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1.  Tumor cells with low proteasome subunit expression predict overall survival in head and neck cancer patients 
BMC Cancer  2014;14:152.
Background
Experimental and clinical data suggest that solid cancers contain treatment-resistant cancer stem cells that will impair treatment efficacy. The objective of this study was to investigate if head and neck squamous cell carcinoma (HNSCC) also contain cancer stem cells that can be identified by low 26S proteasome activity and if their presence correlates to clinical outcome.
Methods
Human HNSCC cells, engineered to report lack of proteasome activity based on accumulation of a fluorescent fusion protein, were separated based on high (ZsGreen-cODCneg) or low (ZsGreen-cODCpos) proteasome activity. Self-renewal capacity, tumorigenicity and radioresistance were assessed. Proteasome subunit expression was analyzed in tissue microarrays and correlated to survival and locoregional cancer control of 174 patients with HNSCC.
Results
HNSCC cells with low proteasome activity showed a significantly higher self-renewal capacity and increased tumorigenicity. Irradiation enriched for ZsGreen-cODCpos cells. The survival probability of 82 patients treated with definitive radio- or chemo-radiotherapy exhibiting weak, intermediate, or strong proteasome subunit expression were 21.2, 28.8 and 43.8 months (p = 0.05), respectively. Locoregional cancer control was comparably affected.
Conclusions
Subpopulations of HNSCC display stem cell features that affect patients’ tumor control and survival. Evaluating cancer tissue for expression of the proteasome subunit PSMD1 may help identify patients at risk for relapse.
doi:10.1186/1471-2407-14-152
PMCID: PMC3975871  PMID: 24593279
Cancer stem cells; Head and neck cancer; Proteasome; Radiotherapy
2.  Intestinal-type of differentiation predicts favourable overall survival: confirmatory clinicopathological analysis of 198 periampullary adenocarcinomas of pancreatic, biliary, ampullary and duodenal origin 
BMC Cancer  2013;13:428.
Background
Periampullary adenocarcinomas comprise pancreatic, distal bile duct, ampullary and duodenal adenocarcinoma. The epithelia of these anatomical structures share a common embryologic origin from the foregut. With steadily increasing numbers of pancreatoduodenectomies over the last decades, pathologists, surgeons and oncologists are more often confronted with the diagnosis of “other than pancreatic” periampullary cancers. The intestinal subtype of ampullary cancer has been shown to correlate with better prognosis.
Methods
Histological subtype and immunohistochemical staining pattern for CK7, CK20 and CDX2 were assessed for n = 198 cases of pancreatic ductal, distal bile duct, ampullary and duodenal adenocarcinoma with clinical follow-up. Routine pathological parameters were included in survival analysis performed with SPSS 20.
Results
In univariate analysis, intestinal subtype was associated with better survival in ampullary, pancreatic ductal and duodenal adenocarcinoma. The intestinal type of pancreatic ductal adenocarcinoma was not associated with intraductal papillary mucinous neoplasm and could not be reliably diagnosed by immunohistochemical staining pattern alone. Intestinal differentiation and lymph node ratio, but not tumor location were independent predictors of survival when all significant predictor variables from univariate analysis (grade, TNM stage, presence of precursor lesions, surgical margin status, perineural, vascular and lymphatic vessel invasion, CK7 and CDX2 staining pattern) were included in a Cox proportional hazards model.
Conclusions
Intestinal type differentiation and lymph node ratio but not tumor location are independent prognostic factors in pooled analysis of periampullary adenocarcinomas. We conclude that differentiation is more important than tumor location for prognostic stratification in periampullary adenocarcinomas.
doi:10.1186/1471-2407-13-428
PMCID: PMC3849372  PMID: 24053229
3.  Isolated hypoplastic circumflex coronary artery: a rare cause of haemorrhagic myocardial infarction in a young athlete 
Diagnostic Pathology  2013;8:91.
