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1.  Reply: A morpho-molecular prognostic model for hepatocellular carcinoma 
British Journal of Cancer  2013;108(3):741.
doi:10.1038/bjc.2012.515
PMCID: PMC3593532  PMID: 23422790
2.  Fibroblast growth factor receptor 4 (FGFR4): a targetable regulator of drug resistance in colorectal cancer 
Cell Death & Disease  2014;5(2):e1046-.
The discovery of underlying mechanisms of drug resistance, and the development of novel agents to target these pathways, is a priority for patients with advanced colorectal cancer (CRC). We previously undertook a systems biology approach to design a functional genomic screen and identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of drug resistance. The aim of this study was to examine the role of FGFR4 in drug resistance using RNAi and the small-molecule inhibitor BGJ398 (Novartis). We found that FGFR4 is highly expressed at the RNA and protein levels in colon cancer tumour tissue compared with normal colonic mucosa and other tumours. Silencing of FGFR4 reduced cell viability in a panel of colon cancer cell lines and increased caspase-dependent apoptosis. A synergistic interaction was also observed between FGFR4 silencing and 5-fluorouracil (5-FU) and oxaliplatin chemotherapy in colon cancer cell lines. Mechanistically, FGFR4 silencing decreased activity of the pro-survival STAT3 transcription factor and expression of the anti-apoptotic protein c-FLIP. Furthermore, silencing of STAT3 resulted in downregulation of c-FLIP protein expression, suggesting that FGFR4 may regulate c-FLIP expression via STAT3. A similar phenotype and downstream pathway changes were observed following FGFR4 silencing in cell lines resistant to 5-FU, oxaliplatin and SN38 and upon exposure of parental cells to the FGFR small-molecule inhibitor BGJ398. Our results indicate that FGFR4 is a targetable regulator of chemo-resistance in CRC, and hence inhibiting FGFR4 in combination with 5-FU and oxaliplatin is a potential therapeutic strategy for this disease.
doi:10.1038/cddis.2014.10
PMCID: PMC3944229  PMID: 24503538
FGFR4; drug resistance; 5-fluorouracil; oxaliplatin; colorectal
3.  Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer 
Cell Death & Disease  2013;4(12):e951-.
Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1–3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents.
doi:10.1038/cddis.2013.481
PMCID: PMC3877552  PMID: 24309938
non-small cell lung cancer; FLIP; caspase-8; TRAIL; HDAC inhibitor
4.  A morpho-molecular prognostic model for hepatocellular carcinoma 
British Journal of Cancer  2012;107(2):334-339.
Background:
Hepatocellular carcinoma (HCC) is the third common cause of cancer-related deaths and its prognostication is still suboptimal. The aim of this study was to establish a new prognostication algorithm for HCC.
Methods:
In all, 13 biomarkers related to the etiopathogenesis of HCC were evaluated by immunohistochemistry using tissue microarrays containing 121 primary HCC resection cases, and validated in subsequent cohort of 85 HCC cases. The results were compared with Affymetrix Gene Chip Human Genome U133Plus microarray data in a separate cohort of 228 HCC patients.
Results:
On immunohistochemical evaluation and multivariate Cox regression analysis p53, alpha fetaprotein (AFP), CD44 and CD31, tumour size and vascular invasion, were significant predictors for worse survival in HCC patients. A morpho-molecular prognostic model (MMPM) was constructed and it was a significant independent predictor for overall survival (OS) and relapse-free survival (RFS) (P<0.000). The OS and RFS of HCClow was higher (104 and 78 months) as compared with HCChigh (73 and 43 months) (P<0.0001for OS and RFS). Hepatocellular carcinoma patients with higher stage (III+IV), >5 cm tumour size, positive vascular invasion and satellitosis belonged to HCChigh group. The validation group reproduced the same findings. Gene expression analysis confirmed that 7 of the 12 biomarkers were overexpressed in >50% of tumour samples and significant overexpression in tumour samples was observed in AFP, CD31, CD117 and Ki-67 genes.
Conclusion:
The MMPM, based on the expression of selected proteins and clinicopathological parameters, can be used to classify HCC patients between good vs poor prognosis and high vs low risk of recurrence following hepatic resection.
doi:10.1038/bjc.2012.230
PMCID: PMC3394972  PMID: 22713659
p53; microvessel density; prognosis; liver cancer; survival
5.  Sequential expression of putative stem cell markers in gastric carcinogenesis 
British Journal of Cancer  2011;105(5):658-665.
