SIGNAL TRANSDUCTJON FOR HISTOGENESIS OF SALIVARY GLAND AND GENE THERAPY FOR SALIVARY GLAND TUMORS.

2003 Fiscal Year Final Research Report Summary

• Project/Area Number: 14370669
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: OSAKA UNIVERSITY
• Principal Investigator: OKURA Masaya OSAKA UNIVERSITY, GRADUATE SCHOOL OF DENTISTRY, ASSOCIATE PROFESSOR, 大学院・歯学研究科, 助教授 (10281130)
• Project Period (FY): 2002 – 2003
• Keywords: salivary gland / salivary gland tumors / differentiation therapy / extracellular matrix / laminin / Src

Research Abstract

Salivary glands begin their development as a double row of cuboidal progenitor cells, which arise from the surface epithelium of the stomatodeum as an invagination into the subjacent mesenchyme, and compose a branching ductal structure. The terminal branches differentiate into the secretory acinar cells. Human salivary gland cells (HSG cells) have the characteristics of intercalated ductal cell and form adenocarcinoma in nude mice. When cultured on Matrigel, HSG cells form acinar-like structure with polarized nuclei and express salivary cystatin within 24-48 h, whereas the cells grown in its absence form a monolayer. In order to clarify signals for acinar differentiation, gelatin gel including one of matrices, such as fibronectin or laminin 1 was made. Only laminin 1 gel can induce acinar differentiation of HSG cells, which was blocked with the antibody to integrin α4β1 or α6β1. HSG cells (SrcK297M cells) expressing a dominant negative Src did not differentiate to acinar cells with laminin 1 gel. Taken together, the engagement of laminin 1 and integrin α4βl or α6β1 induces acinar differentiation of salivary gland cells, and the differentiation is required with Src family tyrosine kinase activity.
Human mucoepidermoid carcinoma cells were established. The cells named by TAK cells had no cytokeratins but expressed vimentin and α-smooth muscle actin. TAK cells were positive for PAS staining. Laminin 1 coated dishes up-regulates HSG, TAK, and adenoid cystic carcinoma (ACC) cells growth. On the other hand, laminin 1 gel down-regulates these cells growth and induce acinar differentiation, luminal ductal differentiation, and apoptosis, respectively. These results suggest the possibility of laminin 1 gel for differentiation therapy of salivary gland tumors.