Precursor Lesions of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, and the seventh leading cause of cancer-related deaths worldwide. An improved understanding of tumor biology and novel therapeutic discoveries are needed to improve overall survival. Recent multi-gene analysis approaches such as next-generation sequencing have provided useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic cancer and precursor lesions are characterized by specific molecular alterations. Genetically engineered mouse models (GEMMs) of PDAC are useful to understand the roles of altered genes. Most GEMMs are driven by oncogenic Kras, and can recapitulate the histological and molecular hallmarks of human PDAC and comparable precursor lesions. Advanced GEMMs permit the temporally and spatially controlled manipulation of multiple target genes using a dual-recombinase system or CRISPR/Cas9 gene editing. GEMMs that express fluorescent proteins allow cell lineage tracing to follow tumor growth and metastasis to understand the contribution of different cell types in cancer progression. GEMMs are widely used for therapeutic optimization. In this review, we summarize the main molecular alterations found in pancreatic neoplasms, developed GEMMs, and the contribution of GEMMs to the current understanding of PDAC pathobiology. Furthermore, we attempted to modify the categorization of altered driver genes according to the most updated findings.

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A Network Pharmacology Approach to Determine the Mechanisms of Action of Shuangshen Granules in Suppressing Pancreatic Cancer Precursor Lesions

10.21203/rs.3.rs-132208/v1 ◽

2020 ◽

Author(s):

Juling Jiang ◽

Zhenhua Zhang ◽

Yixin Yuan ◽

Runzhi Qi ◽

Shuntai Chen ◽

...

Keyword(s):

Pancreatic Cancer ◽

Molecular Docking ◽

Molecular Mechanisms ◽

Enrichment Analysis ◽

Mechanisms Of Action ◽

Network Pharmacology ◽

Precursor Lesions ◽

Active Components ◽

Docking Simulations ◽

Improve Patient Survival

Abstract Background and purpose: Pancreatic cancer is an insidious and highly lethal disease. Recognition and treatment of pancreatic cancer precursor lesions (PCPL) are important measures and can improve patient survival rate. Shuangshen Granules (SSG) have been prescribed for use in clinical practice for more than seven years and are widely used to treat the precursor lesions of various tumours. In this study, we used network pharmacology to explore the pharmacological mechanisms through which SSG suppress PCPL. We aimed to provide a basis for further research and the development of small, molecular, natural chemical drugs.Methods: We first searched databases and screened the bioactive components of SSG and the related targets acting on PCPL to construct a component-target network. Then, network topology analysis was used to analyse the hub target of SSG acting on PCPL. Enrichment analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were also performed to determine the potential pathways. Finally, molecular docking simulations were carried out to investigate the interactions between PCPL-target proteins and the active components of SSG.Results: Seven of the main components of SSG affected PCPL, with 100 key targets including 16 hub targets. In addition, GO and KEGG enrichment analysis revealed that SSG regulated 111 molecular functions, 46 cellular components, 2334 biological processes, and 144 related signalling pathways, of which 26 were closely related to PCPL. Results of molecular docking analysis showed that the PCPL-related targets had strong binding properties with the active components of SSG, quercetin, and ginsenoside rh2, mainly TNF, IL-6, AKT1, TP53, and EGFR.Conclusion: This study has revealed the pharmacological and molecular mechanisms through which SSG acts on PCPL. It also provides powerful evidence to support the exploration of the pharmacological mechanisms of action and clinical applications of traditional Chinese medicine.

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