Epigenomics of Pancreatic Cancer: A Critical Role for Epigenome-Wide Studies

Several challenges present themselves when discussing current approaches to the prevention or treatment of pancreatic cancer. Up to 45% of the risk of pancreatic cancer is attributed to unknown causes, making effective prevention programs difficult to design. The most common type of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), is generally diagnosed at a late stage, leading to a poor prognosis and 5-year survival estimate. PDAC tumors are heterogeneous, leading to many identified cell subtypes within one patient’s primary tumor. This explains why there is a high frequency of tumors that are resistant to standard treatments, leading to high relapse rates. This review will discuss how epigenetic technologies and epigenome-wide association studies have been used to address some of these challenges and the future promises these approaches hold.

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Aberrant MicroRNAs in Pancreatic Cancer: Researches and Clinical Implications

Gastroenterology Research and Practice ◽

10.1155/2014/386561 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 13

Author(s):

Tao Sun ◽

Xiangyu Kong ◽

Yiqi Du ◽

Zhaoshen Li

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Poor Prognosis ◽

Vital Role ◽

High Rate ◽

Ductal Adenocarcinoma ◽

Clinical Implications ◽

Circulating Mirnas ◽

Current Review ◽

Wide Range

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a high rate of mortality and poor prognosis. Numerous studies have proved that microRNA (miRNA) may play a vital role in a wide range of malignancies, including PDAC, and dysregulated miRNAs, including circulating miRNAs, are associated with PDAC proliferation, invasion, chemosensitivity, and radiosensitivity, as well as prognosis. Greater understanding of the roles of miRNAs in PDAC could provide insights into this disease and identify potential diagnostic markers and therapeutic targets. The current review focuses on recent advances with respect to the roles of miRNAs in PDAC and their practical value.

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RAS in pancreatic cancer

Biochemical Society Transactions ◽

10.1042/bst20170521 ◽

2019 ◽

Vol 47 (4) ◽

pp. 961-972 ◽

Cited By ~ 7

Author(s):

Simone Lanfredini ◽

Asmita Thapa ◽

Eric O'Neill

Keyword(s):

Pancreatic Cancer ◽

Neuroendocrine Tumour ◽

Critical Role ◽

Acinar Cell Carcinoma ◽

Genetically Engineered ◽

Ductal Adenocarcinoma ◽

Kras Mutations ◽

Activating Mutations ◽

Downstream Effectors ◽

Almost All

Abstract The pancreas is a gland composed mainly by endocrine and exocrine cells, giving rise to three main tumour types. Pancreatic neuroendocrine tumour or PNET arise from the endocrine portion of the pancreas. On the contrary, pancreatic exocrine neoplasms include pancreatic ductal adenocarcinoma (PDAC) and acinar cell carcinoma. PDAC is the most common type of pancreatic cancer and one of the leading causes of cancer-related death. It has been shown that less than 3% of PDAC patients have an overall survival of up to 5 years in the U.K. This mainly arises since the majority of patients diagnosed with PDAC present with advanced unresectable disease, which is highly resistant to all forms of chemotherapy and radiotherapy. Activating mutations of an isoform of the RAS protein, KRAS, are found in almost all PDAC cases and occur during early stages of malignant transformation. KRAS mutations play a critical role as they are involved in both initiating and maintaining PDAC development. The interaction of RAS with GDP/GTP along with its recruitment to the membrane affects transduction of its activating signals to downstream effectors. In this review, we aim to summarise different mutations of RAS and their prevalence in pancreatic cancer along with other RAS-induced tumours. In addition, we briefly discuss the genetically engineered mouse models that have been developed to study KRAS-mutated adenocarcinomas in the pancreas. These provide an opportunity to also address the importance of targeting RAS for better treatment response in PDAC patients along with the challenges incurred herein.

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Advances in pancreatic cancer biomarkers

Oncology Reviews ◽

10.4081/oncol.2019.410 ◽

2019 ◽

Vol 13 (1) ◽

Cited By ~ 15

Author(s):

Syed Hasan ◽

Rojymon Jacob ◽

Upender Manne ◽

Ravi Paluri

Keyword(s):

Pancreatic Cancer ◽

Poor Prognosis ◽

Essential Role ◽

Predictive Biomarkers ◽

Cancer Biomarkers ◽

Response Assessment ◽

Ductal Adenocarcinoma ◽

Low Sensitivity ◽

Review Current ◽

Early Diagnostic

Biomarkers play an essential role in the management of patients with invasive cancers. Pancreatic ductal adenocarcinoma (PDC) associated with poor prognosis due to advanced presentation and limited therapeutic options. This is further complicated by absence of validated screening and predictive biomarkers for early diagnosis and precision treatments respectively. There is emerging data on biomarkers in pancreatic cancer in past two decades. So far, the CA 19-9 remains the only approved biomarker for diagnosis and response assessment but limited by low sensitivity and specificity. In this article, we aim to review current and future biomarkers that has potential serve as critical tools for early diagnostic, predictive and prognostic indications in pancreatic cancer.

