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[Figure: see text].
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COVID-19/sangre , COVID-19/inmunología , Mediadores de Inflamación/sangre , Mediadores de Inflamación/inmunología , Fagocitos/inmunología , Células Cultivadas , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/virología , Neutrófilos/inmunología , Neutrófilos/virología , Fagocitos/virologíaRESUMEN
Cancer-associated fibroblasts (CAFs) have conflicting roles in the suppression and promotion of cancer. Current research focuses on targeting the undesirable properties of CAFs, while attempting to maintain tumour-suppressive roles. CAFs have been widely associated with primary or secondary therapeutic resistance, and strategies to modify CAF function have therefore largely focussed on their combination with existing therapies. Despite significant progress in preclinical studies, clinical translation of CAF targeted therapies has achieved limited success. Here we will review our emerging understanding of heterogeneous CAF populations in tumour biology and use examples from pancreatic ductal adenocarcinoma to explore why successful clinical targeting of protumourigenic CAF functions remains elusive. Single-cell technologies have allowed the identification of CAF subtypes with a differential impact on prognosis and response to therapy, but currently without clear consensus. Identification and pharmacological targeting of CAF subtypes associated with immunotherapy response offers new hope to expand clinical options for pancreatic cancer. Various CAF subtype markers may represent biomarkers for patient stratification, to obtain enhanced response with existing and emerging combinatorial therapeutic strategies. Thus, CAF subtyping is the next frontier in understanding and exploiting the tumour microenvironment for therapeutic benefit. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Fibroblastos Asociados al Cáncer , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Biomarcadores , Fibroblastos Asociados al Cáncer/patología , Carcinoma Ductal Pancreático/patología , Humanos , Neoplasias Pancreáticas/patología , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
BACKGROUND: The utility of circulating tumour DNA (ctDNA) for longitudinal tumour monitoring in pancreatic ductal adenocarcinoma (PDAC) has not been explored beyond mutations in the KRAS proto-oncogene. Here, we aimed to characterise and track patient-specific somatic ctDNA variants, to assess longitudinal changes in disease burden and explore the landscape of actionable alterations. METHODS: We followed 3 patients with resectable disease and 4 patients with unresectable disease, including 4 patients with ≥ 3 serial follow-up samples, of whom 2 were rare long survivors (> 5 years). We performed whole exome sequencing of tumour gDNA and plasma ctDNA (n = 20) collected over a ~ 2-year period from diagnosis through treatment to death or final follow-up. Plasma from 3 chronic pancreatitis cases was used as a comparison for analysis of ctDNA mutations. RESULTS: We detected > 55% concordance between somatic mutations in tumour tissues and matched serial plasma. Mutations in ctDNA were detected within known PDAC driver genes (KRAS, TP53, SMAD4, CDKN2A), in addition to patient-specific variants within alternative cancer drivers (NRAS, HRAS, MTOR, ERBB2, EGFR, PBRM1), with a trend towards higher overall mutation loads in advanced disease. ctDNA alterations with potential for therapeutic actionability were identified in all 7 patients, including DNA damage response (DDR) variants co-occurring with hypermutation signatures predictive of response to platinum chemotherapy. Longitudinal tracking in 4 patients with follow-up > 2 years demonstrated that ctDNA mutant allele fractions and clonal trends were consistent with CA19-9 measurements and/or clinically reported disease burden. The estimated prevalence of 'stem clones' was highest in an unresectable patient where changes in ctDNA dynamics preceded CA19-9 levels. Longitudinal evolutionary trajectories revealed ongoing subclonal evolution following chemotherapy. CONCLUSION: These results provide proof-of-concept for the use of exome sequencing of serial plasma to characterise patient-specific ctDNA profiles, and demonstrate the sensitivity of ctDNA in monitoring disease burden in PDAC even in unresectable cases without matched tumour genotyping. They reveal the value of tracking clonal evolution in serial ctDNA to monitor treatment response, establishing the potential of applied precision medicine to guide stratified care by identifying and evaluating actionable opportunities for intervention aimed at optimising patient outcomes for an otherwise intractable disease.
