Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8361888 | Seminars in Cancer Biology | 2017 | 50 Pages |
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive neoplasm, predicted to become the second leading cause of cancer-related deaths before 2030. This dismal trend is mainly due to lack of effective treatments against its metastatic behavior. Therefore, a better understanding of the key mechanisms underlying metastasis should provide new opportunities for therapeutic purposes. Genomic analyses revealed that aberrations that fuel PDAC tumorigenesis and progression, such as SMAD4 loss, are also implicated in metastasis. Recently, microRNAs have been shown to play a regulatory role in the metastatic behavior of many tumors, including PDAC. In particular, miR-10 and miR-21 have appeared as master regulators of the metastatic program, while members of the miR-200 family are involved in the epithelial-to-mesenchymal switch, favoring cell migration and invasiveness. Several studies have also found a close relationship between cancer stem cells (CSCs) and biological features of metastasis, and the CSC markers ALDH1, ABCG2 and c-Met are expressed at high levels in metastatic PDAC cells. Emerging evidence reveals that exosomes are involved in the modulation of the tumor microenvironment and can initiate PDAC pre-metastatic niche formation in the liver and lungs. In this review, we provide an overview of the role of all these pivotal factors in the metastatic behavior of PDAC, and discuss their potential exploitation in the clinic to improve current therapeutics and identify new drug targets.
Keywords
CSCEpCAMZEB1CDKN2ACAFsSMOGSK3βHIF1αSPRY2Sprouty2ALDH1TGFβGEMMSNAI1KRASGlypican-1E1A binding protein P300EGFRSTAT3TNFEP300TIP30NF-κBSNAI2cyclin dependent kinase inhibitor 2ADCLK1CTCGPC1FOLFIRINOXDACH1Janus kinaseADAMPancreatic ductal adenocarcinomaPDAC یا pancreatic ductal adenocarcinomaaldehyde dehydrogenase 1epithelial-to-mesenchymal-transitionExosomesoverall survivalTransforming Growth Factor Betaa disintegrin and metalloproteaseEMTShhNovel therapeuticsmicroRNAsPancreatic cancersuppressor of cytokine signaling 1cancer stem cellCancer stem cellsMIFSmoothenedsonic hedgehoghypoxia-inducible factor 1 alphaMigration inhibitory factorIRAK-1Vascular endothelial growth factorVascular Endothelial Growth Factor (VEGF)tumor necrosis factornuclear factor kappa BCancer associated fibroblastssignal transducer and activator of transcription 3Metastasisgenetically engineered mouse modelepithelial cell adhesion moleculeMicroRNAMiRNAextracellular vesicleJAKInterleukin-1 receptor-associated kinasecirculating tumor cellglycogen synthase kinase 3 betaEpidermal growth factor receptor
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Authors
E. Giovannetti, C.L. van der Borden, A.E. Frampton, A. Ali, O. Firuzi, G.J. Peters,