The molecular landscape of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related mortality within the next decade, with limited effective treatment options and a dismal long-term prognosis for patients. Surgical resection of early, localised disease provides the only chance for potentially curative treatment; however, most patients with PDAC present with advanced disease and are not suitable for surgery. Genomic analyses of PDAC tumour lesions have identified a small number of recurrent alterations that are detected across most tumours, and beyond that a large number that either occur at a low (<5%) prevalence or are patient-specific in nature. This molecular heterogeneity has presented a significant challenge for the characterisation of tumour subtypes and effective molecular biomarkers, which have not yet manifested clinical benefits for diagnosis, treatment or prognosis in PDAC. These challenges are compounded by the overall lack of tumour biopsies for sequencing, the invasive nature of tissue sampling and the confounding effects of low tumour cellularity in many PDAC biopsy specimens, which have limited the applications of molecular profiling in unresectable patients and for longitudinal tumour monitoring. Further investigation into alternative sources of tumour analytes that can be sampled using minimally invasive methods and used to complement molecular analyses from tissue sequencing are required.     

Synchronous gastric adenocarcinoma and pancreatic ductal adenocarcinoma

BACKGROUND:The association between gastric and pancreatic carcinoma is a relatively rare condition.In gastric carcinoma patients,the prevalence of second tumors varies 2.8% to 6.8% according to the reported statistics.Gastric cancer associated with pancreatic cancer is uncommon.METHODS:We report a case of a 73-year-old patient hospitalized for vomiting and weight loss.Esophagogastroduodenoscopy demonstrated an ulcerative lesion of the gastric antrum.Computed tomography and magnetic resonance showed a gastri...     

Microbiome and pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) incidence and related-deaths are increasing worldwide. PDAC is characterized by poor prognosis due to late diagnosis, high metastatic capacity and resistance to therapy. This is partially due to its specific microenvironment, where the stroma is prominent over tumor cells. Besides the oral and gut microbiota, the intratumor microbiome, i.e. the bacterial and fungal microorganisms present within the tumor, was recently introduced as a new partner of the tumor microenvironment of PDAC modulating pancreatic carcinogenesis, intratumor immune infiltrates, and response to chemotherapy. In this review, we propose an overview of current knowledge about the roles of bacteria and fungi in PDAC development and biology, and discuss potential therapeutic implications.     

Genomics of pancreatic ductal adenocarcinoma

Pancreatic cancer is one of the worst prognostic cancers because of the late diagnosis and the absence of effective treatment. Within all subtypes of this disease, ductal adenocarcinoma has the shortest survival time. In recent years, global genomics profiling allowed the identification of hundreds of genes that are perturbed in pancreatic cancer. The integration of different omics sources in the study of pancreatic cancer has revealed several molecular mechanisms, indicating the complex history of its development. However, validation of these genes as biomarkers for early diagnosis, prognosis or treatment efficacy is still incomplete but should lead to new approaches for the treatment of the disease in the future.     

Ecoevolutionary biology of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, is an aggressive disease predicted to be the 2nd cause of cancer mortality in the US by 2040. While first-line therapy has improved, 5-year overall survival has only increased from 5 to ～10%, and surgical resection is only available for ～20% of patients as most present with advanced disease, which is invariably lethal. PDAC has well-established highly recurrent mutations in four driver genes including KRAS, TP53, CDKN2A, and SMAD4. Unfortunately, these genetic drivers are not currently therapeutically actionable. Despite extensive sequencing efforts, few additional significantly recurrent and druggable drivers have been identified. In the absence of targetable mutations, chemotherapy remains the mainstay of treatment for most patients. Further, the role of the above driver mutations on PDAC initiation and early development is well-established. However, these mutations alone cannot account for PDAC heterogeneity nor discern early from advanced disease. Taken together, management of PDAC is an example highlighting the shortcomings of the current precision medicine paradigm. PDAC, like other malignancies, represents an ecoevolutionary process. Better understanding the disease through this lens can facilitate the development of novel therapeutic strategies to better control and cure PDAC. This review aims to integrate the current understanding of PDAC pathobiology into an ecoevolutionary framework.     

