Oral Med Pathol 12 (2008) 115

Review Multifunctional roles of growth factors or biologically active peptides in salivary glands and

Masahiko Mori1, Shinichiro Sumitomo1, Prashanta Shrestha2, Shiro Tanaka1, Yoshiaki Takai1, Michio Shikimori1

1Department of Oral-Maxillofacial Surgery, Division of Oral Pathogenesis and Disease Control, Asahi University School of Dentistry, Gifu, Japan 2Division of Oral-Maxillofacial Surgery, Katmandu University Medical School, Katmandu, Nepal

Abstract: Salivary glands secrete saliva which contains mucins, antimicrobial substances and growth factors. Since epidermal (EGF) and nerve growth factor (NGF) were demonstrated in murine submandibular glands (SMGs), several growth factors and biologically-active peptides have been studied in the human or other mammalian salivary glands and saliva. These growth factors may have a functional role in cell migration, proliferation and maturation within not only salivary glands but also other organs. In the SMGs of mice and rats, EGF, NGF and other known growth factors are usually synthesized in granular convoluted tubule cells (GCT). However, human SMGs are devoid of GCT cells, and growth factors in human salivary glands are usually produced in striated ducts. These findings suggest an evolutionary trace of ductal cells in mammals. The present review describes expression patterns of the following salivary gland growth factors: nerve growth factor (NGF); transforming growth factor α and β (TGF-α/β) bone morphogenetic (BMP); -like growth factor (IGF); fibroblastic growth factor (FGF); and , as well as their receptors. This review also discusses their cell biological roles in pathophysiological conditions. [Oral Med Pathol 2008; 12: 115-123 doi: 10.3353/omp.12.115]

Key words: biologically-active peptides, growth factor, , saliva, salivary gland

Correspondence: Michio Shikimori, Department of Oral-Maxillofacial Surgery, Division of Oral Pathogenesis and Disease Control, Asahi University School of Dentistry, Gifu 501-0296, Japan Phone: 81-58-329-1472, Fax: 81-58-329-1472, E-mail: [email protected]

shown that a variety of growth factors are also present in the Introduction human salivary glands and saliva. Salivary growth factors Saliva, which is secreted from major and minor salivary have biological functions in cell migration, proliferation and glands, consists of 99% water and 1% organic and inorganic maturation of not only oral but also other tissues after they components, including sodium, potassium, chloride, calcium, are absorbed from the digestive tract mucosa. Many of these phosphates and bicarbonates (1). The major components of growth factors may function directly or indirectly in the salivary organic molecules are mucins, carbohydrate maintenance and stimulation of salivary gland tissues as complexes, enzymes, anti-microbial peptides and growth well as in distant organs by autocrine or paracrine manners factors or biologically active peptides. Since the detection of (2). nerve growth factor (NGF) and The present review deals with biological and (EGF) in murine submandibular glands, considerable physiological roles of such growth factors produced in advances have been made in understanding the functional salivary glands as nerve growth factor (NGF), transforming role of these growth factors or biologically active peptides, factors α and β, bone morphogenetic protein (BMP), and they are at present a major field of study in cell biology vascular endothelial growth factor (VEGF), insulin-like and oral health sciences (2). growth factor (IGF), (FGF), and Initially, EGF and NGF were reported to be biosynthesized stomatostatin, as well as their receptors. In addition, gene in granular convoluted tubule (GCT) cells of submandibular expression modes of these growth factors are summarized in ducts and secreted in the saliva of mice, and studies have salivary glands and their lesions. 116 Mori et al. Growth factors in salivary glands

