferential staining for c-erbB2 (HercepTest score 3+), whereas the membranous staining of the tissues pretreated with formic acid was significantly weaker. FISH analyses showed no differences in both groups. The hormone receptor expression was not significantly influenced and positivity was maintained in all cases. In breast cancer patients, the pretreatment of tissue with formic acid for prion-decontamination in the case of suspected Creutzfeldt-Jakob disease or other prion diseases can lead to underestimation of the immunohistologically determined c-erbB2 status. In these cases, a c-erbB2-FISH analysis should be performed. For the immunostaining of hormone receptors in breast cancer, formic acid pretreatment can be applied without negative effects on the sensitivity or specificity of the assay.

Breast Neoplasms↗

PubMed2006

Maspin expression is characteristic for cisplatin-sensitive ovarian cancer cells and for ovarian cancer cases of longer survival rates.

High cytoplasmic expression of maspin was described in ovarian cancers of shorter survival rates. Until now, no relationship has been described between expression of maspin and sensitivity to cisplatin in ovarian cancers. This study aimed at examining the relationship between expression of maspin, detected by immunohistochemistry and clinical response to cisplatin in ovarian cancer cases as well as the in vitro sensitivity to cisplatin of 11 ovarian cancer cell lines. The analyzes were performed on 73 samples of ovarian cancer and on A2780P, A2780RCIS, CAOV-3, EFO 21, EFO 27, ES-2, Mdah 2774, OAW 42, OVCAR-3, PA-1, and SKOV-3 ovarian cancer cells. Cytoplasmic maspin expression in studied cells significantly correlated with cisplatin sensitivity. A significantly shorter overall survival and progression-free survival was associated with lower cytoplasmic maspin expression at first-look laparotomies and nuclear maspin expression and secondary cytoreductions. Higher nuclear maspin at first-look laparotomies expression was specific for cases of complete response. In the study, the elevated expression of maspin was shown to be typical for cisplatin-sensitive ovarian cancers.

Aged↗

PubMed2006

Expression patterns of polo-like kinase 1 in human gastric cancer.

Polo-like kinase 1 (PLK1) is centrally involved in the regulation of mitosis in normal and malignant cells. It is known that inhibition of PLK1 expression in vitro and in vivo leads to mitotic arrest, induction of apoptosis and suppression of tumor growth. In the present study, expression of PLK1 was investigated in paraffin tissue of 135 cases of gastric adenocarcinoma and in 46 corresponding lymph node metastases by immunohistochemistry. Expression data were correlated with clinicopathological parameters and patient survival. Seventy-three (54.1%) of 135 carcinomas showed an overexpression of PLK1 compared to normal gastric mucosa. Overexpression of PLK1 correlated positively with tumor stage, nodal status and diffuse growth pattern. PLK1 expression in the primary tumor did not differ from PLK1 expression in the corresponding lymph node metastases. PLK1 expression was a significant prognostic factor in univariate but not in multivariate survival analysis. As a conclusion, upregulated PLK1 expression in gastric cancer correlates with a malignant tumor phenotype and has impact on patient prognosis. These data underscore the importance of PLK1 in gastric carcinogenesis and present a translational link for functional data into potential clinical use by defining PLK1 as an attractive protein for novel targeted chemotherapeutic approaches in gastric cancer.

Adenocarcinoma↗

PubMed2006

Cytokeratin profiles identify diagnostic signatures in colorectal cancer using multiplex analysis of tissue microarrays.

BACKGROUND AND AIMS: Recent cDNA expression profiling analyses indicate that within specific organ cancers Cytokeratins (CKs) dysregulation may identify subgroups with distinct biological phenotypes. Our objectives in this study were (1) to test whether cytokeratins were also distinct on the protein level, (2) to evaluate these biomarkers in a series of well-characterised CRCs, (3) to apply hierarchical cluster analysis to immunohistochemical data. METHODS: Tissue microarrays (TMA) comprising 468 CRC specimens from 203 patients were constructed to evaluate CK5, CK7, CK8, CK13, CK14, CK16, CK17, CK18, CK19 and CK20. In total, 2919 samples were analyzed. RESULTS: Unsupervised hierarchical clustering discovered subgroups represented by reduced CK8 and CK20 expression, that differed by a shorter patients survival. The evaluation of the specific biomarkers by Kaplan-Meier analysis showed that reduced CK8 expression (p<0.01) was significantly associated with shorter patients' survival, but was not an independent factor correlated with tumour stage (pT), grading (G) and nodal stage (pN). CONCLUSIONS: Reduced coexpression of CK8 and CK20 may indicate an epithelial-mesenchymal transition (EMT) representing an important step in the development of more aggressive CRCs. In addition, multiplex analysis of TMAs together with immunohistochemistry (IHC) supplemented by hierarchical clustering are a useful, promising and very powerful tool for the identification of tumour subgroups with diagnostic and prognostic signatures.

Biomarkers, Tumor↗