Background:
Gastric carcinogenesis has been well documented in the step-wise histopathological model, known as Correa pathway. Several biomarkers including CD44, Musashi-1 and CD133 have been reported as putative stem cell (PSC) markers.
Methods:
We investigated expression of PSC markers CD44, Musashi-1 and CD133 in relation to gastric carcinogenesis and prognosis and chemoresponse. Immunohistochemistry staining was performed in gastric cancer (GC) clinical specimens representing different steps of the Correa pathway. Gastric cancer samples taken before and after neoadjuvant chemotherapy with docetaxel, cisplatin and capecitabine (DCX) were also evaluated for PSC marker expression.
Results:
We showed that the expression of three PSC markers was significantly elevated in GC relative to normal gastric mucosa (P<0.001 for each marker). Precancerous lesions, including intestinal metaplasia and dysplasia, demonstrated increased expression of CD44 and Musashi-1. CD133 was predominantly expressed along the border between intramucosal carcinoma and connective tissue at later stages. High CD44 and CD133 expression showed prognostic value for worse patient survival (P=0.014 and P=0.019, respectively). A small number of tumours with high expression of CD44 and CD133 showed pathological response to DCX-based neoadjuvant chemotherapy.
Conclusion:
CD44 and Musashi-1 are frequently expressed in both premalignant gastric lesions and invasive GC, whereas CD133 expression is restricted mainly to neoplastic tissues.
doi:10.1038/bjc.2011.287
PMCID: PMC3188930  PMID: 21829201
CD44; CD133; Musashi-1; Correa pathway; gastric cancer
6.  Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy 
Background
Low tumour expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) have been linked with improved outcome for colorectal cancer (CRC) patients treated with 5-fluorouracil (5-FU). It is unclear whether this occurs because such tumours have better prognosis or they are more sensitive to 5-FU treatment.
Patients and methods
Associations between TS, DPD and TP levels, determined by tissue microarrays and immunohistochemistry, and survival was evaluated in 945 CRC patients according to treatment status.
Results
Low TS and DPD expression associated with worse prognosis in stage II [hazard ratio (HR) = 1.69, 95% confidence interval (CI) (1.09–2.63) and HR = 1.92 (95% CI 1.23–2.94), respectively] and stage III CRC patients treated by surgery alone [HR = 1.39 (95% CI 0.92–2.13) and HR = 1.49 (95% CI 1.02–2.17), respectively]. Low TS, DPD and TP associated with trends for better outcome in stage III patients treated with 5-FU [HR = 0.81 (95% CI 0.49–1.33), HR = 0.70 (95% CI 0.42–1.15) and HR = 0.66 (95% CI 0.39–1.12), respectively].
Conclusion
Low TS and DPD expression are prognostic for worse outcome in CRC patients treated by surgery alone, whereas low TS, DPD and TP expression are prognostic for better outcome in patients treated with 5-FU chemotherapy. These results provide indirect evidence that low TS, DPD and TP protein expression are predictive of good response to 5-FU chemotherapy.
doi:10.1093/annonc/mdm599
PMCID: PMC2931808  PMID: 18245778
colorectal cancer; fluorouracil; predictive; prognostic; thymidylate synthase
7.  The expression of RUNX3 in colorectal cancer is associated with disease stage and patient outcome 
British Journal of Cancer  2009;100(5):676-679.
RUNX3 is believed to have tumour suppressor properties in several cancer types. Inactivation of RUNX3 has been shown to occur by methylation-induced transcriptional silencing and by mislocalization of the protein to the cytoplasm. The aim of this study was to examine the clinical significance of RUNX3 expression in a large series of colorectal cancers using immunohistochemistry and tissue arrays. With advancing tumour stage, expression of RUNX3 in the nucleus decreased, whereas expression restricted to the cytoplasmic compartment increased. Nuclear RUNX3 expression was associated with significantly better patient survival compared to tumours in which the expression of RUNX3 was restricted to the cytoplasm (P=0.025). These results support a role for RUNX3 as a tumour suppressor in colorectal cancer.
doi:10.1038/sj.bjc.6604899
PMCID: PMC2653772  PMID: 19223906
RUNX3; colorectal cancer; tissue arrays; prognosis; Wnt
8.  Discordant quantitative detection of putative biomarkers in nodal micrometastases of colorectal cancer: biological and clinical implications 
Journal of Clinical Pathology  2005;58(8):839-844.
Aims: Nodal expression of the carcinoembryonic antigen (CEA), cytokeratin 20 (CK20), and guanylyl cyclase C (GCC) genes was measured in tandem in patients with colorectal cancer (CRC) to assess whether there would be sufficient agreement between these markers in their ability to detect micrometastasis to qualify one of them as a universal marker, and whether frozen and paraffin wax embedded tissues would yield similar results.
