scholarly journals Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

2021 ◽  
Author(s):  
Jingbo Li ◽  
Rui Kang ◽  
Daolin Tang
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Perineural Invasion ◽  
Molecular Mechanisms ◽  
Ductal Adenocarcinoma

scholarly journals Prognostic Nomogram for Patients With Pancreatic Ductal Adenocarcinoma of Pancreatic Head After Pancreaticoduodenectomy

2021 ◽  
Vol 15 ◽  
pp. 117955492110241
Author(s):  
Hongkai Zhuang ◽  
Zixuan Zhou ◽  
Zuyi Ma ◽  
Shanzhou Huang ◽  
Yuanfeng Gong ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Perineural Invasion ◽  
Cox Regression ◽  
Area Under The Curve ◽  
Pancreatic Head ◽  
Ductal Adenocarcinoma ◽  
R0 Resection ◽  
Cox Regression Analysis ◽  
Ajcc Stage

Background: The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) of pancreatic head remains poor, even after potentially curative R0 resection. The aim of this study was to develop an accurate model to predict patients’ prognosis for PDAC of pancreatic head following pancreaticoduodenectomy. Methods: We retrospectively reviewed 112 patients with PDAC of pancreatic head after pancreaticoduodenectomy in Guangdong Provincial People’s Hospital between 2014 and 2018. Results: Five prognostic factors were identified using univariate Cox regression analysis, including age, histologic grade, American Joint Committee on Cancer (AJCC) Stage 8th, total bilirubin (TBIL), CA19-9. Using all subset analysis and multivariate Cox regression analysis, we developed a nomogram consisted of age, AJCC Stage 8th, perineural invasion, TBIL, and CA19-9, which had higher C-indexes for OS (0.73) and RFS (0.69) compared with AJCC Stage 8th alone (OS: 0.66; RFS: 0.67). The area under the curve (AUC) values of the receiver operating characteristic (ROC) curve for the nomogram for OS and RFS were significantly higher than other single parameter, which are AJCC Stage 8th, age, perineural invasion, TBIL, and CA19-9. Importantly, our nomogram displayed higher C-index for OS than previous reported models, indicating a better predictive value of our model. Conclusions: A simple and practical nomogram for patient prognosis in PDAC of pancreatic head following pancreaticoduodenectomy was established, which shows satisfactory predictive efficacy and deserves further evaluation in the future.

scholarly journals miR-124 Suppresses Pancreatic Ductal Adenocarcinoma Growth by Regulating Monocarboxylate Transporter 1-Mediated Cancer Lactate Metabolism

2018 ◽  
Vol 50 (3) ◽  
pp. 924-935 ◽  
Author(s):  
De-Hai Wu ◽  
Hao Liang ◽  
Shou-Nan Lu ◽  
Hao Wang ◽  
Zhi-Lei Su ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Intracellular Ph ◽  
Molecular Mechanisms ◽  
Monocarboxylate Transporter ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Luciferase Reporter ◽  
Lactate Metabolism ◽  
Rt Pcr ◽  
Monocarboxylate Transporter 1

Background/Aims: Increasing evidence shows that reprogramming of energy metabolism is a hallmark of cancer. Considering the emergence of microRNAs as crucial modulators of cancer, this study aimed to better understand the molecular mechanisms of miR-124 in regulating glycolysis in human pancreatic cancer. Methods: RT-PCR was used to investigate the expression of monocarboxylate transporters (MCTs) in pancreatic ductal adenocarcinoma (PDAC) patient samples and the PANC-1 cell line. A public database and immunochemistry were used for comprehensive analysis of MCT1 expression. The targeting of MCT1 by miR-124 was predicted by software and validated for the MCT1 3’-UTR by dual-luciferase reporter analysis. Cell proliferation, apoptosis, migration, xenografting, and the intracellular pH and L-lactate levels were assessed. Hypoxia-inducible factor-α (HIF-1α) and lactate dehydrogenase A (LDH-A) expression levels were determined by RT-PCR and western blotting. Results: MCT1 expression was higher in PDAC tissue than in normal tissue. Inhibition of MCT1 affected lactate metabolism, resulting in a higher intracellular pH and less proliferation of PANC-1 cells. MCT1 was the target gene of miR-124. In in vitro experiments, miR-124 inhibited the glycolytic activity of PANC-1 cells by targeting MCT1, further decreasing the tumor phenotype by increasing the intracellular pH through LDH-A and HIF-1α. In in vivo experiments, overexpression of miR-124 and silencing of MCT1 significantly inhibited tumor growth. Conclusion: miR-124 inhibits the progression of PANC-1 by targeting MCT1 in the lactate metabolic pathway. Our findings provide novel evidence for further functional studies of miR-124, which might be useful for future therapeutic approaches to PDAC.

P-P13 Long-term outcome after portal vein resection during pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: a propensity score matched analysis

2021 ◽  
Vol 108 (Supplement_9) ◽  
Author(s):  
James Russell ◽  
Claire Stevens ◽  
Rahul Bhome ◽  
Dimitrios Karavias ◽  
Ali Arshad ◽  
...  
Keyword(s):  
Propensity Score ◽  
Portal Vein ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Perineural Invasion ◽  
Nodal Metastasis ◽  
Ductal Adenocarcinoma ◽  
Safe Procedure ◽  
Portal Vein Resection ◽  
Vein Resection ◽  
The Impact