Hypoplastic coronary artery disease is a rare condition that may lead to myocardial infarction and sudden death. Here we describe for the first time an isolated hypoplasia of the left circumflex artery (LCX). An otherwise healthy and athletically active 16-year-old boy was admitted to the intensive care unit (ICU) after out-of-hospital cardiac arrest. He died 12 hours after the initial event. Autopsy revealed an isolated hypoplastic LCX and acute haemorrhagic infarction in the posterolateral myocardium. The existence of isolated hypoplasia of the LCX challenges our understanding of coronary artery development.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1558483061962648
doi:10.1186/1746-1596-8-91
PMCID: PMC3682927  PMID: 23742172
Isolated hypoplasia of the left circumflex artery; Myocardial haemorrhagic infarction; Sudden death in young athletes; Coronary artery development
4.  Acute fibrinous and organizing pneumonia associated with influenza A/H1N1 pneumonia after lung transplantation 
Background
Immunocompromised patients, particularly after lung transplantation, are at high risk to develop atypical forms of pulmonary infections including influenza A/H1N1. Acute Fibrinous and Organizing Pneumonia (AFOP) is a special histological pattern in acute respiratory failure with high mortality.
Case presentation
We describe a 66-year-old woman with double lung transplantation in August 2009 due to end stage pulmonary fibrosis. After prolonged weaning and subsequent promising course, she developed atypical pneumonia with diffuse pulmonary infiltrates in both lungs in January 2010. Infection with influenza A/H1N1 virus was verified. The patient rapidly suffered from respiratory insufficiency and died eight days after this diagnosis. The post-mortem revealed especially in the lower parts of the lungs the classical histological pattern of pure AFOP. Molecular analyses of lung tissue were positive for influenza A/H1N1.
Conclusion
To our knowledge we present the first case of AFOP triggered by viral infection, here proven to be influenza virus A/H1N1. Thus, also in the setting of viral infection the highly deadly differential diagnosis of AFOP must be considered.
doi:10.1186/1471-2466-13-30
PMCID: PMC3662564  PMID: 23683442
AFOP; Influenza A/H1N1; Acute lung failure; Lung transplantation; Viral infection
5.  Simvastatin-induced compartmentalisation of doxorubicin sharpens up nuclear topoisomerase II inhibition in human rhabdomyosarcoma cells 
Tumours, which are initially sensitive to cytotoxic agents, often develop resistance to a broad spectrum of structurally unrelated drugs. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to inhibit ATP-binding cassette (ABC) transporters but have also impact on glycosylation of such proteins. Doxorubicin is a substrate for ABC transporters like P-glycoprotein (ABCB1) which is present in human RD rhabdomyosarcoma cells. It was therefore the aim of this study to identify the compartmentalisation and action of doxorubicin in simvastatin-treated RD cells. Due to autofluorescence of doxorubicin, intracellular distribution was monitored by confocal microscopy. The biological effects were traced on the level of colony formation, caspase activation and DNA injury. Here we show that simvastatin treatment leads to ABCB1 inhibition and down-regulation of the transporter. Consequently, these cells accumulate significant amounts of doxorubicin, predominantly in the nucleus and lysosomes. While clearance of the anthracycline into lysosomes is not altered by simvastatin treatment, it significantly enhanced nuclear accumulation in a HMG-CoA reductase-independent manner. Thus, in such treated cells, topoisomerase II activity is significantly inhibited, which is further corroborated by augmented double-strand DNA breaks. Moreover, colony formation was synergistically inhibited by the combination of simvastatin and doxorubicin. Given the fact that ABCB1 expression correlates with an adverse prognosis in many tumours, adjuvant chemotherapy including statins might represent a novel therapeutic concept to overcome ABCB1-mediated multidrug resistance by direct inhibition and down-regulation.
doi:10.1007/s00210-013-0859-y
PMCID: PMC3676642  PMID: 23564041
ATP-binding cassette transporters; HMG-CoA reductase inhibitors; Apoptosis; Topoisomerase II; Rhabdomyosarcoma
6.  Simultaneous Multi-Antibody Staining in Non-Small Cell Lung Cancer Strengthens Diagnostic Accuracy Especially in Small Tissue Samples 
PLoS ONE  2013;8(2):e56333.
