Publications
818 results found
Coombes RC, Kilburn LS, Tubiana-Mathieu N, et al., 2016, Epirubicin dose and sequential hormonal therapy-Mature results of the HMFEC randomised phase III trial in premenopausal patients with node positive early breast cancer, European Journal of Cancer, Vol: 60, Pages: 146-153, ISSN: 1879-0852
Frampton AE, Krell J, Mato Prado M, et al., 2016, Prospective validation of microRNA signatures for detecting pancreatic malignant transformation in endoscopic-ultrasound guided fine-needle aspiration biopsies, Oncotarget, Vol: 7, ISSN: 1949-2553
Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. Novel biomarkers are required to aid treatment decisions and improve patient outcomes. MicroRNAs (miRNAs) are potentially ideal diagnostic biomarkers, as they are stable molecules, and tumour and tissue specific. Results: Logistic regression analysis revealed an endoscopic-ultrasound fine-needle aspiration (EUS-FNA) 2-miRNA classifier (miR-21 + miR-155) capable of distinguishing benign from malignant pancreatic lesions with a sensitivity of 81.5% and a specificity of 85.7% (AUC 0.930). Validation FNA cohorts confirmed both miRNAs were overexpressed in malignant disease, while circulating miRNAs performed poorly.Methods: Fifty-five patients with a suspicious pancreatic lesion on cross-sectional imaging were evaluated by EUS-FNA. At echo-endoscopy, the first part of the FNA was sent for cytological assessment and the second part was used for total RNA extraction. Candidate miRNAs were selected after careful review of the literature and expression was quantified by qRT-PCR. Validation was performed on an independent cohort of EUS-FNAs, as well as formalin-fixed paraffin embedded (FFPE) and plasma samples.Conclusions: We provide further evidence for using miRNAs as diagnostic biomarkers for pancreatic malignancy. We demonstrate the feasibility of using fresh EUS-FNAs to establish miRNA-based signatures unique to pancreatic malignant transformation and the potential to enhance risk stratification and selection for surgery.
Neofytou K, Giakoustidis A, Neves MC, et al., 2016, Increased carcinoembryonic antigen (CEA) following neoadjuvant chemotherapy predicts poor prognosis in patients that undergo hepatectomy for liver-only colorectal metastases., Langenbecks Archives of Surgery, ISSN: 1435-2451
BACKGROUND: The importance of preoperative chemotherapy in a multimodality management of patients with colorectal liver metastases (CRLM) has been demonstrated. We analyse the carcinoembryonic antigen (CEA) changes following neoadjuvant chemotherapy in patients with CRLM who underwent liver resection. METHODS: The final cohort included 107 eligible patients. Increased CEA levels following neoadjuvant chemotherapy were defined as the increase of baseline CEA level at diagnosis of CRLM compared with the CEA level after completion of neoadjuvant chemotherapy. Disease-free survival (DFS), post-recurrence survival (PRS) and overall survival (OS) were calculated using both Kaplan-Meier and multivariate Cox-regression methods. RESULTS: CEA increase was associated with decreased PRS and OS (HR 2.69; 95 % CI, 1.28-5.63; p = 0.009, and HR 2.50; 95 % CI, 1.12-5.56; p = 0.025, respectively) in multivariate analysis, but there was no association between CEA changes and DFS. CEA increase was only associated with disease progression during preoperative chemotherapy (p = 0.014). Interestingly, this association was not absolute, as only 5 of the 11 patients with disease progression demonstrated CEA increase. Regarding the remaining 12 patients with CEA increase, according to RECIST criteria, eight patients demonstrated partial response and four patients stable disease. CONCLUSION: In this study, we demonstrated the CEA increase following neoadjuvant chemotherapy as an adverse prognostic factor for PRS, and OS but not for DFS in patients undergoing liver resection for liver-only colorectal metastases.