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Carcinoma Ductal Pancreático , ADN Tumoral Circulante , Neoplasias Pancreáticas , Biomarcadores de Tumor/genética , Antígeno CA-19-9 , Carcinoma Ductal Pancreático/patología , ADN Tumoral Circulante/genética , Humanos , Mutación , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias PancreáticasRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundance of stroma. Multiple molecular classification efforts have identified a mesenchymal tumor subtype that is consistently characterized by high-grade growth and poor clinical outcome. The relation between PDAC stroma and tumor subtypes is still unclear. Here, we aimed to identify how PDAC cells instruct the main cellular component of stroma, the pancreatic stellate cells (PSCs). We found in primary tissue that high-grade PDAC had reduced collagen deposition compared to low-grade PDAC. Xenografts and organotypic co-cultures established from mesenchymal-like PDAC cells featured reduced collagen and activated PSC content. Medium transfer experiments using a large set of PDAC cell lines revealed that mesenchymal-like PDAC cells consistently downregulated ACTA2 and COL1A1 expression in PSCs and reduced proliferation. We identified colony-stimulating factor 1 as the mesenchymal PDAC-derived ligand that deactivates PSCs, and inhibition of its receptor CSF1R was able to counteract this effect. In conclusion, high-grade PDAC features stroma that is low in collagen and activated PSC content, and targeting CSF1R offers direct options to maintain a tumor-restricting microenvironment.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/genética , Línea Celular Tumoral , Movimiento Celular , Humanos , Factor Estimulante de Colonias de Macrófagos/genética , Neoplasias Pancreáticas/genética , Células Estrelladas Pancreáticas , Células del Estroma , Microambiente TumoralRESUMEN
BACKGROUND: Pancreatic cancer risk is poorly quantified in relation to the temporal presentation of medical comorbidities and lifestyle. This study aimed to examine this aspect, with possible influence of demographics. METHODS: We conducted a retrospective case-control study on the ethnically-diverse population of East London, UK, using linked electronic health records. We evaluated the independent and two-way interaction effects of 19 clinico-demographic factors in patients with pancreatic cancer (N = 965), compared with non-malignant pancreatic conditions (N = 3963) or hernia (control; N = 4355), reported between April 1, 2008 and March 6, 2020. Risks were quantified by odds ratios (ORs) and 95% confidence intervals (CIs) from multivariable logistic regression models. RESULTS: We observed increased odds of pancreatic cancer incidence associated with recent-onset diabetes occurring within 6 months to 3 years before cancer diagnosis (OR 1.95, 95% CI 1.25-3.03), long-standing diabetes for over 3 years (OR 1.74, 95% CI 1.32-2.29), recent smoking (OR 1.81, 95% CI 1.36-2.4) and drinking (OR 1.76, 95% CI 1.31-2.35), as compared to controls but not non-malignant pancreatic conditions. Pancreatic cancer odds was highest for chronic pancreatic disease patients (recent-onset: OR 4.76, 95% CI 2.19-10.3, long-standing: OR 5.1, 95% CI 2.18-11.9), amplified by comorbidities or harmful lifestyle. Concomitant diagnosis of diabetes, upper gastrointestinal or chronic pancreatic conditions followed by a pancreatic cancer diagnosis within 6 months were common, particularly in South Asians. Long-standing cardiovascular, respiratory and hepatobiliary conditions were associated with lower odds of pancreatic cancer. CONCLUSIONS: Several factors are, independently or via effect modifications, associated with higher incidence of pancreatic cancer, but some established risk factors demonstrate similar magnitude of risk measures of developing non-malignant pancreatic conditions. The findings may inform refined risk-stratification strategies and better surveillance for high-risk individuals, and also provide a means for systematic identification of target population for prospective cohort-based early detection research initiatives.
