Abstract 3391: Tie2 signaling regulates osteoclastogenesis and osteolytic bone invasion of breast cancer

Abstract

Abstract Breast to bone metastasis is a common occurrence in the majority of patients with advanced breast cancer. The resultant metastases are incurable, are associated with bone destruction and high rates of morbidity. Understanding the underlying mechanisms of how metastatic tumor cells induce bone destruction is critically important. We previously reported that Tie2, a receptor tyrosine kinase, is significantly increased in human breast cancer tissues compared to normal and benign breast tumors, and regulates tumor angiogenesis. In this study, we identify a new function of Tie2 in osteoclastogenesis and osteolytic bone invasion of breast cancer. Tie2 is present in hematopoietic stem/precursor cells. Genetic deletion of Tie2 or neutralization of Tie2 function using soluble Tie2 receptor impaired osteoclastogenesis in an embryonic stem (ES) cells differentiation assay. In contrast, deletion of Tie2 has no effect on osteoblastogenesis. As monocyte has the potential to become osteoclast and Tie2 is present in certain population of monocyte, we isolated Tie2+ and Tie2- monocyte. We observed a dramatic reduction of osteoclastogenesis in Tie2- monocyte compared to Tie2+ and total monocyte. These data together reveal a direct role of Tie2 signaling in osteoclast differentiation. Consistently, neutralization of Tie2 activity in vivo significantly inhibited osteolytic bone invasion and tumor growth in a mammary tumor model, which correlated with a significant reduction of osteoclast and tumor angiogenesis. Collectively, these findings identify Tie2 a therapeutic target for controlling not only tumor angiogenesis, but also osteolytic bone metastasis. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3391.