Histological subclassification of non-small cell lung cancer (NSCLC) has growing therapeutic impact. In advanced cancer stages tissue specimens are usually bioptically collected. These small samples are of extraordinary value since molecular analyses are gaining importance for targeted therapies. We therefore studied the feasibility, diagnostic accuracy, economic and prognostic effects of a tissue sparing simultaneous multi-antibody assay for subclassification of NSCLC. Of 265 NSCLC patients tissue multi arrays (TMA) were constructed to simulate biopsy samples. TMAs were stained by a simultaneous bi-color multi-antibody assay consisting of TTF1, Vimentin, p63 and neuroendocrine markers (CD56, chromogranin A, synaptophysin). Classification was based mainly on the current proposal of the IASLC with a hierarchical decision tree for subclassification into adenocarcinoma (LAC), squamous cell carcinoma (SCC), large cell neuroendocrine carcinoma (LCNEC) and NSCLC not otherwise specified. Investigation of tumor heterogeneity showed an explicit lower variation for immunohistochemical analyses compared to conventional classification. Furthermore, survival analysis of our combined immunohistochemical classification revealed distinct separation of each entity's survival curve. This was statistically significant for therapeutically important subgroups (p = 0.045). As morphological and molecular cancer testing is emerging, our multi-antibody assay in combination with standardized classification delivers accurate and reliable separation of histomorphological diagnoses. Additionally, it permits clinically relevant subtyping of NSCLC including LCNEC. Our multi-antibody assay may therefore be of special value, especially in diagnosing small biopsies. It futher delivers substantial prognostic information with therapeutic consequences. Integration of immunohistochemical subtyping including investigation of neuroendocrine differentiation into standard histopathological classification of NSCLC must, therefore, be considered.
doi:10.1371/journal.pone.0056333
PMCID: PMC3572034  PMID: 23418554
7.  Hypofractionated stereotactic radiotherapy of limited brain metastases: a single-centre individualized treatment approach 
BMC Cancer  2012;12:497.
Background
We retrospectively report treatment results of our single-centre experience with hypofractionated stereotactic radiotherapy (hfSRT) of limited brain metastases in primary and recurrence disease situations. Our aim was to find the most effective and safe dose concept.
Methods
From 04/2006 to 12/2010, 75 patients, with 108 intracranial metastases, were treated with hfSRT. 52 newly diagnosed metastases (48%), without up-front whole brain radiotherapy (WBRT), received hfSRT as a primary treatment. 56 metastases (52%) received a prior WBRT and were treated in this study in a recurrence situation. Main fractionation concepts used for primary hfSRT were 6-7x5 Gy (61.5%) and 5x6 Gy (19.2%), for recurrent hfSRT 7-10x4 Gy (33.9%) and 5-6x5 Gy (33.9%).
Results
Median overall survival (OS) of all patients summed up to 9.1 months, actuarial 6-and 12-month-OS was 59% and 35%, respectively. Median local brain control (LC) was 11.9 months, median distant brain control (DC) 3.9 months and intracranial control (IC) 3.4 months, respectively. Variables with significant influence on OS were Gross Tumour Volume (GTV) (p = 0.019), the biological eqivalent dose (calculated on a 2 Gy single dose, EQD2, α/β = 10) < and ≥ median of 39 Gy (p = 0.012), extracerebral activity of the primary tumour (p < 0.001) and the steroid uptake during hfSRT (p = 0.03). LC was significantly influenced by the EQD2, ≤ and > 35 Gy (p = 0.004) in both uni- and multivariate Cox regression analysis. Median LC was 14.9 months for EQD2 >35 Gy and 3.4 months for doses ≤35 Gy, respectively. Early treatment related side effects were usually mild. Nevertheless, patients with a EQD2 >35 Gy had higher rates of toxicity (31%) than ≤35 Gy (8.3%, p=0.026).
