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A7090 - Involvement of Insulin-Like Growth Factor-1 in Receptor Activator of Nuclear Factor Kappa-B Ligand-Targeted Therapy in Mouse Model of Lung Cancer Bone Metastasis
Author Block: H. Goto, T. Yamago, A. Saijo, H. Ogino, M. Tobiume, K. Otsuka, H. Kozai, H. Yoneda, H. Nokihara, Y. Nishioka; Tokushima University, Tokushima, Japan.
[RATIONALE] Receptor activator of nuclear factor kappa-B (RANK) and its ligand (RANKL) play an important role in cancer bone metastasis by activating osteoclasts. Thus, the suppression of osteoclast differentiation by targeting RANKL shows clinical effects to reduce skeletal-related event such as pain and pathological fracture in cancer patients. However, the tumor growth in the bone could not be controlled by anti-RANKL therapy in most cases, suggesting that targeting RANKL is still insufficient to regulate the progression of cancer bone metastasis. In this study, we hypothesized that there might be the signal that rather activated to maintain the survival of cancer cells under the inhibition of RANK-RANKL axis in the microenvironment of bone metastasis. [METHODS] Human small cell lung cancer cell line, SBC-5 cells, was injected into the tail vein of immunodeficient mice. Using this multiple-organ metastasis model, the effect of anti-RANKL antibody on lung, liver and bone metastases was evaluated. For in vitro study, mouse macrophage cell line, RAW264.7 cells, was differentiated to osteoclast by RANKL, and the effect of anti-RANKL antibody on osteoclast differentiation was investigated. [RESULTS] In in vivo study, the treatment with anti-RANKL antibody strongly inhibited bone metastasis with the inhibition of the number of osteoclast, whereas it exhibited no effect on lung or liver metastases. However, we found in the lesion of bone metastasis of anti-RANKL antibody-treated mice that the cancer cells partly remained in the bone pathologically. Ki67 staining showed that these residual cells possessed similar ability of proliferation compared to the cells in the control tumor. Based on the previous report, we focused on insulin-like growth factor (IGF)-1 as the factor which could be up-regulated under the inhibition of osteoclast differentiation, and found that the stromal expression of IGF-1 in the bone was up-regulated by the treatment with anti-RANKL antibody. Anti-RANKL antibody also inhibited the differentiation of RAW264.7 cells to osteoclast in vitro. When RAW264.7 cells were differentiated to osteoclast, the expression of IGF-1 was decreased although the treatment with anti-RANKL antibody rescued this inhibition. [CONCLUSIONS] These results suggested that the suppression of the differentiation of osteoclasts by RANKL inhibition in turn activated IGF-1 expression in the cells, and may contribute to the proliferation and survival of cancer cells in the bone. Targeting IGF-1 in addition to RANKL may provide a therapeutic strategy to more effectively control cancer bone metastasis.