Publications
199 results found
Le Large TYS, Prado MM, Krell J, et al., 2016, Bioinformatic analysis reveals pancreatic cancer molecular subtypes specific to the tumor and the microenvironment, Expert Review of Molecular Diagnostics, Vol: 16, Pages: 733-736, ISSN: 1473-7159
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by a dense desmoplastic reaction surrounding malignant epithelial cells. Interaction between the epithelial and stromal compartments is suggested to enhance its aggressive nature. Indeed, therapies targeting the stroma, as well as the tumor cells, may improve survival outcomes for patients. The evaluated study by Moffitt et al. used bioinformatic techniques to separate gene expression patterns of normal tissues from PDAC and stroma in a large cohort of samples. The researchers identified two different subtypes of PDAC (‘classical’ and ‘basal-like’) and surrounding stroma (‘normal’ and ‘activated’). The basal-like subtype was associated with worse prognosis and a trend towards better response to adjuvant therapy. Hopefully, the molecular stratification of PDAC will potentially allow more personalized treatment strategies and guide clinical decision making.
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.
Jiao LR, Fajardo A, Frampton A, 2016, Gene of the month: HGF, Journal of Clinical Pathology, Vol: 69, Pages: 575-579, ISSN: 0021-9746
Hepatocyte growth factor (HGF) is a multifunctional cytokine with important roles in cell proliferation, survival, motility and morphogenesis. Secreted by cells of mesenchymal origin, HGF is the specific ligand for the tyrosine-kinase receptor c-MET (cellular mesenchymal-epithelial transition), also called MET, which is expressed in different types of epithelial, endothelial and haematopoietic progenitor cells. The HGF/MET axis is involved in several biological processes, such as embryogenesis, organogenesis, adult tissue regeneration (including wound healing and liver regeneration) and carcinogenesis, for both solid and haematological malignancies.1 2 HGF and its particular interaction with the MET receptor have been extensively investigated in the last decades and remain the focus of numerous clinical trials.3–8 This short review focuses on HGF structure and function, as well as its roles in liver regeneration and different types of tumours.
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
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.
Farkas N, Solanki K, Frampton AE, et al., 2016, Are we following an algorithm for managing chronic anal fissure? A completed audit cycle, Annals of Medicine and Surgery, Vol: 5, Pages: 38-44, ISSN: 2049-0801
Background: Anal fissure is one of the commonest proctological diseases with considerable national variation in sequential treatment. We aimed to audit our compliance of chronic anal fissure (CAF) management with national guidance provided by the Association of Coloproctology of Great Britain and Ireland (ACPGBI). Methods: We retrospectively audited patients presenting to outpatient clinics with CAF over a 6-month period. Using electronic patient records, notes and clinic letters, we compared their management with ACPGBI algorithm. A prospective re-audit was then performed. Results: Forty-one patients were included in the analysis (59% male). Sixty-eight percent (n = 28/41) of patients were appropriately started on conservative dietary therapy, of whom only 7.1% (n = 2/28) had treatment success. Eighty-nine percent (n = 25/28) were then appropriately treated with either topical diltiazem 2% or GTN 0.4%. Overall, 43.9% (n = 18/41) of all patients' entire management strategy adhered to the ACPGBI guidelines. In total, 48.8% (n = 20/41) patients had surgical treatment (excluding Botox), of which only 15% (n = 3/20) had undergone ACPGBI-compliant management. After local dissemination of results and education, the re-audit of 20 patients showed significant improvement in adherence to the guidelines (43.9% vs. 95%; P = 0.0001). Conclusions: Topical creams were the most successful treatments (50%; n = 9/18) in ACPGBI-compliant strategies. Importantly, these data suggests that compliance with the ACPGBI algorithm leads to healing without surgery in 83.3% (n = 15/18) of patients, compared to 26.1% (n = 6/23) with non-compliant methods (P = 0.0004). This highlights the benefit of early conservative and medical management of CAF, before attempting surgery.
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.
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.