Nunes J, Zhang H, Angelopoulos N, et al., 2016, ATG9A loss confers resistance to trastuzumab via c-Cbl mediated Her2 degradation, Oncotarget, Vol: 7, Pages: 27599-27612, ISSN: 1949-2553
Acquired or de novo resistance to trastuzumab remains a barrier to patient survival and mechanisms underlying this still remain unclear. Using stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative proteomics to compare proteome profiles between trastuzumab sensitive/resistant cells, we identified autophagy related protein 9A (ATG9A) as a down-regulated protein in trastuzumab resistant cells (BT474-TR). Interestingly, ATG9A ectopic expression markedly decreased the proliferative ability of BT474-TR cells but not that of the parental line (BT474). This was accompanied by a reduction of Her2 protein levels and AKT phosphorylation (S473), as well as a decrease in Her2 stability, which was also observed in JIMT1 and MDA-453, naturally trastuzumab-resistant cells. In addition, ATG9A indirectly promoted c-Cbl recruitment to Her2 on T1112, a known c-Cbl docking site, leading to increased K63 Her2 polyubiquitination. Whereas silencing c-Cbl abrogated ATG9A repressive effects on Her2 and downstream PI3K/AKT signaling, its depletion restored BT474-TR proliferative rate. Taken together, our findings show for this first time that ATG9A loss in trastuzumab resistant cells allowed Her2 to escape from lysosomal targeted degradation through K63 poly-ubiquitination via c-Cbl. This study identifies ATG9A as a potentially druggable target to overcome resistance to anti-Her2 blockade.
Cathcart P, Stebbing J, 2016, Quackery Aloe vera, a natural cancer soother?, Lancet Oncology, Vol: 17, Pages: 421-421, ISSN: 1474-5488
Angelopoulos N, Stebbing J, Xu Y, et al., 2016, Proteome-wide dataset supporting functional study of tyrosine kinases in breast cancer., Data in Brief, Vol: 7, Pages: 740-746, ISSN: 2352-3409
Tyrosine kinases (TKs) play an essential role in regulating various cellular activities and dysregulation of TK signaling contributes to oncogenesis. However, less than half of the TKs have been thoroughly studied. Through a combined use of RNAi and stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics, a global functional proteomic landscape of TKs in breast cancer was recently revealed highlighting a comprehensive and highly integrated signaling network regulated by TKs (Stebbing et al., 2015) [1]. We collate the enormous amount of the proteomic data in an open access platform, providing a valuable resource for studying the function of TKs in cancer and benefiting the science community. Here we present a detailed description related to this study (Stebbing et al., 2015) [1] and the raw data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the identifier PXD002065.
Brown M, Black JRM, Sharma R, et al., 2016, Gene of the month: Axl, Journal of Clinical Pathology, Vol: 69, Pages: 391-397, ISSN: 0021-9746
The interaction between Axl receptor tyrosine kinase and its main ligand Gas6 has been implicated in the progression of a wide number of malignancies. More recently, overexpression of Axl has emerged as a key molecular determinant underlying the development of acquired resistance to targeted anticancer agents. The activation of Axl is overexpression-dependent and controls a number of hallmarks of cancer progression including proliferation, migration, resistance to apoptosis and survival through a complex network of intracellular second messengers. Axl has been noted to influence clinically meaningful end points including metastatic recurrence and survival in the vast majority of tumour types. With Axl inhibitors having gained momentum as novel anticancer therapies, we provide an overview of the biological and clinical relevance of this molecular pathway, outlining the main directions of research.
