Hepatocyte growth factor receptor immunoexpression in human fetal salivary glands

Salivary glands develop at 4-6 weeks of gestation, all in a similar way. However, little is known of their key regulators. Clearly, there is a requirement of coordination between cell proliferation, polarization and differentiation processes, all of which are dependent on epithelial-mesenchymal interactions and on the microenvironment. Met (mesenchymal-epithelial transition factor) is a proto-oncogen encoding a protein, Met, also known as c-Met or hepatocyte growth factor (HGF) receptor. HGF is a hepatotropic factor originally identified in rat serum and platelets. It is essential in fetal tissue development, where it regulates complex morphogenetic processes including extracellular matrix invasion, cell migration, cell polarization and tubulogenesis. The c-Met/HGF system is believed to participate in epithelial-mesenchymal interactions during development. Information on the functional contribution of HGF to salivary gland development is poor, except that HGF stimulates proliferation and expression of activin βA-subunit mRNA in cultured primary epithelial cells from rat submandibular gland. We investigated these intriguing mechanisms by studying for the first time c-Met immunoexpression and localization in human fetal development and morphogenesis. In order to investigate, immunohistochemistry, the c-Met immunoexpression, twelve human fetal salivary glands were analysed. Samples consisted of human minor salivary glands in the bud, proliferation and canalization stages. All specimens showed c-Met immunoexpression. In particular, in the bud and proliferation stages c-Met immunostaining was detected in solid nest cells, where the immunoreaction was mainly seen in the cytoplasm and in the membrane, and was particularly strong in the peripheral layer. Developing salivary gland ducts were observed in the canalization stage; c-Met immunopositivity was observed in the cytoplasm and membrane. Strong c-Met expression involved the luminal pole of duct cells of the canalizing duct system. Immunolabeling was also detected in the stroma surrounding canalizing gland structures. This immunohistochemical study is the first to document c-Met expression in human fetal salivary glands and to suggest the involvement of the c-Met/HGF system.