The TGF-β/Smad4 Signaling Pathway in Pancreatic Carcinogenesis and Its Clinical Significance
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human cancers due to its complicated genomic instability. PDAC frequently presents at an advanced stage with extensive metastasis, which portends a poor prognosis. The known risk factors associated with PDAC include advanced age, smoking, long-standing chronic pancreatitis, obesity, and diabetes. Its association with genomic and somatic mutations is the most important factor for its aggressiveness. The most common gene mutations associated with PDAC include KRas2, p16, TP53, and Smad4. Among these, Smad4 mutation is relatively specific and its inactivation is found in more than 50% of invasive pancreatic adenocarcinomas. Smad4 is a member of the Smad family of signal transducers and acts as a central mediator of transforming growth factor beta (TGF-β) signaling pathways. The TGF-β signaling pathway promotes many physiological processes, including cell growth, differentiation, proliferation, fibrosis, and scar formation. It also plays a major role in the development of tumors through induction of angiogenesis and immune suppression. In this review, we will discuss the molecular mechanism of TGF-β/Smad4 signaling in the pathogenesis of pancreatic adenocarcinoma and its clinical implication, particularly potential as a prognostic factor and a therapeutic target.
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TGF-β/SMAD4 signaling pathway plays a pivotal role in pancreatic carcinogenesis, with TGF-β1 activating a SMAD4-dependent pathway crucial for regulating gene expression in normal pancreatic cells.
“The TGF-β/SMAD4 signaling pathway plays a pivotal role in pancreatic carcinogenesis, with TGF-β1 activating a SMAD4-dependent pathway crucial for regulating gene expression in normal pancreatic cells.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [84]
Smad4 loss or inactivation is linked to adverse prognostic outcomes, with intact SMAD4 expression associated with significantly improved median and five-year survival rates.
“Notably, Smad4 loss or inactivation is linked to adverse prognostic outcomes, with intact SMAD4 expression associated with significantly improved median and five-year survival rates.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [84]
Over 50% of PDAC cases exhibit TGF-β pathway mutations, prominently involving Smad4, which is lost in 60-90% of cases.
“Over 50% of PDAC cases exhibit TGF-β pathway mutations, prominently involving Smad4, which is lost in 60–90% of cases.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [84]
Activated TGFβ signaling is a critical upstream mediator of different pathways related to drug resistance.
“Using ingenuity pathway analysis to assess 950 differentially expressed genes, it was found that activated TGFβ signaling is a critical upstream mediator of different pathways related to drug resistance [148].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [148]
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Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer
Hou, P., Kapoor, A., Zhang, Q., Li, J., Wu, C.-J., Li, J., Lan, Z., Tang, M., Ma, X., Ackroyd, J. J., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0597 · Cited by 154 · see citing works
Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer
Stefanoudakis, D., Frountzas, M., Schizas, D., Michalopoulos, N. V., Drakaki, A., & Toutouzas, K. G. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46040177 · Cited by 110 · see citing works
Truong, L.-H., & Pauklin, S. (2021) · Cancers · doi:10.3390/cancers13195028 · Cited by 102 · see citing works
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Miquel, M., Zhang, S., & Pilarsky, C. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.748631 · Cited by 53 · see citing works
Therapeutic Approaches in Pancreatic Cancer: Recent Updates
Kumar, L., Kumar, S., Sandeep, K., & Patel, S. K. S. (2023) · Biomedicines · doi:10.3390/biomedicines11061611 · Cited by 25 · see citing works
- Authors
- Ahmed, S., Bradshaw, A.-D., Gera, S., Dewan, M., & Xu, R.
- Affiliations
- NYU Langone Health (US)
- Corresponding author
- Xu, Ruliang
- Venue
- Journal of Clinical Medicine
- Publisher
- MDPI AG
- Published
- 2017-01-05
- Volume
- 6
- Issue
- 1
- Pages
- 5
- ISSN
- 2077-0383 (ISSN-L)
- PMC
- PMC5294958
- OpenAlex
- W2571166948
- Cited by
- 174
- References
- 95
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 14 · 2023: 12 · 2022: 29 · 2021: 36 · 2020: 18 · 2019: 20 · 2018: 11 · 2017: 3
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- School of Medicine, New York University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- pancreatic ductal adenocarcinoma, SMAD4 mutation, pancreatic carcinogenesis, KRAS mutation, TP53 mutation, p16, prognostic factors, therapeutic target, tumor angiogenesis, immunosuppression, chronic pancreatitis, metastasis
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