Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment

Wood, Laura D.; Canto, Marcia Irene; Jaffee, Elizabeth M.; Simeone, Diane M.

doi:10.1053/j.gastro.2022.03.056

Cited by 399 publications

(270 citation statements)

References 171 publications

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“…The main reason for the dismal prognosis of PDAC is a late diagnosis, since ≈90% of cancer is detected after spreading beyond the pancreas, with systemic metastases occurring in >50% of patients at the time of diagnosis [ 3 , 4 ] and only 20% of patients meeting the criteria for surgery at the time of diagnosis [ 1 , 5 , 6 ]. PDAC is a multifactorial disease driven by multiple environmental factors, including smoking and excessive alcohol consumption, obesity, diabetes mellitus and chronic pancreatitis, and, at least in part, by somatic mutations in oncogenes and tumour suppressor genes, such as KRAS along with the tumour suppressor genes CDKN2A , TP53 , and SMAD4 [ 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…The standard first-line treatment for stage I and II remains FOLFOX or FOLFIRINOX or gemcitabine plus albumin-bound (nab) paclitaxel [ 13 ]. Precision therapies designed to target specific mutations, including PD1 and PD-L1 in patients with microsatellite instability, are under evaluation [ 8 ]. Unfortunately, up to 50% of patients present a metastatic disease at the time of diagnosis, with a 5-year survival <5%.…”

Section: Introductionmentioning

confidence: 99%

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Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma

Giorgio

Lupia

Marchianò

et al. 2022

Cells

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Pancreatic cancer is a leading cause of cancer mortality and is projected to become the second-most common cause of cancer mortality in the next decade. While gene-wide association studies and next generation sequencing analyses have identified molecular patterns and transcriptome profiles with prognostic relevance, therapeutic opportunities remain limited. Among the genes that are upregulated in pancreatic ductal adenocarcinomas (PDAC), the leukaemia inhibitory factor (LIF), a cytokine belonging to IL-6 family, has emerged as potential therapeutic candidate. LIF is aberrantly secreted by tumour cells and promotes tumour progression in pancreatic and other solid tumours through aberrant activation of the LIF receptor (LIFR) and downstream signalling that involves the JAK1/STAT3 pathway. Since there are no LIFR antagonists available for clinical use, we developed an in silico strategy to identify potential LIFR antagonists and drug repositioning with regard to LIFR antagonists. The results of these studies allowed the identification of mifepristone, a progesterone/glucocorticoid antagonist, clinically used in medical abortion, as a potent LIFR antagonist. Computational studies revealed that mifepristone binding partially overlapped the LIFR binding site. LIF and LIFR are expressed by human PDAC tissues and PDAC cell lines, including MIA-PaCa-2 and PANC-1 cells. Exposure of these cell lines to mifepristone reverses cell proliferation, migration and epithelial mesenchymal transition induced by LIF in a concentration-dependent manner. Mifepristone inhibits LIFR signalling and reverses STAT3 phosphorylation induced by LIF. Together, these data support the repositioning of mifepristone as a potential therapeutic agent in the treatment of PDAC.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma

Giorgio

Lupia

Marchianò

et al. 2022

Cells

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“…Despite numerous progresses in the last years, the number of PDAC patients surviving longer than 5 years is disappointingly low and most patients will succumb to their disease 3–5. Current treatment strategies focus on fighting the advanced disease, present in about half of the cases at diagnosis, by combining standard chemotherapy with targeted and immune-based therapies with limited benefit so far 6 7…”

Section: Introductionmentioning

confidence: 99%

Molecular heterogeneity and commonalities in pancreatic cancer precursors with gastric and intestinal phenotype