Krell J, Stebbing J, Carissimi C, et al., 2016, TP53 regulates miRNA association with AGO2 to remodel the miRNA-mRNA interaction network, GENOME RESEARCH, Vol: 26, Pages: 331-341, ISSN: 1088-9051
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- Citations: 45
Bidard F-C, Peeters D, Fehm T, et al., 2016, Circulating tumor cells count-based nomograms to predict survival of metastatic breast cancer patients: Results from the European pooled analysis, 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Bidard F-C, Peeters D, Fehm T, et al., 2016, Circulating tumor cells count-based nomograms to predict survival of metastatic breast cancer patients: Results from the European pooled analysis, 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Pannuti A, Filipovic A, Hicks C, et al., 2016, Genetic heterogeneity revealed by targeted exome sequencing in advanced triple-negative breast cancer, 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Bidard F-C, Peeters D, Fehm T, et al., 2016, Circulating tumor cells count-based nomograms to predict survival of metastatic breast cancer patients: Results from the European pooled analysis, 38th Annual CTRC-AACR San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Pardo OE, Munro CE, Castellano L, et al., 2016, miR-515-5p controls cancer cell migration through MARK4 regulation, EMBO Reports, Vol: 17, Pages: 570-584, ISSN: 1469-221X
Here we show that miR-515-5p inhibits cancer cell migration and metastasis. RNA-seqanalyses of both estrogen receptor-positive and negative breast cancer cells overexpressingmiR-515-5p reveals down-regulation of NRAS, FZD4, CDC42BPA, PIK3C2Band MARK4 mRNAs. We demonstrate that miR-515-5p inhibits MARK4 directly 3’UTRinteraction and that MARK4 knockdown mimics the effect of miR-515-5p on breast andlung cancer cell migration. MARK4 over-expression rescues the inhibitory effects of miR-515-5p, suggesting miR-515-5p mediates this process through MARK4 down-regulation.Furthermore, miR-515-5p expression is reduced in metastases compared to primarytumours derived from both in vivo xenografts and samples from patients with breastcancer. Conversely, miR-515-5p overexpression prevents tumour cell dissemination ina mouse metastatic model. Moreover, high miR-515-5p and low MARK4 expressioncorrelate with increased breast and lung cancer patients’ survival, respectively. Takentogether, these data demonstrate the importance of miR-515-5p/MARK4 regulation incell migration and metastasis across two common cancers.
Favicchio R, Thepaut C, Zhang H, et al., 2016, Strategies in functional proteomics: Unveiling the pathways to precision oncology., Cancer Letters, ISSN: 1872-7980
Personalised strategies in cancer care are required to overcome the therapeutic challenges posed by variability between patients and disease subsets. To this end, enhanced precision tools must be developed to describe the molecular drivers of malignant proliferation. Such tools must also identify druggable targets and biomarkers in order to provide essential information regarding drug development and therapeutic outcome. Here we discuss how proteomics-based approaches provide a set of viable methodologies capable of delivering quantitative information throughout the main stages of personalised oncology and a ratiometric platform that delivers systems-wide methods for drug evaluation.
Schofield GM, Urch CE, Stebbing J, et al., 2016, Reply: When does a human being die?, QJM-AN INTERNATIONAL JOURNAL OF MEDICINE, Vol: 109, Pages: 146-146, ISSN: 1460-2725
Gao Y, Stebbing J, Tubei K, et al., 2016, Response of TaFLR MAPKKK to wheat leaf rust and Fusarium head blight and the activation of downstream components, TROPICAL PLANT PATHOLOGY, Vol: 41, Pages: 15-23, ISSN: 1983-2052
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- Citations: 4
Mato Prado M, Frampton AE, Stebbing J, et al., 2016, Single-cell sequencing in cancer research., Expert Review of Molecular Diagnostics, Vol: 16, Pages: 1-5, ISSN: 1473-7159
Genome-wide single-cell sequencing investigations have the potential to classify individual cells within a tumor mass. In recent years, various single-cell DNA and RNA quantification techniques have facilitated significant advances in our ability to classify subpopulations of cells within a heterogeneous population. These approaches provide the possibility of unraveling the complex variability in genetic, epigenetic and transcriptional interactions that occur within identical cells in a tumor. This should enhance our knowledge of the underlying biological phenotypes and could have a huge impact in designing more precise anticancer treatments in order to improve outcomes and avoid tumor resistance. In addition, single-cell sequencing analysis has the potential to allow the development of better diagnostic and prognostic biomarkers, and thus aid the delivery of more personalized targeted cancer therapy. Nevertheless, further research is still required to overcome technical, biological and computational problems before clinical application.