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Consumo de Bebidas Alcohólicas , Registros Electrónicos de Salud , Neoplasias Pancreáticas/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Consumo de Bebidas Alcohólicas/epidemiología , Enfermedad Crónica , Comorbilidad , Diabetes Mellitus/epidemiología , Métodos Epidemiológicos , Etnicidad , Femenino , Hernia Abdominal/epidemiología , Humanos , Estilo de Vida , Londres/epidemiología , Londres/etnología , Masculino , Persona de Mediana Edad , Enfermedades Pancreáticas/epidemiología , Neoplasias Pancreáticas/etnología , Neoplasias Pancreáticas/mortalidad , Factores de Riesgo , Fumar/epidemiología , Adulto JovenRESUMEN
INTRODUCTION: The SARS-CoV-2 pandemic presented healthcare providers with an extreme challenge to provide cancer services. The impact upon the diagnostic and treatment capacity to treat pancreatic cancer is unclear. This study aimed to identify national variation in treatment pathways during the pandemic. METHODS: A survey was distributed to all United Kingdom pancreatic specialist centres, to assess diagnostic, therapeutic and interventional services availability, and alterations in treatment pathways. A repeating methodology enabled assessment over time as the pandemic evolved. RESULTS: Responses were received from all 29 centres. Over the first six weeks of the pandemic, less than a quarter of centres had normal availability of diagnostic pathways and a fifth of centres had no capacity whatsoever to undertake surgery. As the pandemic progressed services have gradually improved though most centres remain constrained to some degree. One third of centres changed their standard resectable pathway from surgery-first to neoadjuvant chemotherapy. Elderly patients, and those with COPD were less likely to be offered treatment during the pandemic. CONCLUSION: The COVID-19 pandemic has affected the capacity of the NHS to provide diagnostic and staging investigations for pancreatic cancer. The impact of revised treatment pathways has yet to be realised.
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COVID-19 , Neoplasias Pancreáticas , Anciano , Humanos , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/terapia , Pandemias , SARS-CoV-2 , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with around 9% of patients surviving >5 years. Asymptomatic in its initial stages, PDAC is mostly diagnosed late, when already a locally advanced or metastatic disease, as there are no useful biomarkers for detection in its early stages, when surgery can be curative. We have previously described a promising biomarker panel (LYVE1, REG1A, and TFF1) for earlier detection of PDAC in urine. Here, we aimed to establish the accuracy of an improved panel, including REG1B instead of REG1A, and an algorithm for data interpretation, the PancRISK score, in additional retrospectively collected urine specimens. We also assessed the complementarity of this panel with CA19-9 and explored the daily variation and stability of the biomarkers and their performance in common urinary tract cancers. METHODS AND FINDINGS: Clinical specimens were obtained from multiple centres: Barts Pancreas Tissue Bank, University College London, University of Liverpool, Spanish National Cancer Research Center, Cambridge University Hospital, and University of Belgrade. The biomarker panel was assayed on 590 urine specimens: 183 control samples, 208 benign hepatobiliary disease samples (of which 119 were chronic pancreatitis), and 199 PDAC samples (102 stage I-II and 97 stage III-IV); 50.7% were from female individuals. PDAC samples were collected from patients before treatment. The samples were assayed using commercially available ELISAs. Statistical analyses were performed using non-parametric Kruskal-Wallis tests adjusted for multiple comparisons, and multiple logistic regression. Training and validation datasets for controls and PDAC samples were obtained after random division of the whole available dataset in a 1:1 ratio. The substitution of REG1A with REG1B enhanced the performance of the panel to detect resectable PDAC. In a comparison of controls and PDAC stage I-II samples, the areas under the receiver operating characteristic curve (AUCs) increased from 0.900 (95% CI 0.843-0.957) and 0.926 (95% CI 0.843-1.000) in the training (50% of the dataset) and validation sets, respectively, to 0.936 in both the training (95% CI 0.903-0.969) and the validation (95% CI 0.888-0.984) datasets for the new panel including REG1B. This improved panel showed both sensitivity (SN) and specificity (SP) to be >85%. Plasma CA19-9 enhanced the performance of this panel in discriminating PDAC I-II patients from controls, with AUC = 0.992 (95% CI 0.983-1.000), SN = 0.963 (95% CI 0.913-1.000), and SP = 0.967 (95% CI 0.924-1.000). We demonstrate that the biomarkers do not show significant daily variation, and that they are stable for up to 5 days at room temperature. The main limitation of our study is the low number of stage I-IIA PDAC samples (n = 27) and lack of samples from individuals with hereditary predisposition to PDAC, for which specimens collected from control individuals were used as a proxy. CONCLUSIONS: We have successfully validated our urinary biomarker panel, which was improved by substituting REG1A with REG1B. At a pre-selected cutoff of >80% SN and SP for the affiliated PancRISK score, we demonstrate a clinically applicable risk stratification tool with a binary output for risk of developing PDAC ('elevated' or 'normal'). PancRISK provides a step towards precision surveillance for PDAC patients, which we will test in a prospective clinical study, UroPanc.