Garajova I, Funel N, Fiorentino M, et al., 2015, MicroRNA profiling of primary pulmonary enteric adenocarcinoma in members from the same family reveals some similarities to pancreatic adenocarcinoma-a step towards personalized therapy, Clinical Epigenetics, Vol: 7, ISSN: 1868-7083
Background: Primary pulmonary enteric adenocarcinoma (PEAC) is defined as a pulmonary adenocarcinoma with apredominant component of intestinal differentiation and tumor cells positive for at least one intestinal marker. Theaim of the present study was the molecular and histological characterization of a PEAC from a patient with twoother family members affected by similar lung tumors, which has never been reported before.Findings: We evaluated the molecular characteristics of the proband’s PEAC by using a previously validated47-microRNA (miRNA) cancer-specific array and a predictive method to estimate tissue-of-origin probabilities.Immunohistochemical (IHC) staining for thyroid transcription factor (TTF-1), napsin A, caudal-related homeobox 2(CDX2), cytokeratins, and mucins, as well as mutational analyses for epidermal growth factor receptor (EGFR), Kirstenrat sarcoma viral oncogene homolog (KRAS), and anaplastic lymphoma kinase (ALK) were performed on formalinfixed,paraffin-embedded (FFPE) tissues.The occurrence of PEAC in two family members was associated with similar clinicopathological features (age atdiagnosis, smoking habit, tumor localization, multiple colonic polyps), histologic findings (TTF-1 negativity andCDX2 positivity), and genetic findings (KRAS (Gly12Asp) mutation, but no EGFR/ALK aberrations). miRNA profilingrevealed similarities with non-small cell lung cancer (NSCLC; 75.98 %) and some overlap with pancreatic ductaladenocarcinoma (PDAC; 23.34 %), but not with colorectal cancer (CRC; less than 0.5 %). Notably, these PEACs sharekey PDAC-associated miRNAs associated with tumor aggressiveness (miR-31*/-126*/-506/-508-3p/-514).Conclusions: We describe for the first time PEAC in members from the same family, associated with similar clinicaland genetic features. miRNA profiling of the PEAC resembled a NSCLC signature, with partial overlap to a PDACpattern. This could explain its aggressive behavior and therefore help to guide future tailored-therapeu
Le Large TYS, Meijer LL, Prado MM, et al., 2015, Circulating microRNAs as diagnostic biomarkers for pancreatic cancer, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, Vol: 15, Pages: 1525-1529, ISSN: 1473-7159
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- Citations: 25
Takaori K, Bassi C, Biankin A, et al., 2015, International Association of Pancreatology (IAP)/European Pancreatic Club (EPC) consensus review of guidelines for the treatment of pancreatic cancer, PANCREATOLOGY, Vol: 16, Pages: 14-27, ISSN: 1424-3903
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- Citations: 60
Frampton AE, Krell J, Gall TMH, et al., 2015, miR-15b and miR-17 Are Tumor-derived Plasma MicroRNAs Dysregulated in Colorectal Neoplasia, Annals of Surgery, Vol: 262, Pages: e61-e61, ISSN: 0003-4932
Prado MM, Frampton AE, Stebbing J, et al., 2015, Gene of the month: NANOG, Journal of Clinical Pathology, Vol: 68, Pages: 763-765, ISSN: 0021-9746
Nouraei SAR, Hudovsky A, Frampton AE, et al., 2015, A Study of Clinical Coding Accuracy in Surgery <i>Implications for the Use of Administrative Big Data for Outcomes Management</i>, ANNALS OF SURGERY, Vol: 261, Pages: 1096-1107, ISSN: 0003-4932
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- Citations: 45
Frampton AE, Krell J, Jamieson NB, et al., 2015, microRNAs with prognostic significance in pancreatic ductal adenocarcinoma: A meta-analysis, European Journal of Cancer, Vol: 51, Pages: 1389-1404, ISSN: 1879-0852