Pinato DJ, Stebbing J, 2016, Quackery Melatonin: resetting the clock of cancer progression?, Lancet Oncology, Vol: 17, Pages: 23-24, ISSN: 1474-5488
Pinato DJ, Sharma R, Yen C, et al., 2016, THE ALBI GRADE PROVIDES OBJECTIVE HEPATIC RESERVE PHENOTYPING ACROSS EACH BCLC STAGE OF HEPATOCELLULAR CARCINOMA, EASL International Liver Congress, Publisher: ELSEVIER SCIENCE BV, Pages: S196-S196, ISSN: 0168-8278
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- Citations: 1
Jacob J, Favicchio R, Karimian N, et al., 2015, LMTK3 escapes tumour suppressor miRNAs via sequestration of DDX5., Cancer Letters, Vol: 372, Pages: 137-146, ISSN: 1872-7980
Lemur tyrosine kinase-3 (LMTK3) plays an important role in cancer progression and is associated with breast, lung, gastric and colorectal cancer. MicroRNAs (miRNAs) are small endogenous non-coding RNAs that typically repress target genes at post-transcriptional level and have an important role in tumorigenesis. By performing a miRNA expression profile, we identified a subset of miRNAs modulated by LMTK3. We show that LMTK3 induces miR-34a, miR-196-a2 and miR-182 levels interacting with DEAD-box RNA helicase p68 (DDX5). LMTK3 binds via DDX5 to the pri-miRNA of these three mature miRNAs, thereby sequestrating them from further processing. Ectopic expression of miR-34a and miR-182 in LMTK3-overexpressing cell lines (MCF7-LMTK3 and MDA-MB-231-LMTK3) inhibits breast cancer proliferation, invasion and migration. Interestingly, miR-34a and miR-182 directly bind to the 3'UTR of LMTK3 mRNA and consequently inhibit both its stability and translation, acting as tumour suppressor-like miRNAs. In aggregate, we show that LMTK3 is involved in miRNA biogenesis through modulation of the Microprocessor complex, inducing miRNAs that target LMTK3 itself.
Krell J, Stebbing J, Carissimi C, et al., 2015, TP53 regulates miRNA association with AGO2 to remodel the miRNA-mRNA interaction network., Genome Research, ISSN: 1549-5469
DNA damage activates TP53-regulated surveillance mechanisms that are crucial in suppressing tumorigenesis. TP53 orchestrates these responses directly by transcriptionally modulating genes, including microRNAs (miRNAs), and by regulating miRNA biogenesis through interacting with the DROSHA complex. However, whether the association between miRNAs and AGO2 is regulated following DNA damage is not yet known. Here we show that, following DNA damage, TP53 interacts with AGO2 to induce or reduce AGO2's association of a subset of miRNAs, including multiple let-7 family members. Furthermore, we show that specific mutations in TP53 decrease rather than increase the association of let-7 family miRNAs, reducing their activity without preventing TP53 from interacting with AGO2. This is consistent with the oncogenic properties of these mutants. Using AGO2 RIP-seq and PAR-CLIP-seq we show that the DNA-damage-induced increase in binding of let-7 family members to the RISC complex is functional. We unambiguously determine the global miRNA-mRNA interaction networks involved in the DNA damage response, validating them through the identification of miRNA-target chimeras formed by endogenous ligation reactions. We find that the target complementary region of the let-7 seed tends to have highly fixed positions and more variable ones. Additionally, we observe that miRNAs whose cellular abundance or differential association with AGO2 is regulated by TP53 are involved in an intricate network of regulatory feedback and feedforward circuits. TP53-mediated regulation of AGO2-miRNA interaction represents a new mechanism of miRNA regulation in carcinogenesis.