Abstract Background Portal vein resection (PVR) with pancreaticoduodenectomy (PD) is often performed to achieve clear margins for patients with vascular involvement in pancreatic ductal adenocarcinoma (PDAC). However, there is evidence to suggest that patients undergoing PVR often have more advanced cancers, therefore the impact of PVR on survival and recurrence remains unclear. The aim of this study is to assess overall (OS) and recurrence free (RFS) survival in patients who underwent PVR during PD, with particular attention to margin positivity. Methods A retrospective analysis was performed on 638 patients who underwent PD during a 12-year period. Exclusion criteria included PD for non-PDAC tumours, neoadjuvant chemotherapy or intra-operative radiotherapy. 374 patients were included in the study (90 PVR and 284 non-PVR). Patient characteristics and histopathological factors associated with OS and RFS were then evaluated using univariate and multivariate Cox regression analyses. 270 patients (90 PVR and 180 non-PVR), were matched by propensity score based on perineural invasion, pT and pN staging. The Kaplan-Meier method was used to calculate survival and log-rank tests. Results Resection margin positivity was associated with shorter OS and RFS (p < 0.0001), and the superior mesenteric vein (SMV) margin was the most significant risk factor for survival on competing risks analysis. Absent adjuvant chemotherapy, nodal metastasis and margin positivity were independent risk factors for OS and RFS on multivariate analysis. PVR was associated with higher intra-operative blood loss (p = 0.009), but was not associated with increased length of stay, complications or readmissions. PVR patients had increased pT staging, nodal metastasis and perineural invasion, however, there was no difference in OS (p = 0.551) or RFS (p = 0.256) between PVR and non-PVR after propensity matching. Conclusions Positive resection margins are associated with shorter survival times, and the SMV margin is the most significant prognostic indicator for overall survival and recurrence compared to other margins. PVR is a relatively safe procedure, however, it does not achieve the intended survival benefits of complete margin clearance. The impact on survival for margin positivity, particularly the SMV margin, and nodal metastasis should be considered when making decisions with regards to vein resection and adjuvant treatments.

scholarly journals Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1869 ◽  
Author(s):  
Can Huang ◽  
Wenjun Lan ◽  
Nicolas Fraunhoffer ◽  
Analía Meilerman ◽  
Juan Iovanna ◽  
...  
Keyword(s):  
Cell Death ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Proteasome Inhibitors ◽  
Ductal Adenocarcinoma ◽  
Mitochondrial Stress ◽  
Anticancer Mechanism ◽  
Chemotherapeutic Treatment ◽  
Approved Drugs ◽  
Protein Response

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with almost no curative chemotherapeutic treatment. Besides the development of new compounds, repurposing of approved drugs to treat cancer, alone or in combination, has become an attractive strategy, showing many therapeutic and economic advantages. However, it is necessary to improve our knowledge about the mechanism of cell death elicited by approved drugs itself, but also to rationally develop more powerful multidrug treatments. In this work, we focus our attention on determining the mechanism promoting cell death following trifluoperazine (TFP) treatment, which is an antipsychotic drug with strong anticancer activity in PDAC. We demonstrate that TFP induces cell death by apoptosis and necroptosis, which can be partially inhibited by Z-VAD-FMK as well as necrostatin-1, respectively. This cell death promotion is triggered by a poor ATP content, observed in TFP-treated cells as a consequence of a dramatic decrease in OXPHOS metabolism due to mitochondrial stress. Remarkably, mitochondrial homeostasis was seriously affected, and a loss of mitochondrial membrane potential and ROS overproduction was observed. Moreover, this mitochondrial stress was coupled with an ER stress and the activation of the endoplasmic-reticulum-associated protein degradation (ERAD) and the unf olded protein response (UPR) pathways. We took advantage of this information and inhibited this process by using the proteasome inhibitors MG-132 or bortezomib compounds in combination with TFP and found a significant improvement of the anticancer effect of the TFP on primary PDAC-derived cells. In conclusion, this study not only uncovers the molecular mechanisms that are triggered upon TFP-treatment but also its possible combination with bortezomib for the future development of therapies for pancreatic cancer.

scholarly journals A Network-Based Approach for Identification of Subtype-Specific Master Regulators in Pancreatic Ductal Adenocarcinoma

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 155
Author(s):  
Yuchen Zhang ◽  
Lina Zhu ◽  
Xin Wang
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Network Inference ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Regulatory Mechanism ◽  
Expression Profiles ◽  
Strong Association ◽  
Predictive Biomarkers ◽  
Integrative Analysis ◽  
Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), the predominant subtype of pancreatic cancer, has been reported with equal mortality and incidence for decades. The lethality of PDAC is largely due to its late presentation, when surgical resection is no longer an option. Similar to other major malignancies, it is now clear that PDAC is not a single disease, posing a great challenge to precise selection of patients for optimized adjuvant therapy. A representative study found that PDAC comprises four distinct molecular subtypes: squamous, pancreatic progenitor, immunogenic, and aberrantly differentiated endocrine exocrine (ADEX). However, little is known about the molecular mechanisms underlying specific PDAC subtypes, hampering the design of novel targeted agents. In this study we performed network inference that integrates miRNA expression and gene expression profiles to dissect the miRNA regulatory mechanism specific to the most aggressive squamous subtype of PDAC. Master regulatory analysis revealed that the particular subtype of PDAC is predominantly influenced by miR-29c and miR-192. Further integrative analysis found miR-29c target genes LOXL2, ADAM12 and SERPINH1, which all showed strong association with prognosis. Furthermore, we have preliminarily revealed that the PDAC cell lines with high expression of these miRNA target genes showed significantly lower sensitivities to multiple anti-tumor drugs. Together, our integrative analysis elucidated the squamous subtype-specific regulatory mechanism, and identified master regulatory miRNAs and their downstream genes, which are potential prognostic and predictive biomarkers.

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