Inhibition of TGF-β signalling in combination with nal-IRI plus 5-Fluorouracil/Leucovorin suppresses invasion and prolongs survival in pancreatic tumour mouse models
| Autor: | Jin Sun Heo, Chang Pyo Hong, Seong Jin Kim, Joon Oh Park, Jin Muk Kang, Si Young Lee, Eunji Hong, Seok Hee Park, Su-Jin Park, Akira Ooshima, Haein An, Jinah Park |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Epithelial-Mesenchymal Transition
Stromal cell Combination therapy Carcinogenesis Leucovorin lcsh:Medicine Irinotecan Article Metastasis Cell Movement Transforming Growth Factor beta Cell Line Tumor Pancreatic cancer Antineoplastic Combined Chemotherapy Protocols medicine Animals Chemotherapy Neoplasm Invasiveness Tumour-suppressor proteins lcsh:Science Tumor Stem Cell Assay Aniline Compounds Multidisciplinary business.industry lcsh:R Drug Synergism Triazoles medicine.disease Survival Analysis Chemotherapy regimen Up-Regulation Blockade Gene Expression Regulation Neoplastic Mice Inbred C57BL Pancreatic Neoplasms Disease Models Animal Fluorouracil Liposomes Cancer research Nanoparticles Ectopic expression lcsh:Q Transcriptome business Signal Transduction medicine.drug |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-59893-5 |
| Popis: | Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies. TGF-β is strongly expressed in both the epithelial and stromal compartments of PDAC, and dysregulation of TGF-β signalling is a frequent molecular disturbance in PDAC progression and metastasis. In this study, we investigated whether blockade of TGF-β signalling synergizes with nal-IRI/5-FU/LV, a chemotherapy regimen for malignant pancreatic cancer, in an orthotopic pancreatic tumour mouse model. Compared to nal-IRI/5-FU/LV treatment, combining nal-IRI/5-FU/LV with vactosertib, a TGF-β signalling inhibitor, significantly improved long-term survival rates and effectively suppressed invasion to surrounding tissues. Through RNA-sequencing analysis, we identified that the combination treatment results in robust abrogation of tumour-promoting gene signatures and positive enrichment of tumour-suppressing and apoptotic gene signatures. Particularly, the expression of tumour-suppressing gene Ccdc80 was induced by vactosertib and further induced by vactosertib in combination with nal-IRI/5-FU/LV. Ectopic expression of CCDC80 suppressed migration and colony formation concomitant with decreased expression of epithelial-to-mesenchymal transition (EMT) markers in pancreatic cancer cells. Collectively, these results indicate that combination treatment of vactosertib with nal-IRI/5-FU/LV improves overall survival rates in a mouse model of pancreatic cancer by suppressing invasion through CCDC80. Therefore, combination therapy of nal-IRI/5-FU/LV with vactosertib could provide clinical benefits to pancreatic cancer patients. |
| Databáze: | OpenAIRE |
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