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Biomarcadores de Tumor/orina , Carcinoma Ductal Pancreático/diagnóstico , Detección Precoz del Cáncer , Neoplasias Pancreáticas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Carbohidratos Asociados a Tumores/sangre , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/orina , Europa (Continente) , Femenino , Humanos , Litostatina/orina , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/orina , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factor Trefoil-1/orina , Urinálisis , Proteínas de Transporte Vesicular/orina , Adulto JovenRESUMEN
Cancer-associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro- versus anti-tumoural) in PDAC. We hypothesised that multiple CAF functional subtypes exist in PDAC, that contribute to stromal heterogeneity through interactions with cancer cells. Using molecular and functional analysis of patient-derived CAF primary cultures, we demonstrated that human PDAC-derived CAFs display a high level of inter- and intra-tumour heterogeneity. We identified at least four subtypes of CAFs based on transcriptomic analysis, and propose a classification for human PDAC-derived CAFs (pCAFassigner). Multiple CAF subtypes co-existed in individual patient samples. The presence of these CAF subtypes in bulk tumours was confirmed using publicly available gene expression profiles, and immunostainings of CAF subtype markers. Each subtype displayed specific phenotypic features (matrix- and immune-related signatures, vimentin and α-smooth muscle actin expression, proliferation rate), and was associated with an assessable prognostic impact. A prolonged exposure of non-tumoural pancreatic stellate cells to conditioned media from cancer cell lines (cancer education experiment) induced a CAF-like phenotype, including loss of capacity to revert to quiescence and an increase in the expression of genes related to CAF subtypes B and C. This classification demonstrates molecular and functional inter- and intra-tumoural heterogeneity of CAFs in human PDAC. Our subtypes overlap with those identified from single-cell analyses in other cancers, and pave the way for the development of therapies targeting specific CAF subpopulations in PDAC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Fibroblastos Asociados al Cáncer/patología , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/genética , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Heterogeneidad Genética , Humanos , Estimación de Kaplan-Meier , Neoplasias Pancreáticas/genética , Células Estrelladas Pancreáticas/patología , Fenotipo , Pronóstico , Células del Estroma/patología , Células Tumorales Cultivadas , Microambiente TumoralRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 4% and desperately needs novel effective therapeutics. Integrin αvß6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed that high levels of ß6 mRNA correlated strongly with significantly poorer survival (n = 491 cases, p = 3.17 × 10-8 ). In two separate cohorts, we showed that over 80% of PDACs expressed αvß6 protein and that paired metastases retained αvß6 expression. In vitro, integrin αvß6 promoted PDAC cell growth, survival, migration, and invasion. Treatment of both αvß6-positive human PDAC xenografts and transgenic mice bearing αvß6-positive PDAC with the αvß6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p < 0.0001) and increased survival (log-rank test, p < 0.05). Antibody therapy was associated with suppression of tumour cell activity (suppression of pErk growth signals, increased apoptosis seen as activated caspase-3) and suppression of the pro-tumourigenic microenvironment (suppression of TGFß signalling, fewer αSMA-positive myofibroblasts, decreased blood vessel density). These data show that αvß6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Antígenos de Neoplasias/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Integrinas/metabolismo , Neoplasias Pancreáticas/metabolismo , Animales , Antígenos de Neoplasias/genética , Antineoplásicos Inmunológicos/farmacología , Apoptosis , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/secundario , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Fosfatasa 6 de Especificidad Dual/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Genes ras , Humanos , Integrasas/genética , Integrinas/antagonistas & inhibidores , Integrinas/genética , Italia , Ratones Desnudos , Ratones Transgénicos , Invasividad Neoplásica , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Transducción de Señal , Carga Tumoral , Microambiente Tumoral , Reino Unido , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The Pancreatic Expression Database (PED, http://www.pancreasexpression.org) continues to be a major resource for mining pancreatic -omics data a decade after its initial release. Here, we present recent updates to PED and describe its evolution into a comprehensive resource for extracting, analysing and integrating publicly available multi-omics datasets. A new analytical module has been implemented to run in parallel with the existing literature mining functions. This analytical module has been created using rich data content derived from pancreas-related specimens available through the major data repositories (GEO, ArrayExpress) and international initiatives (TCGA, GENIE, CCLE). Researchers have access to a host of functions to tailor analyses to meet their needs. Results are presented using interactive graphics that allow the molecular data to be visualized in a user-friendly manner. Furthermore, researchers are provided with the means to superimpose layers of molecular information to gain greater insight into alterations and the relationships between them. The literature-mining module has been improved with a redesigned web appearance, restructured query platforms and updated annotations. These updates to PED are in preparation for its integration with the Pancreatic Cancer Research Fund Tissue Bank (PCRFTB), a vital resource of pancreas cancer tissue for researchers to support and promote cutting-edge research.