Dalgleish AG, Stebbing J, 2015, Five year survival in patients with metastatic melanoma receiving IMM-101, Annals of Oncology, Vol: 26, ISSN: 0923-7534
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Krell D, Mulholland P, Stebbing J, et al., 2015, <i>HOT</i> mutation screening in human glioblastomas, FUTURE SCIENCE OA, Vol: 1, ISSN: 2056-5623
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- Citations: 1
Dalgleish AG, Stebbing J, 2015, Five year survival in patients with metastatic melanoma receiving IMM-101, Meeting of the European-Society-for-Medical-Oncology (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 9-10, ISSN: 0923-7534
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- Citations: 2
Rampias T, Favicchio R, Stebbing J, et al., 2015, Targeting tumor-stroma crosstalk: the example of the NT157 inhibitor., Oncogene, ISSN: 1476-5594
Recent clinical research has provided evidence that cancer progression and therapy resistance is driven not only by tumor's genetic profile but also by complex paracrine interactions within the tumor microenvironment (TME). The role of TME in modulating tumor drug sensitivity is increasingly recognized and targeting TME has been the focus of novel therapeutic approaches. Two recent reports show that a new anti-cancer drug, the inhibitor NT157 has the potential to inhibit IGF-1R and STAT3 signaling pathways in cancer cells and stoma cells of TME leading to a decrease in cancer cell survival.Oncogene advance online publication, 19 October 2015; doi:10.1038/onc.2015.392.
Oskrochi Y, Razi K, Stebbing J, et al., 2015, Angiosarcoma and Dialysis-related Arteriovenous Fistulae: A Comprehensive Review., European Journal of Vascular and Endovascular Surgery, Vol: 51, Pages: 127-133, ISSN: 1532-2165
OBJECTIVE/BACKGROUND: To conduct a comprehensive review of cases, presentation, diagnosis, and management of angiosarcoma in arteriovenous fistulae (AVF) created for haemodialysis. METHODS: Two authors independently conducted systematic searches and extraction of articles from the Embase, AMED, Health Management Information Consortium, and MEDLINE databases in keeping with the inclusion/exclusion criteria and Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards. RESULTS: Twenty-two unique patient cases were identified; 20 of the cases were men and mean ± SD age of presentation was 54.9 ± 13.6 years. Nineteen cases were post-transplant and 18 were on antirejection agents. The most common presenting symptom was pain, with or without a mass. The initial diagnosis was most often thrombosis/infection of the AVF and the diagnostic interval to a correct diagnosis of angiosarcoma was between 2 and 40 weeks. Mean ± SD time to presentation of symptoms from fistula formation was 118.9 ± 57.5 months, while from transplant it was 96.9 ± 70.0 months. Amputation was the most common treatment modality and mean ± SD survival was 8.8 ± 3.7 months. CONCLUSION: Angiosarcoma should be suspected in previously quiescent AVF that presents with pain. The presence of a rapidly enlarging mass or bleeding/bruising should be taken as alarm indicators and warrant urgent investigation in accordance with local cancer guidelines. Any surgical procedure should involve histological samples as a matter of course.
Pinato DJ, Chowdhury S, Stebbing J, 2015, TAMing resistance to multi-targeted kinase inhibitors through Axl and Met inhibition., Oncogene, ISSN: 1476-5594
TAM (Tyro3-Axl-Mer) receptor tyrosine kinases and Met are implicated in several hallmarks of cancer progression including sustained angiogenesis, enhanced motility, tissue invasion and acquisition of metastatic potential through the upregulation of epithelial-to-mesenchymal transition. Increasing evidence has confirmed Axl and Met as emerging central drivers of adaptive resistance to targeted therapies across a wide variety of cancers. In this issue of Oncogene, Zhou et al. describe the mechanisms linking Axl and Met activation to acquired resistance to sunitinib in renal cell carcinoma (RCC), providing a pre-clinical rationale for the development of Axl and Met inhibitors including cabozantinib in anti-angiogenic resistant RCC.Oncogene advance online publication, 5 October 2015; doi:10.1038/onc.2015.374.
Cathcart P, de Giorgio A, Stebbing J, 2015, Cannabis and cancer: reality or pipe dream?, Lancet Oncology, Vol: 16, Pages: 1291-1292, ISSN: 1474-5488
Among alternative cancer treatments, cannabis inhabits a peculiarly politicised position, hailed as a suppressed panacea by some, denounced as a psychosis-inducing and illegal drug by others. In the middle ground, there is a growing acceptance of the plant's capacity for effective pain and nausea relief, and even tentative suggestions of potentiation of treatments such as chemotherapy and even direct action to restrain tumour cells by various routes. The doctor is immediately put in a compromising position: legally forbidden from advocating use, but professionally bound to ease suffering to the best of their abilities.