yet fully differentiated in neonatal SMGs. The levels of both 1. Nerve growth factor (NGF) and epidermal growth factors are increased with maturation, with the growth factor (EGF) highest levels in puberty and gradually declining with age Biosynthesis of NGF as well as EGF in granular (22). NGF and EGF in the murine SMGs were dramatically convoluted tubule (GCT) cells has been reported in the lowered by duct ligation. In -treated mice, mouse submandibular gland (SMG), and their expression in lowering levels of both growth factors were induced by duct GCT cells is increased following administration of ligation (23-24). Experimentally-induced carcinoma in and testosterone. The levels of both of these growth murine SMGs was shown to be associated with decreasing factors are shown to be male-hormone dependent, and expression levels of NGF and EGF in duct-like structures, expression of both growth factors in the male SMG is whose epithelial cells were supposed to be responsible for stronger than those in the female gland. Secretion of EGF the tumorigenesis of squamous cell carcinoma (25). In and NGF in the SMG could be controlled by similar cellular pleomorphic adenoma, mRNA for NGF receptor (NGFR) or molecular events, and they function in cell migration, has been reported to be overexpressed (26). differentiation and repair processes (3). Ekstrom and Reinbold (27) recently reported that the The surgical removal of murine adult SMG has been concentration of NGF was five times higher in the parotid shown to cause a significant reduction in plasma and tissue gland than in the SMG of adult female rats. Unilateral concentration of NGF and reduced tyrosine hydroxyease sympathetic denervation of the superior cervical ganglion activity levels in sympathetic ganglions (4). Concentration results in elevated levels and concentrations of NGF in the of serum NGF, however, was not necessarily different SMG, but not in the parotid glands 7-28 days after the between males and females, and the serum NGF level does operation. It is thus suggested that increased levels of NGF not change by removal of SMG (5). Murine 7S NGF from play a role in the activity of choline acetyltransferase, one of the saliva contains more α-submits than that from the SMG the acetylcholine-synthesising enzymes, in rat SMGs. In (6). Salivary NGF discharge is changed by secretagous head and neck surgery, sympathetic denervation may elevate treatments: concentrations of mouse NGF in epinephrine- or activity levels of such enzymes, which may also be -induced saliva (3400 μg/ml and 900 μg/ml, associated with an increased production of NGF. respectively) are higher than in other sources, while the concentrations of NGF in isoproterenol- and pilocarpine- 2. Transforming growth factor-α and -β (TGF-α, induced saliva are relatively low (17 and 2 μg/ml, TGF-β) respectively) (7). NGF secreted from the mouse SMG enters into blood stream within minutes and reaches the highest TGF-α and TGF-β have distinct functional roles. TGF-α level 3-4 hrs later (8). It has been reported that cyclocytidine is biosynthesed by a large variety of cells, such as (Cyclo-C) treatments in mice resulted in an increased NGF keratinocytes, hepatocytes, gastrointestinal cells, and cells level in the serum, that chronic Cyclo-C stimulation of the brain and (28), whereas the biosynthesis of produces an increase in the volume of sympathetic ganglia TGF-β is done in platelets, macrophages, lymphocytes, and neuronal hypertrophy, and that Cyclo-C produces a fibroblasts and keratinocytes (29). TGF-α, a member of the drastic depletion of NGF in GCT cells of the mouse SMG as EGF family, binds with EGF receptors on the cell membrane well as a marked NGF level increase in the bloodstream (9). to exert its biological activities. BMPs are members of the Lipps (10), by using high pressure liquid chromatography, TGF-β superfamily. The TGF-β family consists of TGF-1, 2, found that the molecular weights of human NGF in serum, and 3 and BMPs 1-6, and these TGFs are synthesized by saliva and urine were identical, at 36.0 kDa molecules, while mesenchymal cells including bone cells and osteoprogenitor those of cobra serum and cobra venom were 55.0 kDa and cells. The following paragraphs describe biological and 13.5 kDa, respectively. physiological functions of both TGF-α and -β in salivary Immunohistochemical studies on NGF as well as EGF in glands. SMGs of mice and rats showed sexual dimorphism (8). Expression of TGF-α has been reported in a wide variety Olson et al. (11) described that NGF was immunolocalized of cells in the digestive tract including salivary glands (30). in the apical zone of GCT cells as well as cells responsible TGF-α mRNA has been demonstrated in the salivary and for spermatogenesis in male mice. NGF has been shown to mammary glands (31). TGF-α is also present in human adult be colocalized with