Conclusion
Comparing different dose concepts in hfSRT, a cumulative EQD2 of ≥35 Gy seems to be the most effective concept in patients with primary or recurrent limited brain metastases. Despite higher rates of only mild toxicity, this concept represents a safe treatment option.
doi:10.1186/1471-2407-12-497
PMCID: PMC3531248  PMID: 23098039
Brain tumours; hfSRT; SRS; Fractionation
8.  Molecular modeling and description of a newly characterized activating mutation of the EGFR gene in non-small cell lung cancer 
Diagnostic Pathology  2012;7:146.
Abstract
Lung cancer is the leading cause of death among malignant diseases in humans worldwide. In the last decade development of new targeted drugs for the treatment of non-small cell lung cancer proved to be a promising approach to prolong the otherwise very poor prognosis of patients with advanced UICC stages. Epidermal growth factor receptor (EGFR) has been in the focus of this lung cancer science and specific activating mutations are eligible for the treatment with specific tyrosine kinase inhibitors like gefitinib or erlotinib. Beside typical deletions in exon 19 and point mutations in exons 18 and 21 several insertions in exon 19 have been described and attributed activating properties as well. This is the first European and overall the 5th description in English literature of one of these specific insertions. To elucidate its structural changes leading to the activating properties we performed molecular modeling studies. These revealed conformational and electrostatic force field changes in the kinase domain of EGFR. To not miss uncommon mutations thorough and precise characterization of EGFR hotspots, i. e. at least exons 18, 19 and 21, should therefore be conducted to provide best medical care and to offer lung cancer patients appropriate cancer treatment.
Virtual slides
The vistual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2209889658102062
doi:10.1186/1746-1596-7-146
PMCID: PMC3523061  PMID: 23088930
9.  A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2 
Mice expressing a transgene encoding the transcription factor NF-E2 in hematopoietic cells exhibit features of myeloproliferative neoplasms, including thrombocytosis, Epo-independent colony formation, stem and progenitor cell overabundance, leukocytosis, and progression to acute myeloid leukemia.
The molecular pathophysiology of myeloproliferative neoplasms (MPNs) remains poorly understood. Based on the observation that the transcription factor NF-E2 is often overexpressed in MPN patients, independent of the presence of other molecular aberrations, we generated mice expressing an NF-E2 transgene in hematopoietic cells. These mice exhibit many features of MPNs, including thrombocytosis, leukocytosis, Epo-independent colony formation, characteristic bone marrow histology, expansion of stem and progenitor compartments, and spontaneous transformation to acute myeloid leukemia. The MPN phenotype is transplantable to secondary recipient mice. NF-E2 can alter histone modifications, and NF-E2 transgenic mice show hypoacetylation of histone H3. Treatment of mice with the histone deacetylase inhibitor (HDAC-I) vorinostat restored physiological levels of histone H3 acetylation, decreased NF-E2 expression, and normalized platelet numbers. Similarly, MPN patients treated with an HDAC-I exhibited a decrease in NF-E2 expression. These data establish a role for NF-E2 in the pathophysiology of MPNs and provide a molecular rationale for investigating epigenetic alterations as novel targets for rationally designed MPN therapies.
doi:10.1084/jem.20110540
PMCID: PMC3260873  PMID: 22231305
10.  Multifocal gastric gastrointestinal stromal tumors (GISTs) with lymph node metastases in children and young adults: A comparative clinical and histomorphological study of three cases including a new case of Carney triad 
Diagnostic Pathology  2011;6:52.
Background
Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract usually occurring in the 6th to 7th decade of life, while their occurrence in children is rare (1-2%).
