Role of the TGF-beta signaling pathway in salivary gland inflammation and fibrosis: TGF-beta 1 is a multifunctional cytokine that influences salivary gland development and homeostasis. In particular, TGF-beta 1 is known to regulate extracellular matrix (ECM) deposition, not only by inducing biosynthesis of collagens and fibronectin, but also by promoting the expression of protease inhibitors. Furthermore, TGF-beta 1 is able to encourage an epithelial- mesenchymal transition in some cells that can result in more ECM-producing myofibroblasts. Tissue damage to the salivary glands from inflammation or radiation exposure can result in reparative TGF-beta-induced ECM production. ECM deposition by TGF-beta 1 shapes epithelial-mesenchymal interactions throughout salivary gland organogenesis as well. Along with regulating mesenchymal production of ECM, TGF-beta 1 can also influence salivary gland development by controlling cellular growth and differentiation. The secretion of TGF-beta 1 inhibits the proliferation of epithelial cells by downregulating c-myc, while simultaneously increasing the expression of cyclin-dependent kinase inhibitors such as p15, p21 and p27. Lastly, TGF-beta 1 affects salivary gland physiology by regulating angiogenesis and by suppressing inflammation. TGF-beta 1 and its other two mammalian isoforms, TGF-beta 2 and TGF-beta 3, are all expressed in the salivary gland during development, which suggests an important role for this cytokine in glandular organogenesis. Specifically, the expression of TGF-beta 1 seems to coincide with salivary gland differentiation. TGF-beta 1 is originally detected in both the epithelium and mesenchyme during the initial bud stage, but becomes immunolocalized to only the branching epithelia later in development. In a 14.5 day post-coitum mouse embryo, TGF-beta 1 mRNA expression is localized in the epithelial end buds, sites of active branching in the developing salivary gland. During this stage of development, TGF-beta 1 may act in a paracrine manner on the mesenchyme, and an autocrine manner on epithelial cell growth. Even though the TGF-beta 1 mRNA is localized at sites of active branching, exogenous TGF-beta 1 in salivary gland cultures, which mimics overexpression, inhibits branching morphogenesis. Epithelial growth is disrupted and the ducts appear elongated. However, following glandular development, TGF-beta 1 expression is localized to ductal epithelium in the submandibular gland and is absent in the secretory acini. Besides its role in organogenesis, TGF-beta also impacts salivary gland physiology by regulating ECM production, particularly in response to tissue injury. Aberrant expression of TGF-beta 1 is often associated with cases of pathological fibrosis. In the salivary gland, fibrosis specifically causes constriction of secretory components, leading to hyposalivation and xerostomia. Salivary gland fibrosis typically occurs after repeated episodes of inflammation, which can be caused by processes such as chronic infection in the glands or the autoimmune disease Sjogrens syndrome. Fibrosis of the glands also occurs because of tissue damage from radiation, particularly during radiotherapy treatment for head and neck cancer. Interestingly, radiation exposure has been shown to induce TGF-beta 1 expression. In order to understand the precise role of TGF-beta signaling in salivary gland development and homeostasis, we developed a transgenic mouse that conditionally produces TGF-beta 1 (Beta1glo). The transgene requires Cre-mediated excision of an intervening floxed EGFP gene in order for a ubiquitous promoter to transcribe a TGF-beta 1 cDNA. In the transgene, the TGF-beta 1 cDNA is mutated to prevent assembly of the latent associated peptide, in order to allow direct binding of the secreted ligand to the cell surface receptors. We bred these Beta1glo mice to a mouse mammary tumor virus (MMTV)-Cre (offspring are MC) transgenic line that strongly expresses the Cre recombinase in both the mammary and salivary glands. The broad expression of Cre in the transgenic mice, however, generated a severe phenotype with most of the double positive (Beta1glo/MC) pups, either dying in utero or within 24 hours after birth. Nonetheless, the effect of TGF-beta 1 on the salivary gland could clearly be seen in the Beta1glo/MC pups with increased mesenchyme and disrupted branching. For the Beta1glo/MC mice that survived into adulthood, the salivary glands were severely fibrotic, with signs of atrophy in both the granular convoluted ducts (GCDs) and the acini, and this was associated with hyposalivation. Molecular roles of TGF-beta signaling in head and neck squamous cell carcinogenesis: Head-and-neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer, with an annual incidence of more than 500,000 cases worldwide. In the United States alone, about 47,560 new cases are diagnosed with HNSCC each year. Despite the improvement of diagnosis and comprehensive treatment, the overall 5 year survival rate of HNSCC is only about 50%, and this number has not changed in more than two decades. Tobacco and alcohol consumption, as well as viral agents, are the major risk factors for development of HNSCC. These risk factors, together with genetic susceptibility, result in the accumulation of multiple genetic and epigenetic alterations in a multi-step process of cancer development. However, the underlying cellular and molecular mechanisms that contribute to the initiation and progression from normal epithelia to invasive squamous cell carcinoma have not been delineated. A better understanding of the molecular carcinogenesis of HNSCC may allow for early detection, margin evaluation, prognostication, and development of new strategies for treatment. There is accumulating evidence suggesting the involvement of the TGF-beta signaling pathway in head-and-neck carcinogenesis. TGF-beta is a multifunctional cytokine with diverse biological effects on cellular processes including proliferation, migration, differentiation, and apoptosis. The three mammalian TGF-beta, isoforms beta 1, 2 and 3, exert their functions through a cell surface receptor complex composed of type I (TGFBR1) and type II (TGFBR2) serine/threonine kinase receptors. To produce the full spectrum of TGF-beta responses, both SMAD proteins and other downstream targets including Ras, RhoA, TAK1, MEKK1, PI3K, and PP2A, need to be activated by these receptors. The effects of TGF-beta signaling in carcinogenesis largely depend on the tissue of origin and the tumor type. In most types of human cancers, TGF-beta plays paradoxical roles in cancer development, acting as a tumor suppressor during the early stages and as a promoter of tumor metastasis during the later stages. This is because, as cells progress towards fully malignant tumor cells, they undergo changes that result in reduced expression of TGF-beta receptors, increased expression of TGF-beta ligands, and resistance to inhibition of growth by TGF-beta. Thus, during a late stage of cancer development, TGF-beta evokes tumorigenicity and finally promotes tumor metastasis. In head-and-neck cancer, TGF-beta functions as a potent tumor suppressor. However, it is not clear whether it acts in a pro-oncogenic manner in advanced late-stage HNSCCs. Transfection of a dominant negative TGFBR2 (dn RII) cDNA in a human oral carcinoma cell line, which contained normal Ras and was growth inhibited by TGF-beta, leads to an increase in migration and invasion, and the development of the metastatic phenotype. Distribution of efforts between these two projects: Salivary Gland Disorders: 30%;HNSCC: 70%

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