EGF, rennin, and protease A in murine saliva (32). Ogbureke et al. (33) have reported TGF-α SMGs (12). The coexistence of NGF and EGF has also been immunolocalization in the human ductal cells in salivary reported (13-14). There are some other reports demonstrating glands, but acinar and myoepithelial cells are unreactive. similar tissue distributions of NGF (15) α and g units of Whole salivary fluids from rat, mouse, and human have been 7S-NGF (16) in mouse SMG. In-situ hybridization for NGF demonstrated to contain a high concentration of TGF-α by mRNA revealed that GCT cells in male mouse SMGs as well using radioimmunoassay. TGF-α in unstimulated human as ductal cells in sublingual glands were responsible for saliva is reduced with age (55-70 yrs. 0.4 ± 0.1 nM) but NGF production (17-18). Similar results were obtained in increased in xerostomia (57-70 yrs, 0.8 ± 0.2 nM) and the prostate gland of the guinea pig (19-21). Paget's disease (58-70 yrs, 0.8 ± 0.2 nM). TGF-α mRNAs Expression levels of NGF and EGF in SMGs of mice are expressed in the parotid gland and the SMG of rats and and rats are at low levels at birth, because GCT cells are not mice, suggesting its endogenous synthesis by salivary Oral Med Pathol 12 (2008) 117 glands. TGFα concentration in saliva in mice and rats is also an osteogenic protein. Heterotopic bone formation much higher in males than in females; male mice had occurs in non-osteogenetic tissues; for instance, BMP concentrations of 134.1 ± 31.6 nM and female mice 87.6 ± transplanted in urinary bladder epithelium results in bone 11.4 nM, whereas the values were 10.3 ± 2.3 nM in male rats induction (48-49), and enzyme histochemical studies on and 4.8 ± 4.3 in female rats. The concentration of TGF-α in such heterotopic bone formation have been evaluated (50). human saliva is 10-fold lower than in rat saliva, and Ectopic or heterotopic ossification are also seen in tumors approximately 58-and 83-fold lower when compared to such as osteoma cutis, osteoma of the tongue, and bone female and male mice (34). Sandwich enzyme immunoassay formation in calcifying epithelioma of Malherbe (51), and of TGF-α using polyclonal antibodies in human saliva stromal ossification of the breast and salivary gland tumors shows the protein to be present in both SMG and SLG saliva are not uncommon. BMPs are also associated with tooth (35). Histochemical study of TGF-β1 in the rat SMG has morphogenesis and craniofacial development (52). been reported (36). TGF-β expression in immunohistological The expressions of BMPs in salivary glands and their studies has been reported in normal salivary glands and tumors have been observed in the duct cells of the normal inflamed glands, as well as in their tumors. It has been glands and duct-like structure and neoplastic myoepithelial pointed out that TGF-β1 is strongly expressed in duct cells and chondroid cells in pleomorphic ademomas (53-55). epithelial cells (37) compared to TGF-β2 in the intercalated BMPs in tumors cells of pleomorphic adenoma may have a ducts and mucous cells (38). In chronic obstructive role in tumor-cell differentiation and in the genesis of sialadenitis in humans, TGF-β1 mRNA increases significantly chondroic changes, as immunoreactive BMPs are also seen with progression of the disease (39). Salivary gland in chondrocytes. Mixed tumors of skin show a similar pleomorphic adenoma expresses TGF-β2 and TGF-β3 (38). expression pattern of BMPs as in salivary pleomorphic In pleomorphic adenoma, genes for TGF-β receptors (TGF- adenoma (56). Chondrocytes and chondrosarcoma cells βRs) have been observed, in addition to such highly- show a coexpression of BMPs and calcium binding S-100 expressed genes as those for S-100 protein, vimentin, and , suggesting their role in the calcium signaling type I collagen (40). pathway; however, the detail mechanism is yet poorly TGFβ isoforms and receptors have been observed in understood in neoplastic myoepithelial cells or chondroid labial salivary glands with systemic sclerosis (SSc) cells in the hyalinous structure of pleomorphic adenoma. specifically within the glandular epithelium, fibroblasts, BMPs have not been detected in secreted saliva. vascular endothelium and inflammatory cells. The percentage HSG-S8, a human salivary adenocarcinoma cell line, of TGF-β2 reactive fibroblasts is significantly higher in SSc expresses BMPs, and its transcripts for BMP-2 have been