Abstract
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.
Highlights
In humans, transforming growth factor β (TGF-β) plays an important role in both physiological and pathological processes
Over 50% of Pancreatic ductal adenocarcinoma (PDAC) patients present with a mutation in the TGF-β pathway, with the most common mutation found in Smad4
TGF-β/Smad4 as a Therapeutic target for PDAC. All of these abovementioned studies have supported a strong association of TGF-β with the development of pancreatic adenocarcinoma (50% of PDAC is due to mutations of TGF-β), metastasis, and prognosis
Summary
In humans, transforming growth factor β (TGF-β) plays an important role in both physiological and pathological processes. TGF-β is a cytokine that resides in the extracellular matrix and is synthesized by macrophages, lymphocytes, fibroblasts, epithelial cells, and platelets [1,2]. It is involved in prenatal and postnatal development, reconstruction, maintenance of normal organ structure, and wound healing [3]. Because the TGF-β pathway has an important role in the pancreatic carcinogenesis, many studies have focused on the impact of this pathway on the development of pancreatic cancers, and on its potential clinical use in aiding in clinical management, including early detection, prognostication, and as a therapeutic option
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