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Bases de Datos Genéticas , Expresión Génica , Páncreas/metabolismo , Neoplasias Pancreáticas/genética , Animales , Variaciones en el Número de Copia de ADN , Humanos , Ratones , Mutación , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidadRESUMEN
Recently, stromal targeting, by agents such as All trans retinoic acid (ATRA), has been regarded as a promising avenue for the treatment of pancreatic ductal adenocarcinoma (PDAC). The intra-cellular transportation of ATRA to the nuclear receptors is performed by either: fatty acid binding protein 5 (FABP5) or cellular retinoic acid binding protein 2 (CRABP2), dictating the transcription of downstream genes and, thus, eventual cell phenotype. Here, we explored the levels of each protein, in pancreatic tissues of patients presenting with a range of pancreatic diseases (pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), cholangiocarcinoma (CC)). We demonstrate that there is a significantly lower CRABP2 and FABP5 expression in activated fibroblasts or pancreatic stellate cells (PSC) in PDAC, as well as other diseased pancreas as in CC and CP, versus quiescent fibroblasts. The quiescent fibroblasts consistently show a pattern of high FABP5:CRABP2 ratio, whereas PSC in all non-PDAC tissues showed a low FABP5:CRABP2 ratio. PSC in PDAC patients had a range of FABP5:CRABP2 ratios (high, even and low). There was a lower CRABP2 expression in cancerous epithelial cells (PDAC) versus normal epithelial cells. This is also present in other disease states (CP, CC). Contrasting to the patterns seen for fibroblasts, the FABP5 expression in PDAC epithelial cells matched that of the normal epithelial cells. However, the normal epithelial cells had a high FABP5:CRABP2 ratio, compared to the PDAC epithelial cells. These ratios may have correlation with tumor progression, and overall survival. These findings could be confirmed in in vitro cell lysates. CRABP2 and FABP5 levels and ratios could serve as valuable biomarkers.
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Carcinoma Ductal Pancreático/metabolismo , Proteínas de Unión a Ácidos Grasos/genética , Páncreas/patología , Receptores de Ácido Retinoico/genética , Tretinoina/farmacocinética , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de los Conductos Biliares/patología , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Progresión de la Enfermedad , Células Epiteliales/metabolismo , Proteínas de Unión a Ácidos Grasos/efectos de los fármacos , Fibroblastos/metabolismo , Técnica del Anticuerpo Fluorescente/métodos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Páncreas/fisiopatología , Pancreatitis Crónica/metabolismo , Pancreatitis Crónica/patología , Receptores de Ácido Retinoico/efectos de los fármacos , Análisis de Supervivencia , Análisis de Matrices Tisulares/métodos , Tretinoina/farmacología , Tretinoina/uso terapéuticoRESUMEN
BACKGROUND AND OBJECTIVES: Approximately 30-50% of patients with colorectal cancer develop liver metastasis for which liver resection is the only hope for potential cure. However, hepatic resection is associated with considerable morbidity. The aim was to detect early complications by utilising the neutrophil: lymphocyte ratio (NLR). METHODS: We performed a retrospective cohort study of patients undergoing hepatic resection at a single institution between 2008 and 2016. Baseline demographics and complications within 30 days following surgery were recorded, with blood tests measured until day 7. Statistical analysis was performed using Mann Whitney and ROC analysis. RESULTS: One hundred eighty-eight operations were included. 47.3% had an associated complication, of which 31.46% were major. The median NLR was 6.31 across the cohort, 5.44 for uncomplicated procedures, 7.0 for complications and 10.65 in major complications. Median NLR was the best parameter for detecting major complications versus minor complications (AUC 0.74) as opposed to lymphocytes (AUC 0.65), neutrophils (AUC 0.60), and CRP (AUC 0.60). The diagnostic ability of NLR increased further when predicting major complications versus an uncomplicated recovery (AUC 0.78), and it was the only significant parameter in the early post-operative period on days 2, 3, and 4 (AUC 0.70, 0.72, and 0.75). CONCLUSIONS: The NLR may have a role in predicting complications following hepatic resection for CLM, and with earlier detection, potentially improving outcomes.