胰腺导管腺癌microRNA表达谱的研究

目的 应用microRNA( miRNA)高通量生物芯片筛选胰腺导管腺癌及癌旁组织差异表达的miRNA,分析其相关的靶基因.方法 收集9例新鲜的胰腺导管腺癌和3例癌旁组织,运用标记713个miRNA的Agilent miRNA生物芯片筛选胰腺导管腺癌差异表达的miRNA,应用荧光实时定量PCR方法验证表达上调的miRNA.采用TargetScan 5.1和miRandaV5分析软件分析差异表达miRNAs的靶基因.结果 miRNA芯片筛选出11个胰腺导管腺癌相关的差异表达的miRNA,其中miR-194*、miR-192*、miR-602、miR-194表达上调,miR-139-3p、miR-513a-5p、miR-630、miR-30c-1*、miR-887、miR-508-5p、miR-516a-5p表达下调.miR-192、miR-194及其同源体的表达在31例胰腺癌组织中得到验证.经软件分析,miR.192靶基因有ZEB2、CXCL-2、EEF1A1、ERCC3,miR-192*靶基因有DCC、SMAD4、FAS,miR-194靶基因有DACH1、IGSF11、PTPN2、RBBP4,miR-194*靶基因有CD40LG、CIDEB、FHL1.结论胰腺导管腺癌存在11个表达差异的miRNA,这些miRNA可能与胰腺导管腺癌的发生、发展有关.     

Mechanisms of thrombosis in pancreatic ductal adenocarcinoma

Patients with pancreatic cancer have a very high risk of both venous and arterial thrombosis compared with other cancers, caused by a tumour-driven hypercoagulable state. Better understanding of pancreatic cancer-associated prothrombotic and proinflammatory mechanisms opens the door to controlling prothrombotic states, ideally, without affecting the overall haemostasis. This narrative review brings together currently available evidence on epidemiology and pathogenesis of thrombotic complications in pancreatic adenocarcinoma. We describe risk factors for thrombosis and established and novel mechanisms of hypercoagulability. Among novel pathways of hypercoagulability, the release of neutrophils extracellular traps (NETs) by activated neutrophils and the crucial role of extracellular vesicles (EV) in participating in platelet and coagulation activation were described. We also reported recent evidence on EV role in thrombin generation amplification through the activation of the intrinsic pathway, discussing potential molecules implicated in this process.     

Sialylated MUC1 mucin expression in normal pancreas, benign pancreatic lesions, and pancreatic ductal adenocarcinoma.

BACKGROUND/AIMS: Pancreatic cancer has the poorest prognosis of all gastrointestinal cancers. Because sialylated mucin influences the biologic behavior of carcinoma cells, we investigated sialylated MUC1 mucin expression in patients with pancreatic ductal adenocarcinoma. METHODOLOGY: The expression of sialylated MUC1 mucin was examined in 55 pancreatic ductal adenocarcinomas, 2 normal pancreas specimens, 3 chronic pancreatitis specimens, 1 ductal hyperplasia of the pancreas, 3 mucinous cystadenomas, and 2 liver metastases from pancreatic ductal adenocarcinoma. Expression was assessed by immunohistochemistry with a new monoclonal antibody (mAb) (MY.1E12). RESULTS: Sialylated MUC1 mucin was expressed in the cancer cell membrane in all the ductal carcinomas. The reaction product was seen at the apical aspect of cells when these were in tubule formation. This pattern was also detected in mucinous cystadenomas. However, it was seen diffusely in the cell membrane in single cancer cells or small clusters of cells without tubule formation and in metastatic liver tumors. Namely, invading or metastatic cancer cells expressed this type of mucin throughout the entire cell membrane. The expression of sialylated MUC1 mucin was not observed in specimens from normal pancreas, chronic pancreatitis, or ductal hyperplasia of the pancreas. In normal pancreas and these lesions, expression of sialylated Mession of sialylated MUC1 was limited to acini and secreted mucin. CONCLUSIONS: Sialylated MUC1 mucin, which is expressed throughout the cancer cell membrane, may be a factor in the metastatic potential of pancreatic ductal adenocarcinoma.     

Semi-quantitative analysis of telomerase in pancreatic ductal adenocarcinoma

Using a polymerase chain reaction-based amplification assay, we measured telomerase activity in surgically resected pancreatic ductal carcinomas (n=16 cases) and normal ducts (n=6), comparing findings with the telomerase activity of a human pancreatic cancer cell line, MIA PaCa-2, as a standard, i.e., relative telomerase activity was determined. Telomerase activity was expressed as the equivalent telomerase intensity of the number of cells of MIA PaCa-2 per μg protein of tissue samples. The median value for telomerase activity in normal pancreatic ducts was 0.13 and the 25th and 75th percentile were 0.01 and 0.76. The median value for telomerase activity in pancreatic ductal adenocarcinoma was 34.7 (25th percentile, 4.98; and 75th percentile, 296), significantly higher than that of normal ducts (P<0.001). When the cut-off value was set at 1.0 and 3.0, the telomerase positivity rate of pancreatic ductal adenocarcinomas was 100% and 81.3%, respectively. Telomerase may be a specific marker for pancreatic ductal carcinomas.