Mechanism for bone invasion of oral cancer cells mediated by interleukin‐6 in vitro and in vivo

Abstract

BACKGROUND Osteoclastic bone resorption is an important step in bone invasion in several malignancies. Although interleukin (IL)‐6 accelerates osteoclastic bone resorption, it remains unclear whether IL‐6 may be involved in bone invasion of oral cancer. METHODS The pit formation assay with calf femur‐derived bone slices was performed to examine the bone‐resorbing activity of osteoclasts and cancer cells. The chemotaxis activity of the culture media was analyzed by the use of Boyden chamber technique. Nude mice, which were inoculated with IL‐6–producing oral cancer cells into masseter, were treated with anti–IL‐6 neutralizing antibody, and mandibular‐bone invasion of the cells was assessed. RESULTS BHY, a bone‐invasive oral cancer cell line, but not HNT, a noninvasive cell line, produced large amounts of IL‐6. In a pit formation assay, addition of conditioned medium (CM) derived from BHY but not HNT increased osteoclastic bone resorption, and the effects were inhibited by anti–IL‐6 antibody. BHY‐secreted IL‐6 showed significant chemotaxis activity for osteoclasts. Of note, CM from the cocultivation of osteoclasts and BHY markedly enhanced the cancer cell migration, and the chemotaxis activity was significantly reduced when anti–IL‐6 antibody was added into the coculture and then CM were collected, but not when the antibody was added into the CM after they were collected. Furthermore, treatment with anti–IL‐6 antibody almost completely inhibited mandibular bone invasion of BHY in nude mice. CONCLUSIONS These results strongly suggest that IL‐6 secreted by oral cancer cells plays a significant role in bone invasion. Cancer 2000;89:1966–75. © 2000 American Cancer Society.

Establishment of a murine model of bone invasion by oral squamous cell carcinoma

“…2,3,8 In our animal models, it was possible to confirm the expression of these cytokines from the SCCVII cultured cells at the mRNA level. Roughly the same results (i.e., enhanced expression of all cytokines at the mRNA level) were also obtained with neoplastic tumor tissues that had been transplanted.…”

“…Its invasion into the adjoining maxilla and mandible, in particular, is a major clinical problem. 1,2 While gingival and oral floor carcinoma are frequently associated with mandibulectomy the extent of bone invasion can only be assessed by diagnostic imaging. It has been pointed out that resection of the maxilla and mandible occasionally amounts to oversurgery.…”

“…9 Okamoto et al produced evidence in their in -vitro study that IL-6 is involved in the bone invasion of OSCC. 2 Recently, it has been clarified that the differentiation and functions of osteoclasts are strictly controlled by the RANKL expressed on the cell membranes of the osteoblasts or marrow interstitial cells. 10 We, for our part, have carried out immunohistochemical analyses on various osteoclast related cytokines, and have been able to demonstrate the possibility that IL-6, TNF-α, and PTHrP may be involved at least in bone invasion by human gingival cancer.…”

Effect of YM529 on a Model of Mandibular Invasion by Oral Squamous Cell Carcinoma in Mice

“…Mandibular invasion by tumor requires surgical resection of the involved bone, potentially compromising mandibular function. How OSCC invades bone and how to prevent such invasion remain unsolved problems (1,2).…”

Effects of endogenous nitric oxide induced by 5-fluorouracil and L-Arg on liver carcinoma in nude mice

“…These effects may be mediated by TNF-alpha production [13] . 5-FU could induce the cytokines such as interleukin-1beta (IL-1beta) and TNF-alpha [14] . Other studies showed that the iNOS expression was stimulated by interleukin-1beta (IL-1beta) and TNF-alpha [15] .…”