BackgroundReports have described the prognostic relevance of microRNAs (miRNAs) in patients treated for pancreatic ductal adenocarcinoma (PDAC). However, many of these include small numbers of patients. To increase statistical power and improve translation, we performed a systematic review and meta-analysis to determine a pooled conclusion. We examined the impact of miRNAs on overall survival (OS) and disease-free survival (DFS) in PDAC.MethodsEligible studies were identified and quality assessed using multiple search strategies (last search December 2014). Data were collected from studies correlating clinical outcomes with dysregulated tumoural or blood miRNAs. Studies were pooled, and combined hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate strength of the associations.ResultsTwenty studies involving 1525 patients treated for PDAC were included. After correcting for publication bias, OS was significantly shortened in patients with high tumoural miR-21 (adjusted HR = 2.48; 1.96–3.14). This result persisted when only studies adjusting for adjuvant chemotherapy were combined (adjusted HR = 2.72; 1.91–3.89). High miR-21 also predicted reduced DFS (adjusted HR = 3.08; 1.78–5.33). Similarly, we found significant adjusted HRs for poor OS for high miR-155, high miR-203, and low miR-34a; and unadjusted HRs for high miR-222 and high miR-10b. The small number of studies, limited number of miRNAs and paucity of multivariate analyses are the limitations of our study.ConclusionsThis is the first rigorous pooled analysis assessing miRNAs as prognostic biomarkers in PDAC. Tumoural miR-21 overexpression emerged as an important predictor of poor prognosis after PDAC resection independent of other clinicopathologic factors, including adjuvant chemotherapy use.
Roca-Alonso L, Castellano L, Mills A, et al., 2015, Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in beta-adrenergic signaling and enhances apoptosis, Cell Death & Disease, Vol: 6, ISSN: 2041-4889
The use of anthracyclines such as doxorubicin (DOX) has improved outcome in cancer patients, yet associated risks ofcardiomyopathy have limited their clinical application. DOX-associated cardiotoxicity is frequently irreversible and typicallyprogresses to heart failure (HF) but our understanding of molecular mechanisms underlying this and essential for development ofcardioprotective strategies remains largely obscure. As microRNAs (miRNAs) have been shown to play potent regulatory roles inboth cardiovascular disease and cancer, we investigated miRNA changes in DOX-induced HF and the alteration of cellularprocesses downstream. Myocardial miRNA profiling was performed after DOX-induced injury, either via acute application toisolated cardiomyocytes or via chronic exposure in vivo, and compared with miRNA profiles from remodeled hearts followingmyocardial infarction. The miR-30 family was downregulated in all three models. We describe here that miR-30 act regulating theβ-adrenergic pathway, where preferential β1- and β2-adrenoceptor (β1AR and β2AR) direct inhibition is combined with Giα-2targeting for fine-tuning. Importantly, we show that miR-30 also target the pro-apoptotic gene BNIP3L/NIX. In aggregate, wedemonstrate that high miR-30 levels are protective against DOX toxicity and correlate this in turn with lower reactive oxygenspecies generation. In addition, we identify GATA-6 as a mediator of DOX-associated reductions in miR-30 expression. Inconclusion, we describe that DOX causes acute and sustained miR-30 downregulation in cardiomyocytes via GATA-6. miR-30overexpression protects cardiac cells from DOX-induced apoptosis, and its maintenance represents a potential cardioprotectiveand anti-tumorigenic strategy for anthracyclines.