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Neoplasias Colorrectales/patología , Hepatectomía/efectos adversos , Neoplasias Hepáticas/secundario , Linfocitos/patología , Neutrófilos/patología , Complicaciones Posoperatorias/diagnóstico , Anciano , Neoplasias Colorrectales/cirugía , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/cirugía , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND/OBJECTIVES: Polymeric immunoglobulin receptor (pIgR) traffics Immunoglobulins (IgA and IgM) through epithelial cells in normal mucosae but neither are expressed in the normal pancreas. Recent work from our laboratory suggested pIgR may be upregulated in pancreatic ductal adenocarcinoma (PDAC). Our aim was to assess the role of pIgR in human PDAC. METHODS: pIgR expression was manipulated (siRNA and shRNA) in cell lines to evaluate its subsequent effect on cell behaviour in 2D assays as well as 3D organotypics models. Tissue Microarrays of 88 patients with PDAC were analysed after pIgR, αSMA, E-Cadherin and Picrosirius Red staining to assess their role as a combined bio-marker panel. RESULTS: Cytokines such as interleukin 4 (IL4) and Tumour Necrosis Factor (TNFα) could not modulate pIgR expression in PDAC cell lines despite this effect being seen in other studies. Down-regulation in pIgR expression in Capan1 cancer cell line resulted in reduction of cellular proliferation, adhesion and migration in 2D assays. In 3D physiomimetic organotypic models, pIgR downregulation resulted in reduced cancer cell invasion, alteration of apico-basal polarity and diminished stromal activity. In human PDAC, decreased E-cadherin expression correlates with increased pIgR expression through pancreatic intra-epithelial neoplasia (PanIN) progression. In combination with enhanced stromal indices (α-smooth muscle action (SMA) and Picrosirius red), low pIgR scores had a trend towards better survival. CONCLUSION: pIgR may be involved in PDAC progression and may be linked stromal activity. Further work on its precise role is mandated in in vivo models, to understand its influence on cancer progression.
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Adenocarcinoma/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Neoplasias Pancreáticas/metabolismo , Receptores de Inmunoglobulina Polimérica/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patología , Receptores de Inmunoglobulina Polimérica/genética , Análisis de Matrices TisularesRESUMEN
Stromal targeting for pancreatic ductal adenocarcinoma (PDAC) is rapidly becoming an attractive option, due to the lack of efficacy of standard chemotherapy and increased knowledge about PDAC stroma. We postulated that the addition of stromal therapy may enhance the anti-tumour efficacy of chemotherapy. Gemcitabine and all-trans retinoic acid (ATRA) were combined in a clinically applicable regimen, to target cancer cells and pancreatic stellate cells (PSCs) respectively, in 3D organotypic culture models and genetically engineered mice (LSL-Kras(G12D) (/+) ;LSL-Trp53(R172H) (/+) ;Pdx-1-Cre: KPC mice) representing the spectrum of PDAC. In two distinct sets of organotypic models as well as KPC mice, we demonstrate a reduction in cancer cell proliferation and invasion together with enhanced cancer cell apoptosis when ATRA is combined with gemcitabine, compared to vehicle or either agent alone. Simultaneously, PSC activity (as measured by deposition of extracellular matrix proteins such as collagen and fibronectin) and PSC invasive ability were both diminished in response to combination therapy. These effects were mediated through a range of signalling cascades (Wnt, hedgehog, retinoid, and FGF) in cancer as well as stellate cells, affecting epithelial cellular functions such as epithelial-mesenchymal transition, cellular polarity, and lumen formation. At the tissue level, this resulted in enhanced tumour necrosis, increased vascularity, and diminished hypoxia. Consequently, there was an overall reduction in tumour size. The enhanced effect of stromal co-targeting (ATRA) alongside chemotherapy (gemcitabine) appears to be mediated by dampening multiple signalling cascades in the tumour-stroma cross-talk, rather than ablating stroma or targeting a single pathway. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Adenocarcinoma/terapia , Antimetabolitos Antineoplásicos/uso terapéutico , Carcinoma Ductal Pancreático/terapia , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/terapia , Transducción de Señal/efectos de los fármacos , Adenocarcinoma/patología , Animales , Apoptosis/efectos de los fármacos , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desoxicitidina/uso terapéutico , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Ratones , Neoplasias Pancreáticas/patología , Células Estrelladas Pancreáticas/efectos de los fármacos , Células Estrelladas Pancreáticas/patología , GemcitabinaRESUMEN
BACKGROUND/OBJECTIVES: The vascular heterogeneity of pancreatic ductal adenocarcinoma (PDAC) has never been characterised. We analysed the heterogeneous vascular density of human PDAC along with its prognostic correlation. METHODS: Tissue Microarrays of 87 patients with different pancreatico-biliary pathologies were analysed in an automated manner (Ariol™) after CD31 staining to assess vascular density in juxta-tumoral and panstromal compartments. In vitro and ex vivo assays were carried out to assess the role of PSC. RESULTS: PDAC has a distinct vascular density and distribution of vessels compared to cholangiocarcinoma. The PDAC juxta-tumoral stroma was hypovascular and the normal adjacent rim was hypervascular compared to the panstromal compartment. These features adversely affected patient prognosis, suggesting a model for spatio-temporal PDAC evolution. Mice aortic rings and 3D organotypic cultures demonstrated pro- and anti-angiogenic signalling from activated PSC and cancer cells respectively. ATRA-induced quiescence suppressed the pro-angiogenic activity of PSC. CONCLUSION: Human PDAC has variable vascularity at microscopic level suggesting that novel stromal directed therapies would need to be determined by pathological characteristics.
