SMAD4 and the TGFβ Pathway in Patients with Pancreatic Ductal Adenocarcinoma
Open Access
- 15 May 2020
- journal article
- review article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 21 (10), 3534
- https://doi.org/10.3390/ijms21103534
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death worldwide. PDAC is an aggressive disease with an 11-month median overall survival and a five-year survival of less than 5%. Incidence of PDAC is constantly increasing and is predicted to become the second leading cause of cancer in Western countries within a decade. Despite research and therapeutic development, current knowledge about PDAC molecular mechanisms still needs improvements and it seems crucial to identify novel therapeutic targets. Genomic analyses of PDAC revealed that transforming growth factor β (TGFβ) signaling pathways are modified and the SMAD4 gene is altered in 47% and 60% of cases, respectively, highlighting their major roles in PDAC development. TGFβ can play a dual role in malignancy depending on the context, sometimes as an inhibitor and sometimes as an inducer of tumor progression. TGFβ signaling was identified as a potent inducer of epithelial-to-mesenchymal transition (EMT), a process that confers migratory and invasive properties to epithelial cells during cancer. Therefore, aberrant TGFβ signaling and EMT are linked to promoting PDAC aggressiveness. TGFβ and SMAD pathways were extensively studied but the mechanisms leading to cancer promotion and development still remain unclear. This review aims to describe the complex role of SMAD4 in the TGFβ pathway in patients with PDAC.Keywords
This publication has 81 references indexed in Scilit:
- Transforming Growth Factor-β in the Gastrointestinal and Hepatic Tumor MicroenvironmentGastroenterology, 2011
- FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic CancerNew England Journal of Medicine, 2011
- Transforming growth factor-β and the hallmarks of cancerCellular Signalling, 2010
- Ubiquitin Ligase Nedd4L Targets Activated Smad2/3 to Limit TGF-β SignalingMolecular Cell, 2009
- Epithelial-Mesenchymal Transitions in Development and DiseaseCell, 2009
- TRAF6 Mediates Smad-Independent Activation of JNK and p38 by TGF-βMolecular Cell, 2008
- TGFβ in CancerCell, 2008
- TGF-β activates Erk MAP kinase signalling through direct phosphorylation of ShcAThe EMBO Journal, 2007
- Cell size and invasion in TGF-β–induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathwayThe Journal of cell biology, 2007
- Smad-dependent and Smad-independent pathways in TGF-β family signallingNature, 2003