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Developmental Pathways Direct Pancreatic Cancer Initiation from Its Cellular Origin

Stem Cells International ◽

10.1155/2016/9298535 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Maximilian Reichert ◽

Karin Blume ◽

Alexander Kleger ◽

Daniel Hartmann ◽

Guido von Figura

Keyword(s):

Pancreatic Cancer ◽

Poor Prognosis ◽

Intraepithelial Neoplasia ◽

Developmental Pathways ◽

Ductal Adenocarcinoma ◽

Pancreatic Intraepithelial Neoplasia ◽

Cellular Origin ◽

Mucinous Neoplasm ◽

Cancer Initiation ◽

Advanced Stages

Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis, since it is usually diagnosed at advanced stages. In order to employ tools for early detection, a better understanding of the early stages of PDA development from its main precursors, pancreatic intraepithelial neoplasia (PanIN), and intraductal papillary mucinous neoplasm (IPMN) is needed. Recent studies on murine PDA models have identified a different exocrine origin for PanINs and IPMNs. In both processes, developmental pathways direct the initiation of PDA precursors from their cellular ancestors. In this review, the current understanding of early PDA development is summarized.

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Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.624837 ◽

2021 ◽

Vol 11 ◽

Author(s):

Qing Hua ◽

Tianjiao Li ◽

Yixuan Liu ◽

Xuefang Shen ◽

Xiaoyan Zhu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Poor Prognosis ◽

Culture Media ◽

Disease Free Survival ◽

Mtor Pathway ◽

Gene Set Enrichment Analysis ◽

Human Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is a growing cause of cancer-related mortality worldwide. Kallikrein-related peptidase 8 (KLK8) has potential clinical values in many cancers. However, the clinicopathological significances of KLK8 in PDAC remain unknown. We explored the relationship of KLK8 to clinicopathological features of PDAC based on public databases. KLK8 expression was examined in human PDAC tissues. Cell proliferation and apoptosis were evaluated in KLK8-overexpressed human pancreatic cancer cell lines Mia-paca-2 and Panc-1. The related signaling pathways of KLK8 involved in pancreatic cancer progression were analyzed by gene set enrichment analysis (GSEA) and further verified in in vitro studies. We found that KLK8 was up-regulated in tumor tissues in the TCGA-PAAD cohort, and was an independent prognostic factor for both overall survival and disease-free survival of PDAC. KLK8 mRNA and protein expressions were increased in PDAC tissues compared with para-cancerous pancreas. KLK8 overexpression exerted pro-proliferation and anti-apoptotic functions in Mia-paca-2 and Panc-1 cells. GSEA analysis showed that KLK8 was positively associated with PI3K-Akt-mTOR and Notch pathways. KLK8-induced pro-proliferation and anti-apoptotic effects in Mia-paca-2 and Panc-1 cells were attenuated by inhibitors for PI3K, Akt, and mTOR, but not by inhibitor for Notch. Furthermore, overexpression of KLK8 in Mia-paca-2 and Panc-1 cells significantly increased epidermal growth factor (EGF) levels in the culture media. EGF receptor (EGFR) inhibitor could block KLK8-induced activation of PI3K/Akt/mTOR pathway and attenuate pro-proliferation and anti-apoptotic of KLK8 in Mia-paca-2 and Panc-1 cells. In conclusion, KLK8 overexpression exerts pro-proliferation and anti-apoptotic functions in pancreatic cancer cells via EGF signaling-dependent activation of PI3K/Akt/mTOR pathway. Upregulated KLK8 in PDAC predicts poor prognosis and may be a potential therapeutic target for PDAC.

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The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer

Cancers ◽

10.3390/cancers10020033 ◽

2018 ◽

Vol 10 (2) ◽

pp. 33 ◽

Cited By ~ 43

Author(s):

Sandra Valle ◽

Laura Martin-Hijano ◽

Sonia Alcalá ◽

Marta Alonso-Nocelo ◽

Bruno Sainz Jr.

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Stem Cell ◽

Epithelial To Mesenchymal Transition ◽

Patient Survival ◽

Biological Properties ◽

Common Type ◽

Ductal Adenocarcinoma ◽

Mesenchymal Transition ◽

Metastatic Capacity

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is the 4th most frequent cause of cancer-related death worldwide, primarily due to the inherent chemoresistant nature and metastatic capacity of this tumor. The latter is believed to be mainly due to the existence of a subpopulation of highly plastic “stem”-like cells within the tumor, known as cancer stem cells (CSCs), which have been shown to have unique metabolic, autophagic, invasive, and chemoresistance properties that allow them to continuously self-renew and escape chemo-therapeutic elimination. As such, current treatments for the majority of PDAC patients are not effective and do not significantly impact overall patient survival (<7 months) as they do not affect the pancreatic CSC (PaCSC) population. In this context, it is important to highlight the need to better understand the characteristics of the PaCSC population in order to develop new therapies to target these cells. In this review, we will provide the latest updates and knowledge on the inherent characteristics of PaCSCs, particularly their unique biological properties including chemoresistance, epithelial to mesenchymal transition, plasticity, metabolism and autophagy.