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Adenocarcinoma/patología , Vasos Sanguíneos/patología , Carcinoma Ductal Pancreático/patología , Células Estrelladas Pancreáticas/patología , Animales , Células Cultivadas , Colangiocarcinoma/patología , Humanos , Ratones , Análisis por Micromatrices , Microcirculación/efectos de los fármacos , Neovascularización Patológica/patología , Técnicas de Cultivo de Órganos , Pronóstico , Análisis de Supervivencia , Tretinoina/uso terapéutico , Microambiente TumoralRESUMEN
The many benefits of laparoscopy, including smaller incision, reduced length of hospital stay and more rapid return to normal function, have seen its popularity grow in recent years. With concurrent improvements in non-surgical cancer management the importance of accurate staging is becoming increasingly important. There are two main applications of laparoscopic surgery in managing hepato-pancreatico-biliary (HPB) malignancy: accurate staging of disease and resection. We aim to summarize the use of laparoscopy in these contexts. The role of staging laparoscopy has become routine in certain cancers, in particular T[2] staged, locally advanced gastric cancer, hilar cholangiocarcinoma and non-Hodgkin's lymphoma. For other cancers, in particular colorectal, laparoscopy has now become the gold standard management for resection such that there is no role for stand-alone staging laparoscopy. In HPB cancers, although staging laparoscopy may play a role, with ever improving radiology, its role remains controversial.
Asunto(s)
Neoplasias del Sistema Biliar/cirugía , Tumor de Klatskin/cirugía , Laparoscopía , Linfoma no Hodgkin/cirugía , Neoplasias del Sistema Biliar/patología , Humanos , Tumor de Klatskin/patología , Linfoma no Hodgkin/patología , Estadificación de Neoplasias , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugíaRESUMEN
This study highlights the highly dynamic nature of SULF1/SULF2 splice variants in different human pancreatic cancers that regulate the activities of multiple cell signalling pathways in development and disease. Most pancreatic tumours expressed variable levels of both SULF1 and SULF2 variants including some expression during inflammation and pancreatitis. Many ductal and centro-acinar cell-derived pancreatic tumours are known to evolve into lethal pancreatic ductal adenocarcinomas but the present study also detected different stages of such tumour progression in the same tissue biopsies of not only acinar cell origin but also islet cell-derived cancers. The examination of caerulein-induced pancreatic injury and tumorigenesis in a Kras-driven mouse model confirmed the activation and gradual increase of SULF1/SULF2 variants during pancreatitis and tumorigenesis but with reduced levels in Stat3 conditional knockout mice with reduced inflammation. The significance of differential spatial and temporal patterns of specific SULF1/SULF2 splice variant expression during cancer growth became further apparent from their differential stimulatory or inhibitory effects on growth factor activities, tumour growth and angiogenesis not only during in vitro but also in vivo growth thus providing possible novel therapeutic targets.