Carney triad (CT), a non-hereditary association of gastric GIST with pulmonary chondroma and/or extraadrenal paraganglioma, is an even much rarer disease (to date ~120 cases reported worldwide) usually affecting young adult females. Pediatric GISTs differ from CT-associated GISTs solely by the absence of other components of the triad and are completely different from sporadic GISTs of the adult. Both, pediatric and CT-GISTs, metastasize frequently to regional lymph nodes (29%) and are usually wild type (WT) for common KIT-/PDGFRA mutations.
Case presentation and results
We compare one new CT GIST with two pediatric/young adult multifocal gastric GISTs presenting with lymph node metastases. We put special focus on histomorphological growth pattern in the primary tumors and in the metastases.
The two cases of pediatric/young adult GIST without the other components of CT showed all the features of the triad: female gender, young age, multifocal antral-based gastric GIST with biphasic histological growth pattern, lymph node metastases, hypercellularity and WT status for common KIT-, PDGFRA- and B-RAF mutations.
Discussion and conclusion
Pediatric/CT-associated GISTs and sporadic GISTs of the adults differ significantly from each other with regard to patients' age, gender, tumor localisation, histomorphological growth pattern, mutational status and risk for metastasis. Our cases of pediatric/young adult GISTs show all characteristics of CT except for the absence of other components of the triad.
Therefore these GISTs are probably not sporadic, but may represent either early manifestation or forme fruste of the CT. Thus, these patients need to be regularly examined for the development of extraadrenal paraganglioma or pulmonary chondroma.
doi:10.1186/1746-1596-6-52
PMCID: PMC3130635  PMID: 21663639
11.  Occurrence of multipolar mitoses and association with Aurora-A/-B kinases and p53 mutations in aneuploid esophageal carcinoma cells 
BMC Cell Biology  2011;12:13.
Background
Aurora kinases and loss of p53 function are implicated in the carcinogenesis of aneuploid esophageal cancers. Their association with occurrence of multipolar mitoses in the two main histotypes of aneuploid esophageal squamous cell carcinoma (ESCC) and Barrett's adenocarcinoma (BAC) remains unclear. Here, we investigated the occurrence of multipolar mitoses, Aurora-A/-B gene copy numbers and expression/activation as well as p53 alterations in aneuploid ESCC and BAC cancer cell lines.
Results
A control esophageal epithelial cell line (EPC-hTERT) had normal Aurora-A and -B gene copy numbers and expression, was p53 wild type and displayed bipolar mitoses. In contrast, both ESCC (OE21, Kyse-410) and BAC (OE33, OE19) cell lines were aneuploid and displayed elevated gene copy numbers of Aurora-A (chromosome 20 polysomy: OE21, OE33, OE19; gene amplification: Kyse-410) and Aurora-B (chromosome 17 polysomy: OE21, Kyse-410). Aurora-B gene copy numbers were not elevated in OE19 and OE33 cells despite chromosome 17 polysomy. Aurora-A expression and activity (Aurora-A/phosphoT288) was not directly linked to gene copy numbers and was highest in Kyse-410 and OE33 cells. Aurora-B expression and activity (Aurora-B/phosphoT232) was higher in OE21 and Kyse-410 than in OE33 and OE19 cells. The mitotic index was highest in OE21, followed by OE33 > OE19 > Kyse-410 and EPC-hTERT cells. Multipolar mitoses occurred with high frequency in OE33 (13.8 ± 4.2%), followed by OE21 (7.7 ± 5.0%) and Kyse-410 (6.3 ± 2.0%) cells. Single multipolar mitoses occurred in OE19 (1.0 ± 1.0%) cells. Distinct p53 mutations and p53 protein expression patterns were found in all esophageal cancer cell lines, but complete functional p53 inactivation occurred in OE21 and OE33 only.
