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.
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.
Kayamori
Kou
K
Section of Oral Pathology, Graduate School of Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
Sakamoto
Kei
K
Nakashima
Tomoki
T
Takayanagi
Hiroshi
H
Morita
Kei-Ichi
K
Omura
Ken
K
Nguyen
Su Tien
ST
Miki
Yoshio
Y
Iimura
Tadahiro
T
Himeno
Akiko
A
Akashi
Takumi
T
Yamada-Okabe
Hisafumi
H
Ogata
Etsuro
E
Yamaguchi
Akira
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D010010:Osteoclasts / Q000378:metabolism / Q000502:physiology*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014183:Transplantation, Heterologous
D015850:Interleukin-6; D044162:Parathyroid Hormone-Related Protein