Methods: One hundred and seventy five frozen lymph nodes (FT) and 158 formalin fixed, paraffin wax embedded lymph nodes (PET) from 28 CRC cases were analysed using gene specific quantitative real time polymerase chain reaction, carried out on the LightCycler® system with SYBR Green chemistry.
Results: There was significant disparity in positive detection of the three biomarkers in FT versus PET, with notable agreement achieved only for CEA (66.6%) in FT versus PET in Dukes’ B disease, and between CK20 and GCC (44.6%) in FT, also in Dukes’ B disease. One patient with full concordance in all three tumour markers with both tissue types suffered a relapse and died within two years of follow up.
Conclusions: There was considerable discordance in the positive detection of the three tumour markers in both tissue types (FT versus PET). This brings into question whether using a single tumour marker to detect micrometastasis in one tissue type (FT or PET) is adequately representative, and challenges the concept of universal markers for molecular CRC metastatic detection. Multiple tumour markers would predict more accurately the metastatic potential of Dukes’ B CRCs.
doi:10.1136/jcp.2004.023853
PMCID: PMC1770861  PMID: 16049286
metastasis; real time polymerase chain reaction; tumour marker; mRNA; lymph nodes
9.  Tissue microarrays characterise the clinical significance of a VEGF-A protein expression signature in gastrointestinal stromal tumours 
British Journal of Cancer  2007;96(5):776-782.
A tissue microarray analysis of 22 proteins in gastrointestinal stromal tumours (GIST), followed by an unsupervised, hierarchical monothetic cluster statistical analysis of the results, allowed us to detect a vascular endothelial growth factor (VEGF) protein overexpression signature discriminator of prognosis in GIST, and discover novel VEGF-A DNA variants that may have functional significance.
doi:10.1038/sj.bjc.6603551
PMCID: PMC2360083  PMID: 17299397
gastrointestinal stromal tumours; VEGF; tissue microarrays
10.  Lymphocytic gastritis-like T cell lymphoma: molecular evidence of an unusual recurrence 
Journal of Clinical Pathology  2004;57(11):1222-1224.
This report describes a patient with a gastric biopsy specimen showing histomorphological and immunohistochemical appearances indistinguishable from those usually present in lymphocytic gastritis, a rare condition of unknown aetiology with a distinctive phenotype. The patient had a history of a biopsy confirmed T cell non-Hodgkin lymphoma at two anatomical sites (bladder and stomach), which was subsequently treated. Molecular analysis of the T cell receptor (TCR) γ chain gene rearrangements showed a distinct monoclonal T cell population in the bladder and gastric biopsies. The same analysis in the lymphocytic gastritis-like biopsy sample showed a monoclonal population with identical base pair size to that identified in the other specimens. This report highlights the importance of TCR gene rearrangement analysis in the diagnosis of unusual gastric inflammation, and the use of capillary electrophoresis based polymerase chain reaction in the follow up of lymphoproliferative disorders.
doi:10.1136/jcp.2004.017350
PMCID: PMC1770480  PMID: 15509690
T cell receptor gene rearrangements; lymphocytic gastritis; T cell lymphoma
11.  Interobserver variation in cell selection for DNA image cytometry. 
Journal of Clinical Pathology  1995;48(7):616-619.
AIMS--To describe a systematic investigation of interobserver differences in interpretation of nuclear morphology in preparations of small cell lung cancer (SCLC). METHODS--The screening/reviewing facility on the highly optimised microscope environment was used to individually tag 127 nuclei, chosen to reflect the spectrum of morphological appearances in nuclear preparations from three biopsy specimens of SCLC. Each nucleus was reviewed and labelled as control (lymphocyte), malignant or unsatisfactory by each of four observers. DNA histograms were plotted for each specimen using the nuclei identified as malignant by each participant. The histograms were compared in terms of identification of DNA stemlines and by calculation of a 5c exceeding rate (5cER). RESULTS--Interobserver variation in assessment of morphology was seen in 55.1% of nuclei. Disagreement occurred most frequently in the malignant/unsatisfactory category. Differences in morphological classification had little influence on histogram assessment by means of visual inspection but did show an effect on 5cER. CONCLUSIONS--There are significant interobserver differences in subjective assessment of nuclear morphology in cytometric preparations. This effect may seriously influence cytometric measurements.
Images
PMCID: PMC502710  PMID: 7560166

Results 1-11 (11)