Conclusions
High Aurora-A expression alone is not associated with overt multipolar mitoses in aneuploid ESCC and BAC cancer cells, as specifically shown here for OE21 and OE33 cells, respectively. Additional p53 loss of function mutations are necessary for this to occur, at least for invasive esophageal cancer cells. Further assessment of Aurora kinases and p53 interactions in cells or tissue specimens derived from non-invasive dysplasia (ESCC) or intestinal metaplasia (BAC) are necessary to disclose a potential causative role of Aurora kinases and p53 for development of aneuploid, invasive esophageal cancers.
doi:10.1186/1471-2121-12-13
PMCID: PMC3094318  PMID: 21470402
13.  Standards and Impact of Hematopathology in Myelodysplastic Syndromes (MDS) 
Oncotarget  2010;1(7):483-496.
The diagnosis, classification, and prognostication of patients with myelodysplastic syndromes (MDS) are usually based on clinical parameters, analysis of peripheral blood and bone marrow smears, and cytogenetic determinants. However, a thorough histologic and immunohistochemical examination of the bone marrow is often required for a final diagnosis and exact classification in these patients. Notably, histology and immunohistology may reveal dysplasia in megakaryocytes or other bone marrow lineages and/or the presence of clusters of CD34-positive precursor cells. In other cases, histology may reveal an unrelated or co-existing hematopoietic neoplasm, or may support the conclusion the patient is suffering from acute myeloid leukemia rather than MDS. Moreover, histologic investigations and immunohistology may reveal an increase in tryptase-positive cells, a coexisting systemic mastocytosis, or bone marrow fibrosis, which is of prognostic significance. To discuss diagnostic algorithms, terminologies, parameters, and specific issues in the hematopathologic evaluation of MDS, a Working Conference involving a consortium of US and EU experts, was organized in June 2010. The outcomes of the conference and resulting recommendations provided by the faculty, are reported in this article. These guidelines should assist in the diagnosis, classification, and prognostication in MDS in daily practice as well as in clinical trials.
PMCID: PMC3248141  PMID: 21317447
MDS; hematopathology; diagnostic criteria; prognostication
14.  Lactate-Dehydrogenase 5 is overexpressed in non-small cell lung cancer and correlates with the expression of the transketolase-like protein 1 
Diagnostic Pathology  2010;5:22.
Aims
As one of the five Lactate dehydrogenase (LDH) isoenzymes, LDH5 has the highest efficiency to catalyze pyruvate transformation to lactate. LDH5 overexpression in cancer cells induces an upregulated glycolytic metabolism and reduced dependence on the presence of oxygen. Here we analyzed LDH5 protein expression in a well characterized large cohort of primary lung cancers in correlation to clinico-pathological data and its possible impact on patient survival.
Methods
Primary lung cancers (n = 269) and non neoplastic lung tissue (n = 35) were tested for LDH5 expression by immunohistochemistry using a polyclonal LDH5 antibody (ab53010). The results of LDH5 expression were correlated to clinico-pathological data as well as to patient's survival. In addition, the results of the previously tested Transketolase like 1 protein (TKTL1) expression were correlated to LDH5 expression.
Results
89.5% (n = 238) of NSCLC revealed LDH5 expression whereas LDH5 expression was not detected in non neoplastic lung tissues (n = 34) (p < 0.0001). LDH5 overexpression was associated with histological type (adenocarcinoma = 57%, squamous cell carcinoma = 45%, large cell carcinoma = 46%, p = 0.006). No significant correlation could be detected with regard to TNM-stage, grading or survival. A two sided correlation between the expression of TKTL1 and LDH5 could be shown (p = 0.002) within the overall cohort as well as for each grading and pN group. A significant correlation between LDH5 and TKTL1 within each histologic tumortype could not be revealed.
Conclusions
LDH5 is overexpressed in NSCLC and could hence serve as an additional marker for malignancy. Furthermore, LDH5 correlates positively with the prognostic marker TKTL1. Our results confirm a close link between the two metabolic enzymes and indicate an alteration in the glucose metabolism in the process of malignant transformation.
doi:10.1186/1746-1596-5-22
PMCID: PMC2861018  PMID: 20385008
15.  Gene expression profiles of lung adenocarcinoma linked to histopathological grading and survival but not to EGF-R status: a microarray study 
BMC Cancer  2010;10:77.
