RRC ID 69601
Author Kayamori K, Sakamoto K, Nakashima T, Takayanagi H, Morita K, Omura K, Nguyen ST, Miki Y, Iimura T, Himeno A, Akashi T, Yamada-Okabe H, Ogata E, Yamaguchi A.
Title Roles of interleukin-6 and parathyroid hormone-related peptide in osteoclast formation associated with oral cancers: significance of interleukin-6 synthesized by stromal cells in response to cancer cells.
Journal Am J Pathol
Abstract We investigated the roles of interleukin-6 (IL-6) and parathyroid hormone-related peptide (PTHrP) in oral squamous cell carcinoma (OSCC)-induced osteoclast formation. Microarray analyses performed on 43 human OSCC specimens revealed that many of the specimens overexpressed PTHrP mRNA, but a few overexpressed IL-6 mRNA. Immunohistochemical analysis revealed that IL-6 was expressed not only in cancer cells but also in fibroblasts and osteoclasts at the tumor-bone interface. Many of the IL-6-positive cells coexpressed vimentin. Conditioned medium (CM) derived from the culture of oral cancer cell lines (BHY, Ca9-22, HSC3, and HO1-u-1) stimulated Rankl expression in stromal cells and osteoclast formation. Antibodies against both human PTHrP and mouse IL-6 receptor suppressed Rankl in ST2 cells and osteoclast formation induced by CM from BHY and Ca9-22, although the inhibitory effects of IL6 antibody were greater than those of PTHrP antibody. CM derived from all of the OSCC cell lines effectively induced IL-6 expression in stromal cells, and the induction was partially blocked by anti-PTHrP antibody. Xenografts of HSC3 cells onto the periosteal region of the parietal bone in athymic mice presented histology and expression profiles of RANKL and IL-6 similar to those observed in bone-invasive human OSCC specimens. These results indicate that OSCC provides a suitable microenvironment for osteoclast formation not only by producing IL-6 and PTHrP but also by stimulating stromal cells to synthesize IL-6.
Volume 176(2)
Pages 968-80
Published 2010-2-1
DOI 10.2353/ajpath.2010.090299
PII S0002-9440(10)60407-5
PMID 20035059
PMC PMC2808100
MeSH Adult Aged Aged, 80 and over Animals Bone Neoplasms / genetics Bone Neoplasms / metabolism Bone Neoplasms / secondary Carcinoma, Squamous Cell / genetics Carcinoma, Squamous Cell / pathology Carcinoma, Squamous Cell / physiopathology* Cell Differentiation / drug effects Cell Differentiation / genetics* Cells, Cultured Female Gene Expression Regulation, Neoplastic Humans Interleukin-6 / genetics Interleukin-6 / metabolism Interleukin-6 / pharmacology Interleukin-6 / physiology* Male Mice Mice, Inbred C57BL Mice, Nude Middle Aged Mouth Neoplasms / genetics Mouth Neoplasms / pathology Mouth Neoplasms / physiopathology* Osteoclasts / metabolism Osteoclasts / physiology* Parathyroid Hormone-Related Protein / genetics Parathyroid Hormone-Related Protein / metabolism Parathyroid Hormone-Related Protein / pharmacology Parathyroid Hormone-Related Protein / physiology* Stromal Cells / drug effects Stromal Cells / metabolism* Stromal Cells / pathology Transplantation, Heterologous
IF 3.491
Human and Animal Cells EBC-1(RCB1965) MKN28(RCB1000) A549(RCB0098) ST2(RCB0224)