glands compared with controls, and a lower percentage of demonstrated by Northern blot analysis (57). Recently, gene Raynaud's phenomenon fibroblasts express TGF-β3 expressions for BMP-2A, BMP-4 (2B), BMP-4 type II compared with controls and the SSc glands (41). HSG, a receptor, BMP-5, and BMP-7 have been identified in human human SMG cell line, was shown to produce TGF-β2 in its salivary glands, although no BMP-3 was found. The most acinar structures (42). Warthin's tumor shows a negative important BMPs detected immunohistochemically in human reaction for TGF-α; however, the duct-like components are salivary glands and in their tumors were possibly BMP-4 reactive for TGF-β2, TGF-β receptors (TGF-βR) I and II (58). (43). TGF-β2 genes are expressed in human salivary gland. Morphological effects of TGF-β on salivary gland cells 4. Vascular endothelial growth factor (VEGF) have revealed that the cloned myoepithelial cells, but not the cloned ductal cells, produce type IV collagen in response to VEGF, also known as vascular permeability factor TGF-β1 (44). TGF-β1 down-regulates NF-kβ activity (VPF), is a heparin-binding glycoprotein consisting of four through induction of IkB-α expression in human salivary molecular forms (121, 165, 189, and 206 amino acids), gland cell line (HSC), and inhibition of NF-kβ activity which are generated by alternative splicing of mRNA from suppresses the growth rate of HSC cells (45). one gene. VEGF is a major regulator in pathophysiologic It has been reported that the glucocorticoid receptor angiogenesis and is particularly present in the endothelial pathway modulates morphogenesis by cells. VEGFs have a role in angiogenesis and in altering regulating TGF-β2 and TGF-β3 mRNA (46). Morphogenesis permeability in endothelial cells through binding to of embryonic salivary glands in mice involves stage-specific VEGFR-1 (FH-1) and VEGFR-2 (Fik, KDR). In addition to expression of TGF-α/EGF, TGF-β and other growth factors. EGF, TGF-α, and bFGF, VEGF seems to also be one of the The protein expression in embryonic SMGs of the signal most important mediators for angiogenesis in wound transduction pathway is performed as TGF-α/EGF/EGF-R, healing. IGF-II/IGF-I R/TGFR-IIR, TGF-βs and cognate receptors in The expression of VEGF in saliva or in salivary glands individual stages (47). has been described in two studies to date (59-60). Using ELISA, a median concentration of 460 pg/ml of VEGF has been estimated to be present in the whole human saliva. The 3. Bone morphogenetic proteins (BMPs) concentration of SMG-SLG saliva is 80 pg/ml and far less BMPs-2-8 are members of a TGF-β superfamily, and than that in the whole human saliva, and VEGF mRNA and BMP-2 shows the strongest bone-forming effect. BMP-7 is the protein have been found to be present in serous acinar 118 Mori et al. Growth factors in salivary glands cells and ductal cells. Pammer et al. (60) reported that in highest concentration of IGF-I was found in plasma (68). normal salivary glands, VEGF mRNA and protein were The parotid gland, devoid of GCT segments, is the main strongly localized in acinar cells, whereas there were little or source of IGF-I production, which may take place in its no expressions in ductal cells. In chronic inflammatory acinar cells, although at a low level. IGF-I concentration in conditions of salivary glands, VEGF was also demonstrated the whole saliva has been examined in clinically healthy in mononuclear cells in addition to ductal ones. individuals (n=327, adolescents), where the flow rate of analyses of the human SMG have saliva and IGF-I levels in secreted saliva in 24 hr period shown relatively higher levels of VEGFR-1 and VEGF-β, were found to be similar between males and females, and positive expressions of VEGFR-3 and VEGFR-2. although the IGF-I levels were low in early childhood, Salivary VEGF may originate from acinar and/or ductal peaked in puberty and fell during the late adolescence. cells, and salivary VEGF seems to play an important Salivary IGF-I concentrations (70 ± 50 pm) have been biological role in the maintenance of the of shown to be 100~200 fold less than those in the plasma (69). saliva, rapid induction of neoangiogenesis, and accelerated Concentrations of insulin, IGF-I, and IGF-II in the murine wound healing in the oral cavity, which is similar to saliva were demonstrated to be almost the same between functions of other growth factors. Booth