Both epithelial and mesenchymal cells produce the basement membrane and stromal extracellular matrix. The composition of the extracellular matrix varies from region to region during branching, and bundles of cCollagen I, type I, Collagen typeIV and fFibronectin are thought to directly control the maturation process. Low concentrations of fFibronectin and gGlycosaminoglycans facilitate the area of bud growth, while accumulation of fFibronectin, cCollagen IV and gGlycosaminoglycans limit epithelial activity of the peripheral nervous system also participates in directing salivary growth and stabilizsing the basal lamina, determining sites where branching and clefting occurs ^[4][5]. The peripheral nervous system participates in directing salivary gland maturation. The primordial epithelial structure is innervated by cholinergic neuronves, whose axonal growth follows the ramified pattern of the developing gland ^[6]. Local release of acetylcholine induces proliferation of epithelial progenitor which positively regulate epithelial branching ^[7][8][9].

A network of capillaries derived from terminal arterioles develops in parallel with the acini-duct systems and has an instructive role in the establishment of the epithelial patterning ^[10].

Innervation of the salivary glands starts during embryonic development and progress in parallel with the organ definition. Neural crest-derived cells migrate to their appropriate location in the oral epithelium to instruct the thickening for the placode formation. The neural crest-derived precursors differentiate to form the parasympathetic submandibular ganglion (PSG) surrounding the epithelial primordia of the major secretory duct. As branching proceeds further with the developmental process, the gland is highly branched and fully innervated. Axons from the PSG extend along the epithelium to envelop the secretory end-pieces. By E14 in the mouse, the gland is highly branched and fully innervated ^[17]. The instructive role of the PSG is currently gathering interest, as ablation of the PSG reduces expression of epithelial progenitor markers such as Kertatin5 and Krteratin15, and might, therefore, be implicated in the maintenance of endogenous stem cells ^[18]. Similarly, acetylcholine induces proliferation of Kertatin5-expressing progenitor cells via regulation of the EGF pidermal Growth Factor (EGF) pathway, suggesting that the parasympathetic activity coordinates the maintenance of the undifferentiated pool and their balance during organogenesis ^[18].

The development of the sympathetic innervation proceeds conjointly with acinar and ductal maturation, which suggests a role in the final specification of the salivary gland.

The primary sympathetic salivary centres are located in the upper thoracic spinal cord, and reach the salivary gland via the superior cervical ganglion. Sympathetic axons enter the SMG in parallel with the vascular system, and vascular-derived guidance cues are needed for sympathetic neurons to grow. Mice lacking endothelin3 or endothelin-receptor type-A have reduced sympathetic innervation of the salivary glands and defects in SMG secretion ^[19][20].

Despite developing with a similar timing and being surrounded by the same mesenchymal cap, the SL gland contains only a few sympathetic nerves, while the SMG has rich innervation. This dichotomy is probably to be associated with the different levels of Nerve GF (hirowth Factor (NGF), which is high in the SMG and low in SL) ^[21]. After submandibular gland removal, the NGF levels drop dramatically in the plasma, to then go back to a normal level after several weeks. It has, therefore, been postulated that the submandibular gland in mice might work as source of NGF ^[22]. Nevertheless, removal of the SMG in mice has no deleterious systemic effect, indicating more of an accessory role in NGF secretion rather than a primary one ^[23].

Once reaching the salivary gland, the independent innervation of parasympathetic and sympathetic efference bundles up together surrounded by Schwann myelinating cells ^[24]. Dual innervation can be found in myoepithelial cells, acinar end-pieces and local blood vessels, all of which plays a functional role in salivary gland secretion ^[25].

The aetiology of the salivary gland tumour is mainly described by the multicellular theory, by which each cell type can give rise to a specific type of tumour ^{[29][30][31][32][33]}.

In addition to being a site for primary tumours, salivary glands are also a site for tumorigenic cells to establish metastases, originating from other primary cancers, mainly skin malignancies.

The most common malignant tumour is mucoepidermoid carcinoma, potentially arising in any salivary tissue, but mostly affecting the PG. Mucoepidermoid carcinoma is associated with a specific genetic translocation between chromosomes 11 and 19, which produces a fusion gene (MECT1) involved in the Notch-pathway and cAMP-responsive element binding (CREB) activation. The product of gene fusion was detected in genomic screenings together with alteration of the EGF-receptor pathway and aberrant activation of p53 regulator of apoptosis ^[34][35]. The specificity of the novel gene-fusion for mucoepidermoid carcinoma cells has improved diagnostic capacity and brought increased focus on the study of the molecular mechanisms supporting the disease. Identification of the fusion product (CRTC1-MAML2) or constitutive activation of the Notch pathway via high levels of the Notch target  Hes1  are indicative of cancer progression ^[36][37].

 Similarly, in adenoid cystic carcinoma, mutations in  NOTCH1  and  NOTCH2  have been identified as altered targets in various genomic screenings ^[38][39], and knock-down of  Notch1  or  Notch2  inhibits proliferation of adenoid cystic carcinomas in models of the disease ^[40][41]. These findings suggest that this pathway has a central role in the initiation of the most common neoplasms affecting salivary glands.