Le Large TYS, Frampton AE, Meijer LL, et al., 2015, Usefulness of Measuring microRNAs in Bile and Plasma for Pancreatic Ductal Adenocarcinoma Diagnosis, AMERICAN JOURNAL OF GASTROENTEROLOGY, Vol: 110, Pages: 768-769, ISSN: 0002-9270
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- Citations: 2
Frampton AE, Stebbing J, Gall TMH, et al., 2015, Activating mutations of <i>GNAS</i> and <i>KRAS</i> in cystic fluid can help detect intraductal papillary mucinous neoplasms of the pancreas, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, Vol: 15, Pages: 325-328, ISSN: 1473-7159
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- Citations: 7
Pai M, Frampton AE, Jiao LR, 2015, Integrating the Evidence for Single-incision Laparoscopic Cholecystectomy: Is It "Looking" Good?, ANNALS OF SURGERY, Vol: 261, Pages: E85-E87, ISSN: 0003-4932
Frampton AE, Castellano L, Colombo T, et al., 2015, Integrated molecular analysis to investigate the role of microRNAs in pancreatic tumour growth and progression, LANCET, Vol: 385, Pages: 37-37, ISSN: 0140-6736
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- Citations: 8
Krell J, Stebbing J, Frampton AE, et al., 2015, The role of TP53 in miRNA loading onto AGO2 and in remodelling the miRNA-mRNA interaction network, LANCET, Vol: 385, Pages: 15-15, ISSN: 0140-6736
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- Citations: 3
Gall TMH, Sodergren MH, Frampton AE, et al., 2015, Radio-frequency-assisted Liver Partition With Portal Vein Ligation (RALPP) for Liver Regeneration, ANNALS OF SURGERY, Vol: 261, Pages: E45-E46, ISSN: 0003-4932
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- Citations: 64
Alshaker H, Wang Q, Frampton AE, et al., 2015, Sphingosine kinase 1 contributes to leptin-induced STAT3 phosphorylation through IL-6/gp130 transactivation in oestrogen receptor-negative breast cancer, BREAST CANCER RESEARCH AND TREATMENT, Vol: 149, Pages: 59-67, ISSN: 0167-6806
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- Citations: 25
Frampton AE, Krel J, Gall TM, et al., 2015, Prospective Validation of Microrna Signatures for Detecting Pancreatic Malignant Transformation in Endoscopic-Ultrasound Guided Fine-Needle Aspiration Biopsies, International Surgical Congress of the Association-of-Surgeons-of-Great-Britain-and-Ireland (ASGBI), Publisher: WILEY-BLACKWELL, Pages: 7-7, ISSN: 0007-1323
Gall TMH, Sodergren M, Fan R, et al., 2015, The Hammersmith Laparoscopic Pancreaticogastrostomy: a Novel Laparoscopic Pancreatic Anastomosis During Central Pancreatectomy, International Surgical Congress of the Association-of-Surgeons-of-Great-Britain-and-Ireland (ASGBI), Publisher: WILEY-BLACKWELL, Pages: 266-266, ISSN: 0007-1323
Alshaker H, Krell J, Frampton AE, et al., 2015, Leptin receptor-dependent and -independent STAT3 phosphorylation in oestrogen receptor-negative breast cancer, INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, Vol: 36, Pages: S6-S6, ISSN: 1107-3756
Badreldin W, Krell J, Chowdhury S, et al., 2014, The efficacy of irinotecan, paclitaxel, and oxaliplatin (IPO) in relapsed germ cell tumors with high dose chemotherapy as consolidation- a non-cisplatin- based induction approach., BJU International, Vol: 117, Pages: 418-423, ISSN: 1464-4096
OBJECTIVES: To determine the outcome of an expanded cohort of patients with relapsed germ cell tumors (GCT) treated with a salvage chemotherapy regimen consisting of irinotecan, paclitaxel and oxaliplatin (IPO) and assess the role of IPO as an alternative to standard cisplatin-based chemotherapy regimens in this setting. PATIENTS AND METHODS: The results of 72 consecutive patients were reviewed retrospectively. IPO was used either as a second-line treatment (n=29), of which 20 patients subsequently received high-dose chemotherapy (HDCT), or third-line (n=43), of which 32 patients proceeded to HDCT. RESULTS: The 2-year PFS and 3-year OS rates for the whole cohort were 30.2% (95%CI 17.3-40.5%) and 33.4% (95%CI: 20.1-43.8 %) respectively. CR was achieved in 3%, m-ve PR in 41%, m+ve PR in 18%, SD in 17% and PD in 20%. In the second-line setting, the 2-year PFS rate was 43.5% (95%CI: 21.7-60.8%) and 3-year OS 49.1% (95%CI: 24.2-65.1%). In the third-line setting, the 2-year PFS rate was 21.0% (95%CI 9.5-35.4%) and the 3-year OS rate was 23.9% (95%CI 11.7-38.2).According to the current international prognostic factor study group criteria for first relapse for the high and very high risk group the 2 year PFS rates were 50% and 30% respectively. There were 2 treatment related deaths from IPO, and 4 from HDCT. Grade 3 or 4 toxicities included neutropenia (35%), thrombocytopenia (18%), infection (15%), diarrhea (11%) and lethargy (8%). CONCLUSIONS: IPO offers an effective, well-tolerated, non-nephrotoxic alternative to cisplatin-based salvage regimens for patients with relapsed GCT. It appears particularly useful in high risk patients and for those in whom cisplatin is ineffective or contra-indicated.