Liffers

Godfrey

Frohn

et al. 2022

Gut

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ObjectiveDue to the limited number of modifiable risk factors, secondary prevention strategies based on early diagnosis represent the preferred route to improve the prognosis of pancreatic ductal adenocarcinoma (PDAC). Here, we provide a comparative morphogenetic analysis of PDAC precursors aiming at dissecting the process of carcinogenesis and tackling the heterogeneity of preinvasive lesions.DesignTargeted and whole-genome low-coverage sequencing, genome-wide methylation and transcriptome analyses were applied on a final collective of 122 morphologically well-characterised low-grade and high-grade PDAC precursors, including intestinal and gastric intraductal papillary mucinous neoplasms (IPMN) and pancreatic intraepithelial neoplasias (PanIN).ResultsEpigenetic regulation of mucin genes determines the phenotype of PDAC precursors. PanIN and gastric IPMN display a ductal molecular profile and numerous similarly regulated pathways, including the Notch pathway, but can be distinguished by recurrent deletions and differential methylation and, in part, by the expression of mucin-like 3. Intestinal IPMN are clearly distinct lesions at the molecular level with a more instable genotype and are possibly related to a different ductal cell compartment.ConclusionsPDAC precursors with gastric and intestinal phenotype are heterogeneous in terms of morphology, genetic and epigenetic profile. This heterogeneity is related to a different cell identity and, possibly, to a different aetiology.

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“…Pancreatic cancer (PC) is a relatively common malignancy of the digestive system and one of the human malignancies with the worst prognosis [ 1 ]. Approximately 213,000 people worldwide die from PC each year [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Nerve Growth Factor (NGF) Encourages the Neuroinvasive Potential of Pancreatic Cancer Cells by Activating the Warburg Effect and Promoting Tumor Derived Exosomal miRNA-21 Expression

Peng

Guo

Gan

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. It has been reported that signaling from the nerve growth factor (NGF) pathway associated with peripheral nerves is able to contribute to perineural invasion (PNI) of pancreatic cancer (PC). Nevertheless, the underlying mechanism by which NGF leads to PNI remained poorly understood. Methods. Western blotting was employed to determine NGF level in PC and paracarcinoma tissues and in PC cell lines as well as pancreatic ductal epithelial cells. MiaPaCa-2 and CFPAC-1 cells were treated with 100 ng/ml of NGF or the NGF inhibitor Tanezumab for 24 h, CCK-8 and Transwell assays were employed to test cell proliferation, invasion, and migration, respectively. TrkA expression was knocked down in MiaPaCa-2 and dorsal root ganglion (DRG) cells treated with NGF to determine its effect on the Warburg effect. To reveal that the NGF-TrkA signaling pathway was closely associated with PC PNI, in vitro neuroinvasion model was established by using MiaPaCa-2 cells via coculturing DRG cells in Matrigel. Further, exosomes were extracted from PC cells and identified by examining the levels of specific markers for exosomes. Then RT-qPCR was applied to test miR-21-5p level in tumor derived exosomal (TDE-miR-21-5p). RIP assay was performed to validate NGF and miR-21 binding ability in MiaPaCa-2 cells. Rescue experiments were performed by using coprocessing of Tanezumab and miR-21-5p mimic on MiaPaCa-2 cells, followed by coculture with DRG cells. Subsequently, we used a model of neuroinvasion in nude mice to assess the effect of NGF in vivo on tumor nerve invasion as well as on nociceptive transmission. Results. NGF level was preeminently higher in PC tissues and cell lines than in paracarcinoma tissues and normal pancreatic epithelial cell lines. NGF promoted MiaPaCa-2 and CFPAC-1 cell invasion and migration, while Tanezumab treatment showed the opposite results. Besides, NGF binding to TrkA receptors encouraged the intracellular Warburg effect in PC and DRG cells. TrkA blocking-up could restrain NGF induced PC cell migration and neural invasion. Mechanistically, NGF could upregulate TDE-miR-21-5p levels, and DRG cells took up TDE to activate the Warburg effect and stimulate nociceptor gene expression. miR-21-5p inhibitor could abolish the facilitative effect of NGF on PNI in MiaPaCa-2 cells. In vivo tumorigenesis experiments, Tanezumab markedly alleviated nerve invasion of PC cells as well as relieved nociceptive conduction in animal models. Conclusions. These findings displayed that NGF/TrkA encouraged the neuroinvasive potential of PC cells by activating the Warburg effect in DRG cells through upregulation of TDE-miR-21-5p expression.

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Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment

Cited by 399 publications

References 171 publications

Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma

Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma

Molecular heterogeneity and commonalities in pancreatic cancer precursors with gastric and intestinal phenotype

Nerve Growth Factor (NGF) Encourages the Neuroinvasive Potential of Pancreatic Cancer Cells by Activating the Warburg Effect and Promoting Tumor Derived Exosomal miRNA-21 Expression

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