Background
Several different gene expression signatures have been proposed to predict response to therapy and clinical outcome in lung adenocarcinoma. Herein, we investigate if elements of published gene sets can be reproduced in a small dataset, and how gene expression profiles based on limited sample size relate to clinical parameters including histopathological grade and EGFR protein expression.
Methods
Affymetrix Human Genome U133A platform was used to obtain gene expression profiles of 28 pathologically and clinically annotated adenocarcinomas of the lung. EGFR status was determined by fluorescent in situ hybridization and immunohistochemistry.
Results
Using unsupervised clustering algorithms, the predominant gene expression signatures correlated with the histopathological grade but not with EGFR protein expression as detected by immunohistochemistry. In a supervised analysis, the signature of high grade tumors but not of EGFR overexpressing cases showed significant enrichment of gene sets reflecting MAPK activation and other potential signaling cascades downstream of EGFR. Out of four different previously published gene sets that had been linked to prognosis, three showed enrichment in the gene expression signature associated with favorable prognosis.
Conclusions
In this dataset, histopathological tumor grades but not EGFR status were associated with dominant gene expression signatures and gene set enrichment reflecting oncogenic pathway activation, suggesting that high immunohistochemistry EGFR scores may not necessarily be linked to downstream effects that cause major changes in gene expression patterns. Published gene sets showed association with patient survival; however, the small sample size of this study limited the options for a comprehensive validation of previously reported prognostic gene expression signatures.
doi:10.1186/1471-2407-10-77
PMCID: PMC2843676  PMID: 20196851
16.  STAT3 mRNA and protein expression in colorectal cancer: effects on STAT3‐inducible targets linked to cell survival and proliferation 
Journal of Clinical Pathology  2007;60(2):173-179.
Aims
To evaluate mRNA and protein expression of signal transducers and activators of transcription (STAT)3 in colorectal carcinomas (CRCs) and to define the association of STAT3 activity with the STAT3‐inducible targets cyclin D1, survivin, Bcl‐xl and Mcl‐1.
Materials and methods
Matching serial sections of normal colonic epithelium and invasive CRCs (n = 32) were subjected to quantitative reverse transcriptase polymerase chain reaction specific to STAT3, cyclin D1, survivin, Bcl‐xl and Mcl‐1, as well as immunohistochemistry. For STAT3 immunohistochemistry, two antibodies, recognising unphosphorylated (UP‐) and phosphorylated (tyr705, P‐) STAT3 were used. Ki‐67 (MIB‐1) staining was included as a proliferation marker.
Results
Compared with normal colonic epithelium, UP‐STAT3 and P‐STAT3 (p = 0.023 and 0.006) protein expression and expression of its associated targets cyclin D1, survivin and Bcl‐xl were significantly (all p<0.001) increased in carcinoma. In carcinomas, STAT3 (p = 0.019) and Bcl‐xl (p = 0.001) mRNAs were correlated with lymph node status. Moreover, nuclear P‐STAT3 protein expression (active state) was associated with the expression of its target genes Bcl‐xl (p = 0.038) and survivin (p = 0.01) as well as with Ki‐67 (p = 0.017). By contrast, cytoplasmic UP‐STAT was significantly linked to Bcl‐xl mRNA (p = 0.024) and protein (p = 0.001) as well as to cytoplasmic survivin protein expression (p = 0.019).
Conclusion
Both inactive (UP‐STAT3) and active (P‐STAT3) STAT3 proteins are markedly increased in invasive CRCs. This is associated with Bcl‐xl and survivin induction, increased proliferation and lymph node metastasis. This study therefore provides the basis for further examination of the prognostic or predictive value of these molecular markers in CRC.
doi:10.1136/jcp.2005.035113
PMCID: PMC1860635  PMID: 17264243

Results 1-16 (16)