et al. (61) have males and females, and these molecules were localized in reported higher concentrations of VEGF in the saliva as well the duct epithelial cells of both parotid and submandibular as in the diseased gingival crevicular fluid of patients with glands (70). Interestingly, salivary insulin and IGF-I levels periodontal diseases as compared to those of healthy were shown to be elevated in autoimmune type 1 controls. VEGF levels in the saliva of patients (n=30) with mice or of non-obese diabetic (NOD) mice than in a second aphthous stomatitis have been shown to be decreased (765 ± inbred BALB/C mice. At the onset of diabetes in NOD mice, 458 pg/ml in stage I and 341 ± 109 pg/ml in stage II) as insulin levels declined, although IGF-I and IGF-II levels compared with healthy controls (1652 ± 567 pg/ml, P<0.01), tended to be lower, when compared with those in non- suggesting that a marked reduction of salivary VEGF levels diabetic mice (70). IGF binding proteins (IGFBPs) have may be associated with aphthous stomatitis (62). been detected by western-blot type binding assays. The have been found in both BALB/C and diabetic NOD mice sera with molecular masses between 25 and 45 kDa but 5. Insulin-like growth factor (IGF) not in their saliva. In diabetic mice, there was a detectable IGF-I and IGF-II are collectively known as . change in the concentrations of IGFBPs relative to BALB/C IGF-I and IGF-II are single-chain peptides of about 7.5 kDa mice, which resulted in higher uptakes of IGF-I and IGF-II in blood plasma. IGF circulating in the blood is produced in in mice saliva independently of specific IGFBPs (71). the , while a larger extent of tissue IGF is synthesized Concentration of IGF-I in the bovine milk was lower than locally. IGFs are single-chain peptides consisting of four that in human milk, but similar to that in human saliva; the peptide domains: domains A and B are structurally IGF-I concentration in milk was higher in early lactation homologous to the A and B chains of insulin, domain C is than during mid and late lactation (72). analogous to the C peptide of proinsulin, and domain D is The expression of IGF-IR and insulin-like receptors not found in insulin. The structures, tissue distribution have been investigated immunohistochemically in the receptors, signal transduction and biological effects of IGF-I submandibular and labial glands in patients with Sjögren's and IGF-II have been reviewed extensively by Humbel (63), Syndrome (SS) (73), in which insulin receptor was expressed and the biological function of IGF binding protein-1 has also more than control tissues obtained from mucoceles, while been nicely reviewed by Lee et al. (64). IGF-IR was more intense in the controls (73). It was also There may be a functional role of IGFs in salivary suggested that IGF-IR in SS was down-regulated, triggering glands, although it has not been studied in great detail. a compensatory feedback mechanism for increased Hausson and Tunhall (65) have described that IGF-I was production of the ligand (74). In human salivary glands, localized in granular convoluted tubules (GCT) as well as in insulin-like receptors and insulin, or IGF-I may act in an intercalated, striated and excretory ducts in salivary glands autocrine fashion to maintain its physiological function. of adult male rats and mice, showing that IGF-I was much Gene expressions for IGF-1A and IGFBP-3 have been more widespread than EGF or NGF, which were confined to demonstrated in the human submandibular glands (67-68). the granular cells of GCT segments. The same group, using During development of salivary glands, IGF-II and the rabbit antisera, reported that IGF-I and EGF were expressed receptors IGF-IR and IGF-IIR have been demonstrated in in a variety of rat tissues and organs including salivary the initial bud stage of branching morphogenesis in murine glands, in which duct epithelial cells were immunolabeled submandibular glands: these molecules were expressed for these proteins (66). IGF-I mRNAs in matured rats have throughout the glandular epithelia as well as in the been found to be expressed at a higher level in the SMG than surrounding connective tissues. In the terminal bud stage, in the liver, where they were localized in GCT cells, and a IGF-IR was primarily detected in ductal epithelia and 1.8 kb mRNA for IGF-I was expressed at a lower level in weakly in bud epithelia (75). HSC, a human salivary cell acinar and ductal cells (67). IGF-I in the rat saliva was line, expressed IGF with mitogen stimulation, and IGFBPs shown to be produced locally by demonstrating a 4.7 kb were released by HSC cells following stimulation by EGF as IGF-I mRNA transcript in the rat parotid gland, although the well as an antibody against IGF-1R (α1R3), indicating that Oral Med Pathol 12 (2008) 119

