| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Shunji Cancer Chemotherapy Center, Senior Investigator, 研究員 (90221358)
SEKINE Imao Cancer Institute, Senior Investigator, 研究員 (10134602)
MATSUMOTO Toshio University of Tokyo, 4th Dept.of Internal Medicine, Lecturer, 医学部, 講師 (20157374)
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| Research Abstract |
In order to clarify the mechanism of develoment as well as to establish methods for the diagnosis and treatment of metastatic bone lesions, the following studies were performed :
1.Effects of adhesion of tumor cells to bone matrix and stromal cells : Many tumor cells that have metastatic potential express alpha4beta1 integrin, and bone marrow stromal cells (BMSC) constitutively express vascular cell adhesion molecule (VCAM)-1 that can bind to alpha4beta1 integrin. We have demonstrated that anti-VCAM-1 or anti-alpha4beta1 integrin antibody can inhibit adhesion of clonal melanoma cells, B16, to BMSC,and that the inhibition of adhesion by these antibodies blocks the adhesion-induced inhibition of BMSC differentiation into osteoblasts. The adhesion of B16 cells with BMSC also enhanced osteoclast formation supported by BMSC.Furthermore, pretreatment with anti-VCAM-1 or anti-alpha4beta1 integrin antibody caused an inhibition of osteoclast formation enhanced by the adhesion of B16 cells. These
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results demonstrate that adhesion of tumor cells with BMSC via the binding of alpha4beta1 integrin with BMSC causes not only the inhibition of osteoblastic differentiation but also the stimulation of osteoclast formation. These changes caused by the adhesion of tumor cells with BMSC may play an important role in the establishment and expansion of metastatic bone lesions.
2.Role of annexin II on the stimulation of bone resorption by tumor cells : We have cloned cDNA for human annexin II as a stimulatory factor of osteoclast formation, and established a breast cancer cell line over expressing annexin ii. We now have established cell lines that stably express antisense annexin II RNA to block the expression of annexin II.Using these cell lines, we are in the process of analyzing the effect of co-culture of these cell lines with bone marrow cells on osteoclast formation and bone resorption. These studies should enable us to clarify the role of annexin II produced by tumor cells on the enhancement of bone resorption at metastatic bone lesions.
3.Effect of bone metastasis on bone turnover : The effect of bisphosphonates, a potent inhibitor of bone resorption, on the development of metastatic bone lesions was examined. These was a significant correlation between the inhibition of bone resorption assessed by bone metabolic markers and the extent of metastatic lesions assessed by tumor markers. These results suggest that inhibition of bone resorption can also suppress the development of metastatic bone lesions. Less
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