Overexpression of cadherins suppresses pulmonary metastasis of osteosarcoma in vivo

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Abstract
Osteosarcoma by nature shows aggressive pulmonary metastasis; however, the underlying molecular mechanisms remain unclear. We previously showed that N‐cadherin and cadherin‐11 (OB‐cadherin), which are highly expressed in normal osteoblasts, are anomalously expressed in human osteosarcoma (Kashima et al., Am J Pathol 1999;155:1549–55). In the present study, we examined the role of cadherins in osteosarcoma metastasis using the mouse osteosarcoma cell line Dunn and its highly metastatic subline LM8. Oligonucleotide array and RT‐PCR analyses demonstrated that Dunn and LM8 cells did not express appreciable levels of several members of the cadherin family, and Western blot analysis confirmed that Dunn and LM8 cells did not express P‐cadherin, E‐cadherin, N‐cadherin or cadherin‐11 protein. We therefore investigated the functional consequences of cadherin overexpression on cell migration and in vivo metastatic potential of LM8 cells. Several LM8 clones were isolated which expressed exogenous N‐cadherin and cadherin‐11 localized to the cell membrane and able to bind to β‐catenin. Overexpression of N‐cadherin or cadherin‐11 in LM8 cells did not affect cell proliferation but caused an inhibitory effect on cell migration in vitro. In vivo analysis showed that N‐cadherin‐ and cadherin‐11‐overexpressing cells exhibited a marked reduction in their ability to form pulmonary metastases, with significant decreases in lung weight and the number and weight of metastatic lesions, as well as the size and weight of primary lesions at the s.c.‐inoculated site. These observations demonstrate that disruption of N‐cadherin‐ and cadherin‐11‐mediated cell–cell adhesion is critical in the pulmonary metastasis of osteosarcoma.