IGFBPs had an important role in HSC proliferation (76). growth factor receptor 1 (VEGFR-1) and downregulation of mRNAs for FGF-8 compared to normal parotid gland has been shown (26). erbB3 encodes one homologue of EGFR 6. Fibroblastic growth factors (FGF) and acts as by converting ras-GDP to ras- Fibroblastic growth factors (FGFs) constitute a family of GTP via growth factor receptor binding protein (GRB). ras- heparin-binding growth factors, which have been classified GDP stimulates several pathways to enhance cell into nine distinct proteins: FGF-1 (acidic FGF or aFGF), proliferation. Upregulation of erbB3, together with several FGF-2 (basic FGF or bFGF), n FGF-3 (Int-2), FGF-4 (hst/k- G-proteins and transcription factors may contribute to FGF), FGF-5, FGF-6, FGF-7 (keratinicyte growth factor, salivary tumor growth. KGF), FGF-8 and FGF-9. The function of FGF-1 and FGF-2 During embryonic morphogenesis of SMG in normal are mediated by high-affinity transmembrane receptors that mice and mice with abnormal SMG phenotypes, FGF-2/ consist of an intercellular tyrosine kinase domain and an FGFR-1, FGF-8/FGFR-2 (111c) and FGF-10/FGFR-2 extra cellular binding domain with an immunoglobulin (111b) signaling were observed from the initial bud stage to motif, and both FGFs have 53% amino acid sequence pseudo-glandular stage. In the pseudo-glandular stage, homology. bFGF mediates the function of paracrine or FGF-2/FGFR-1 and FGF-7/FGFR-2 have been found to autocrine factors that regulate migration and proliferation in function in paracrine and juxtracrine manners, and FGF-10/ cells following tissue damage. FGFR-2b, FGF-8/FGFR-26, and FGF-8/FGFR-4 were in An ELISA analysis of 16 saliva samples has shown that juxtracrine (88). FGF-8 is involved in several signaling 87.5% (14 samples) of them contained bFGF, with cascades during embryogenesis such as the processes of concentrations varying from 0.1 pg/ml to 8.4 pg/ml, with a gastrulation, neural patterning, and axis determination, and mean concentration of 3.8 ± 3.5 SD pg/ml (77). Another one of the key roles of FGF-8 is related to cranio-facial, study has shown a mean bFGF concentration ranging from cardiovascular and pharyngeal development. FGF-8 induces 0.3 to 1.9 pg/ml in 28 subjects, with no difference observed downstream signal transduction pathway during embryonic for age-dependent changes, sex and race (European and development including SMG morphogenesis (89). Asian); however, smokers showed significantly higher salivary bFGF than non-smokers (78). 7. Somatostatin After bFGF was initially reported in rat salivary glands, immunohistological studies have detected bFGF in ductal Somatostatin, also known as somatotropin release segments and in GCT of the SMG, including pillar cells inhibiting factor (SRIF) or inhibiting (79). FGF-1, FGF-2 and FGFR-1 were not found or weakly hormone (GHIH), is a cyclic tetradecapeptide and an positive in human normal salivary glands, whereas these inhibitor of growth hormone secretion. It has a hormone-like molecules were over-expressed in malignant tumors (80). function and acts as a neurotransmitter in the central nervous FGF-1 and FGF-2 were co-expressed with FGFR-1 in system and gastrointestinal tract. Somatostatin is a mixoid and chondroid stromal areas of pleomorphic adenoma neurotrophic protein firstly found in the sympathetic dorsal (81). root ganglion and motor . Somatostatin is mediated FGF-1 has been immunolocalized in the intercalated by at least four subtypes of GTP-binding protein (G-protein) duct cells and basal cells of excretory ducts of the human coupled receptor (90). The functional roles and biological salivary gland, while FGF-2 was expressed in the basement properties of somatostatin in salivary glands have been membrane of acini and ducts (82). Salivary FGF may be explored in imnunohistological and physiological studies. secreted from ductal cells, and benign and malignant Somatoatatin has been observed in ductal epithelium in salivary tumors may synthesize FGFs: the