Alshaker H, Krell J, Frampton AE, et al., 2014, Leptin induces upregulation of sphingosine kinase 1 in oestrogen receptor-negative breast cancer via Src family kinase-mediated, janus kinase 2-independent pathway, Breast Cancer Research, Vol: 16, ISSN: 1465-542X
Introduction: Obesity is a known risk factor for breast cancer. Sphingosine kinase 1 (SK1) is an oncogenic lipidkinase that is overexpressed in breast tumours and linked with poor prognosis, however, its role in obesity-drivenbreast cancer was never elucidated.Methods: Human primary and secondary breast cancer tissues were analysed for SK1 and leptin receptorexpression using quantitative real-time polymerase chain reaction (qRT-PCR) assay. Leptin-induced signalling wasanalysed in human oestrogen receptor (ER)-positive and negative breast cancer cells using Western blotting,qRT-PCR and radiolabelling assays.Results: Our findings show for the first time that human primary breast tumours and associated lymph nodemetastases exhibit a strong correlation between SK1 and leptin receptor expression (Pearson R = 0.78 and R = 0.77,respectively, P <0.001). Both these genes are elevated in metastases of ER-negative patients and show a significantincrease in patients with higher body mass index (BMI). Leptin induces SK1 expression and activation in ER-negativebreast cancer cell lines MDAMB-231 and BT-549, but not in ER-positive cell lines. Pharmacological inhibition andgene knockdown showed that leptin-induced SK1 activity and expression are mediated by activation of extracellularsignal-regulated kinases 1/2 (ERK1/2) and Src family kinase (SFK) pathways, but not by the major pathwaysdownstream of leptin receptor (LEPR) - janus kinase 2 (JAK2) and signal transducer and activator of transcription 3(STAT3). Src-homology 2 domain-containing phosphatase 2 (SHP2) appeared to be key to SK1 activation, and mayfunction as an adaptor protein between SFKs and LEPR. Importantly, leptin-induced breast cancer cell proliferationwas abrogated by SK1-specific small interfering RNA (siRNA).Conclusions: Overall, our findings demonstrate a novel SFK/ERK1/2-mediated pathway that links leptin signallingand expression of oncogenic enzyme SK1 in breast tumours and suggest the potential significance
Miller H, Castellano L, Frampton A, et al., 2014, 1158PROLE OF MICRORNA AS BIOMARKERS IN SMALL BOWEL NEUROENDOCRINE TUMOURS., Ann Oncol, Vol: 25
Garajová I, Le Large TY, Frampton AE, et al., 2014, Molecular mechanisms underlying the role of microRNAs in the chemoresistance of pancreatic cancer, BioMed Research International, Vol: 2014, ISSN: 2314-6133
Pancreatic ductal adenocarcinoma (PDAC) is an extremely severe disease where the mortality and incidence rates are almost identical. This is mainly due to late diagnosis and limited response to current treatments. The tumor macroenvironment/microenvironment have been frequently reported as the major contributors to chemoresistance in PDAC, preventing the drugs from reaching their intended site of action (i.e., the malignant duct cells). However, the recent discovery of microRNAs (miRNAs) has provided new directions for research on mechanisms underlying response to chemotherapy. Due to their tissue-/disease-specific expression and high stability in tissues and biofluids, miRNAs represent new promising diagnostic and prognostic/predictive biomarkers and therapeutic targets. Furthermore, several studies have documented that selected miRNAs, such as miR-21 and miR-34a, may influence response to chemotherapy in several tumor types, including PDAC. In this review, we summarize the current knowledge on the role of miRNAs in PDAC and recent advances in understanding their role in chemoresistance through multiple molecular mechanisms.
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