Nachiappan S, Askari A, Mamidanna R, et al., 2015, The impact of adjuvant chemotherapy timing on overall survival following colorectal cancer resection, European Journal of Surgical Oncology, Vol: 41, Pages: 1636-1644, ISSN: 0748-7983
BackgroundSeveral studies including two meta-analyses have showed that delay between surgery and adjuvant chemotherapy adversely impacts colorectal cancer survival. This study investigated this impact at a population level over a fifteen year period in England.MethodsThe Hospital Episode Statistics database was analysed between 1997 and 2012. Colonic cancer and rectal cancer patients were collated and multivariate Cox regression analyses were undertaken to ascertain the relationship between chemotherapy delay and overall survival.ResultsA total of 181 984 patients underwent resection without any reoperation (106 477 (58.5%) having colonic cancer and 75 507 (41.5%) having rectal cancer). In total, 30 836 (16.9%) received adjuvant chemotherapy.9019 (49.3%), 4573 (25.0%), 2587 (14.1%), 1323 (7.2%) and 804 (4.4%) of 18 306 colonic cancer patients received within 8 weeks, 8–10 weeks, 10–12 weeks, 12–14 weeks and 14–16 weeks, respectively. Sequentially worse overall survival was observed: <8 weeks: Ref; 8–10 wks: Hazard Ratio (HR) 1.09; 10–12 wks: HR 1.13; 12–14 wks HR 1.32 and 14–16 wks: HR 1.32, p < 0.001.5625 (44.9%), 3087 (24.6%), 1940 (15.5%), 1162 (9.3%) and 716 (5.7%) of 12 530 rectal cancer patients received within 8 weeks, 8–10 weeks, 10–12 weeks, 12–14 weeks and 14–16 weeks, respectively. Sequentially worse overall survival was observed: <8 weeks: Ref; 8–10 wks: HR 1.09; 10–12 wks: HR 1.22; 12–14 wks HR 1.23 and 14–16 wks: HR 1.31, p < 0.001.ConclusionAdjuvant chemotherapy delay adversely impacts colonic and rectal cancer survival. Efforts to prevent complications such as reoperation and to improve access to chemotherapy services, will improve survival in this patient cohort.
Stebbing J, Zhang H, Xu Y, et al., 2015, Characterization of the Tyrosine Kinase-Regulated Proteome in Breast Cancer by Combined use of RNA interference (RNAi) and Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC) Quantitative Proteomics, Molecular & Cellular Proteomics, Vol: 14, Pages: 2479-2492, ISSN: 1535-9484
Tyrosine kinases (TKs) are central regulators in cellular activities and perturbations of TK signaling contribute to oncogenesis. However, less than half of the TKs have been thoroughly studied and a global functional analysis of their proteomic portrait is lacking. Here we conducted a combined approach of RNA interference (RNAi) and stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics to decode the TK-regulated proteome and associated signaling dynamics. As a result, a broad proteomic repertoire modulated by TKs was revealed, upon silencing of the 65 TKs expressed in MCF7 breast cancer cells. This yielded 10 new distinctive TK clusters according to similarity in TK-regulated proteome, each characterized by a unique signaling signature in contrast to previous classifications. We provide functional analyses and identify critical pathways for each cluster based on their common downstream targets. Analysis of different breast cancer subtypes showed distinct correlations of each cluster with clinical outcome. From the significantly up- and down-regulated proteins, we identified a number of markers of drug sensitivity and resistance. These data supports the role of TKs in regulating major aspects of cellular activity, but also reveals redundancy in signaling, explaining why kinase inhibitors alone often fail to achieve their clinical aims. The TK-SILACepedia provides a comprehensive resource for studying the global function of TKs in cancer.
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