production of salivary glands of monkeys (91). Heterogeneous distribution FGFs seems to be more frequently associated with tumor of somatostatin was imunohistochemically demonstrated in cell differentiation or with formation of chondroid stroma in acinar cells as well as in striated duct and GCT cells in mice pleomorphic adenoma. The bFGF expression has been by using antibodies to synthetic somatostatin and its amino associated with fibrosis and angiogenesis in gastric terminus peptides (92). carcinomas (83). In renal carcinomas, bFGF has been Based on immunoreactivities for somatostatin and the associated with tumor growth and neovascularization (84). other such as vasoactive interstinal peptide FGFR-1 in pancreatic adenocarcinoma may have an aberrant (VIP) and substance P in the human embryonal salivary autocrine function (85). In rat SMG, bFGF could accelerate glands, their roles have been suggested in the development tissue repair after surgical injury (86). bFGF acts as a of salivary glands (93). There has been a case report of mitogenic stimulus in cultured rat and human SMG cells mucinous adenocarcinoma with neuroendocrine differen­ (87). Gene expressions for FGF-3, FGF-1, FGF-6, FGF-7, tiation in the mandibular bone with immunoreactivities for FGF-8, FGF-9, FGFR2, and FGFR-3 have been found in the somatostatin, , and GFAP, in which the tumor was ductal epithelial cells of the human SMG. suggested to originate from heterolopic or misplaced In cystadenoma, characteristic upregulation of mRNAs salivary gland (94). for c-sis (PDGFB), FGF-9, erbB3, cysteine-rich fibroblast The expression of somatostatin in salivary glands is still growth factor receptor (FGFR), platelet-derived growth obscure, and it is necessary to examine its expression more factor receptor β (PDGFR-β), and vascular endothelial carefully with specific antibodies and appropriate fixation 120 Mori et al. Growth factors in salivary glands protocols. In salivary glands, somatostatin seems to function GCT and located between intercalated and striated ducts, as a modulator that influences salivary secretion under which contained a lot of growth factors or biologically physiological and stimulated conditions. In rat parotid active peptides to be discharged into the oral cavity. The saliva, somatostatin was modulated by stimulation of saliva of rodents is composed of two different properties: cholinergic, adrenergic and peptidergic agents, which also one is that of digestive enzyme, and the other is that of affected the calcium pathway but did not inhibit amylase growth factor, which has also been confirmed in human secretion (95). Recently, the same group has shown that salivary glands. It is now widely accepted that human somatostatin modulated rat SMG protein secretion by salivary glands also produce a lot of growth factors in the prolonging cytosolic calcium signals in acini, which remains striated and excretory ducts and secret them into saliva, high after stimulus, with the fluorescence measurement which might maintain various oral functions. After secretion, using Ca2+ sensitive dye fluo3 (96). A low concentrations of salivary growth factors is firstly contacted with the oral somatostatin mRNA and angiotensin-like peptide receptor mucosal surface and with the gingival sulcus and then mixed have been found in the salivary glands (97). Somatostatin with bio-film or dental plaque on the tooth surface. Growth has been reported in AR4-2J, a rat pancreatic cell line, which factors in saliva enter into the and digestive tracts to also retained both specificity and affinity of pancreatic be absorbed into bloodstream or denatured by enzymes and acinar cell receptors for somatostatin (98). It is thus finally may play own physiological roles in remote tissues suggested that even in the salivary gland somatostatin and organs. It is therefore necessary to explore the inhibits secretory activities, as indicated in the other pathophysiological function of human salivary growth digestive organs. factors in greater detail for controlling oral health. Manetti et al. (99) demonstrated an increased volume of the submandibular gland in forty acromegalic patients (18 References males and 22 females, ranging 22-74 yrs). Enlargement of the submandibular gland, measured by ultrasound, has been 1. Almstahl A, Wikstrom M. 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Received June 1 , 2008 Accepted June 16 , 2008