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Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-106961 ◽

2020 ◽

pp. jmedgenet-2020-106961 ◽

Cited By ~ 1

Author(s):

Alice Alessandra Galeotti ◽

Manuel Gentiluomo ◽

Cosmeri Rizzato ◽

Ofure Obazee ◽

John P Neoptolemos ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Risk Prediction ◽

Association Studies ◽

Statistical Significance ◽

Ductal Adenocarcinoma ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Individual Snps ◽

Risk Snps

BackgroundMost cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection.ObjectiveWe generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score.MethodsWe tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes.ResultsThe scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10−10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10−8, highest vs lowest quintile of the weighted multifactorial score).ConclusionWe found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.

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Emerging Role of miR-345 and Its Effective Delivery as a Potential Therapeutic Candidate in Pancreatic Cancer and Other Cancers

Pharmaceutics ◽

10.3390/pharmaceutics13121987 ◽

2021 ◽

Vol 13 (12) ◽

pp. 1987

Author(s):

Nagabhishek Sirpu Natesh ◽

Brianna M. White ◽

Maia M. C. Bennett ◽

Metin Uz ◽

Rakhee Rathnam Kalari Kandy ◽

...

Keyword(s):

Pancreatic Cancer ◽

Critical Role ◽

Tumor Development ◽

Treatment Strategies ◽

Underlying Mechanism ◽

Therapeutic Interventions ◽

Ductal Adenocarcinoma ◽

Desmoplastic Reaction ◽

Cancer Pathogenesis ◽

Effective Delivery

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality, poor prognosis, and palliative treatments, due to the rapid upregulation of alternative compensatory pathways and desmoplastic reaction. miRNAs, small non-coding RNAs, have been recently identified as key players regulating cancer pathogenesis. Dysregulated miRNAs are associated with molecular pathways involved in tumor development, metastasis, and chemoresistance in PDAC, as well as other cancers. Targeted treatment strategies that alter miRNA levels in cancers have promising potential as therapeutic interventions. miRNA-345 (miR-345) plays a critical role in tumor suppression and is differentially expressed in various cancers, including pancreatic cancer (PC). The underlying mechanism(s) and delivery strategies of miR-345 have been investigated by us previously. Here, we summarize the potential therapeutic roles of miR-345 in different cancers, with emphasis on PDAC, for miRNA drug discovery, development, status, and implications. Further, we focus on miRNA nanodelivery system(s), based on different materials and nanoformulations, specifically for the delivery of miR-345.

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Perineural Invasion and Associated Pain Transmission in Pancreatic Cancer

Cancers ◽

10.3390/cancers13184594 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4594

Author(s):

Jialun Wang ◽

Yu Chen ◽

Xihan Li ◽

Xiaoping Zou

Keyword(s):

Pancreatic Cancer ◽

Poor Prognosis ◽

Neurogenic Inflammation ◽

Perineural Invasion ◽

Ductal Adenocarcinoma ◽

Paracrine Signaling ◽

Pain Transmission ◽

Neural Interactions ◽

Central Nervous Systems ◽

Aggressive Tumor

Pancreatic ductal adenocarcinoma (PDAC) is one of the cancers with the highest incidence of perineural invasion (PNI), which often indicates a poor prognosis. Aggressive tumor cells invade nerves, causing neurogenic inflammation; the tumor microenvironment also induces nerves to undergo a series of structural and functional reprogramming. In turn, neurons and the surrounding glial cells promote the development of pancreatic cancer through autocrine and/or paracrine signaling. In addition, hyperalgesia in PDAC patients implies alterations of pain transmission in the peripheral and central nervous systems. Currently, the studies on this topic are relatively limited. This review will elaborate on the mechanisms of tumor–neural interactions and its possible relationship with pain from several aspects that have been focused on in recent years.

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Tumours of the pancreas

Oxford Textbook of Medicine ◽

10.1093/med/9780199204854.003.152403_update_001 ◽

2010 ◽

pp. 2574-2578

Author(s):

Edward Britton ◽

Martin Lombard

Keyword(s):

Pancreatic Cancer ◽

Old Age ◽

Median Survival ◽

Poor Prognosis ◽

Developed Countries ◽

Ductal Adenocarcinoma

Pancreatic cancer, most commonly in the form of a solid ductal adenocarcinoma, accounts for 3% of all cancers but ranks in the top five leading causes of cancer deaths in most developed countries, reflecting the fact that it has a very poor prognosis (median survival 6 to 9 months). It is a disease of old age (85% of patients >65 years), and commoner in smokers....

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