Asunto(s)
Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Sulfotransferasas/fisiología , Carga Tumoral/genética , Adulto , Animales , Embrión de Pollo , Progresión de la Enfermedad , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Isoenzimas/genética , Isoenzimas/fisiología , Ratones , Ratones Noqueados , Neoplasias Pancreáticas/metabolismo , Sulfatasas , Sulfotransferasas/genética , Células Tumorales Cultivadas , Neoplasias PancreáticasAsunto(s)
Biomarcadores de Tumor/orina , Carcinoma Ductal Pancreático/orina , Neoplasias Pancreáticas/orina , Compuestos Orgánicos Volátiles/orina , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Carcinoma Ductal Pancreático/diagnóstico , Femenino , Humanos , Espectrometría de Movilidad Iónica , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/diagnóstico , Valor Predictivo de las Pruebas , Curva ROC , UrinálisisRESUMEN
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic microenvironment that contains many different immune cells. Activated pancreatic stellate cells (PSCs) contribute to the desmoplasia. We investigated whether distinct stromal compartments are differentially infiltrated by different types of immune cells. METHODS: We used tissue microarray analysis to compare immune cell infiltration of different pancreaticobiliary diseased tissues (PDAC, ampullary carcinoma, cholangiocarcinoma, mucinous cystic neoplasm, chronic inflammation, and chronic pancreatitis) and juxtatumoral stromal (<100 µm from tumor) and panstromal compartments. We investigated the association between immune infiltrate and patient survival times. We also analyzed T-cell migration and tumor infiltration in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice and the effects of all-trans retinoic acid (ATRA) on these processes. RESULTS: Juxtatumoral compartments in PDAC samples from 2 independent groups of patients contained increased numbers of myeloperoxidase(+) and CD68(+) cells compared with panstromal compartments. However, juxtatumoral compartments of PDACs contained fewer CD8(+), FoxP3(+), CD56(+), or CD20(+) cells than panstromal compartments, a distinction absent in ampullary carcinomas and cholangiocarcinomas. Patients with PDACs that had high densities of CD8(+) T cells in the juxtatumoral compartment had longer survival times than patients with lower densities. In KPC mice, administration of ATRA, which renders PSCs quiescent, increased numbers of CD8(+) T cells in juxtatumoral compartments. We found that activated PSCs express cytokines, chemokines, and adhesion molecules that regulate T-cell migration. In vitro migration assays showed that CD8(+) T cells, from patients with PDAC, had increased chemotaxis toward activated PSCs, which secrete CXCL12, compared with quiescent PSCs or tumor cells. These effects could be reversed by knockdown of CXCL12 or treatment of PSCs with ATRA. CONCLUSIONS: Based on studies of human PDAC samples and KPC mice, activated PSCs appear to reduce migration of CD8(+) T cells to juxtatumoral stromal compartments, preventing their access to cancer cells. Deregulated signaling by activated PSCs could prevent an effective antitumor immune response.
Asunto(s)
Adenocarcinoma/patología , Linfocitos T CD8-positivos/patología , Carcinoma Ductal Pancreático/patología , Movimiento Celular/fisiología , Neoplasias Pancreáticas/patología , Células Estrelladas Pancreáticas/patología , Adenocarcinoma/fisiopatología , Animales , Antígenos CD20/fisiología , Antígeno CD56/fisiología , Carcinoma Ductal Pancreático/fisiopatología , Adhesión Celular/fisiología , Células Cultivadas , Quimiocina CXCL12/fisiología , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/fisiología , Humanos , Ratones , Ratones Endogámicos , Neoplasias Pancreáticas/fisiopatologíaRESUMEN
FGFR (fibroblast growth factor receptor) signalling plays critical roles in embryogensis, adult physiology, tissue repair and many pathologies. Of particular interest over recent years, it has been implicated in a wide range of cancers, and concerted efforts are underway to target different aspects of FGFR signalling networks. A major focus has been identifying the canonical downstream signalling pathways in cancer cells, and these are now relatively well understood. In the present review, we focus on two distinct but emerging hot topics in FGF biology: its role in stromal cross-talk during cancer progression and the potential roles of FGFR signalling in the nucleus. These neglected areas are proving to be of great interest clinically and are intimately linked, at least in pancreatic cancer. The importance of the stroma in cancer is well accepted, both as a conduit/barrier for treatment and as a target in its own right. Nuclear receptors are less acknowledged as targets, largely due to historical scepticism as to their existence or importance. However, increasing evidence from across the receptor tyrosine kinase field is now strong enough to make the study of nuclear growth factor receptors a major area of interest.