Transforming growth factor-β pathway: Role in pancreas development and pancreatic disease
Introduction
The transforming growth factor-β (TGF-β) factor was identified two decades ago and named so based on initial experiments that demonstrated its ability to induce malignant behavior of normal fibroblasts [1]. Since that discovery, many TGF-β-related factors have been identified, purified and their diverse roles in a myriad of cellular and developmental pathways [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], mediated by the transcription factors called Smads [2], [6], [11], [12], [13], have been enumerated. TGF-β1 can also activate alternative signaling pathways [8], including that involving MAPK (ERK, JNK and p38). This interaction may mediate or enhance Smad-dependent responses, or can exert Smad-independent effects. The complexity of this signaling cascade, allows the TGF-β superfamily to perform primarily unique, many a times overlapping and sometimes redundant functions. In addition to the topics reviewed in this special issue, readers are referred to several expert reviews that describe the structure function relationships [3], [4], [5], [6], [7], [8], [13], biology in normal development [14] and the implicated roles in diseases [2], [9], [10], [14] of the TGF-β superfamily. Collectively, the compendium of the TGF-β literature is evidence of an enormously complex and central role for the TGF-β superfamily in organismal development and disease pathogenesis. Such a pleiotropic and universal “access” allows TGF-β and the related proteins to have an important role in many, if not all, organismal functions. Loss of function, via either genetic, epigenetic or somatic mutations, of components of the TGF-β pathway therefore leads to abnormal organ development and predisposes to aberrant physiological behavior [14]. Abnormal expression levels of the TGF-β ligands and altered expression levels of TGF-β receptors are seen in many pathological syndromes. In addition, the Smad transcription factors are also targeted for inactivation in many disorders [12], [15].
Similar to its functions in other organs, the TGF-β superfamily plays an important role during pancreas development [16], [17], [18], [19], [20], [21], [22], [23], [24]. The TGF-β signaling pathway is often inactivated via mutations or altered expression of its components during pancreas disease progression [19], [25]. Here, we review the importance of TGF-β family proteins in pancreas development, document the alterations in TGF-β pathway components in diseases of the pancreas and conclude by discussing the potential of rational TGF-β targeted therapeutic intervention strategies for these diseases.
Section snippets
Origin and specification
The pancreas is a complex endocrine and exocrine gland that is essential for life, playing a central role in glucose homeostasis and digestion by virtue of its capacity to produce hormones and enzymes [19], [20], [21], [22], [24]. The pancreas has two distinct components, both morphologically and physiologically, the exocrine and endocrine portions [19], [26], [27], [28], [29]. The exocrine component, representing approximately 95% of the adult pancreas, has a highly branched structure composed
Expression and localization
TGF-β signaling components including the ligands activin and TGF-β1 and their respective receptors; ligand antagonists including follistatin, noggin and gremlin are expressed in the epithelium and mesenchyme of embryonic pancreas and in adult pancreas [51]. Although cytoplasmic immunoreactivity for TGF-β1, TGF-β2 and TGF-β3 is found in islet cells, acinar cells and ductal cells, a differential immunostaining pattern for TGF-β isoforms is observed. In the endocrine pancreas, the islet cells
Cancer
The World Health Organization (WHO) estimates pancreatic cancer is a frequent occurring and deadly malignancy that afflicts 232,306 people worldwide with an expected mortality of 227,023 individuals (98% mortality; Globocan Statistics 2002). In the USA in 2005, according to the American Cancer Society (ACS; 2005 statistics), 32,180 individuals are estimated to be newly diagnosed with pancreas cancer and 31,800 patients will die of the disease (99% mortality). Therefore, pancreas cancer is not
Therapeutic considerations
The complex TGF-β signaling system provides multiple levels of regulation and numerous targets for intervention [9], [115], [116]. For example, the ability of TGF-β to bind with its receptor could be reduced by inhibiting its proteolytic activation or by scavenging active TGF-β with excess latency-associated protein (LAP), with isoform-selective antibodies, with pan-neutralizing antibodies or with other binding proteins (such as decorin). Intracellular inhibition of the type I TGF-β-receptor
Conclusions
The TGF-β family proteins circulate in the body and engage specific receptors in virtually every cell type in an organism [1]. Such a pleiotropic and universal “access” underlies the critical role that these cytokines play in many, if not all, organismal functions. Therefore, it is only natural that loss of function, via either genetic, epigenetic or somatic mutations, of components of the TGF-β pathway predisposes to aberrant physiological behavior and pathological outcome [14]. To make
Acknowledgements
The generous support and excellent encouragement provided by Anita B. Roberts is greatly appreciated. We apologize to the many researchers whose work could not be cited because of space limitations or was only cited indirectly by referring to reviews or more recent papers. This work was supported by a National Cancer Institute (NCI) Scholar Award (CA90790-01) to S.G.R.
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2015, Journal of Surgical ResearchCitation Excerpt :The cascade of events is initiated by acinar cell injury. Intracellular zymogens become prematurely activated, and pancreatic autodigestion generates proinflammatory mediators such as TGF-β [27] and PTHrP [11,12]. PSCs play a central role in the normal physiologic response to injury, secreting, and remodeling the ECM [9].