Tie-2 regulates the stemness and metastatic properties of prostate cancer cells

// Kai-Dun Tang 1 , Boris M. Holzapfel 1 , Ji Liu 1 , Terence Kin-Wah Lee 2 , Stephanie Ma 3 , Lidija Jovanovic 1 , Jiyuan An 1 , Pamela J. Russell 1 , Judith A. Clements 1 , Dietmar W. Hutmacher 1 and Ming-Tat Ling 1 1 Australian Prostate Cancer Research Centre-Queensland and Institute of Health and Biomedical Innovation, Queensland University of Technology and Translational Research Institute, Woolloongabba, Qld, Australia 2 Department of Pathology, Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China 3 Department of Anatomy, Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China Correspondence to: Ming-Tat Ling, email: // Keywords : Tie-2; prostate cancer; metastasis; cancer stem cells Received : June 23, 2014 Accepted : April 08, 2015 Published : April 29, 2015 Abstract Ample evidence supports that prostate tumor metastasis originates from a rare population of cancer cells, known as cancer stem cells (CSCs). Unfortunately, little is known about the identity of these cells, making it difficult to target the metastatic prostate tumor. Here, for the first time, we report the identification of a rare population of prostate cancer cells that express the Tie-2 protein. We found that this Tie-2 High population exists mainly in prostate cancer cell lines that are capable of metastasizing to the bone. These cells not only express a higher level of CSC markers but also demonstrate enhanced resistance to the chemotherapeutic drug Cabazitaxel. In addition, knockdown of the expression of the Tie-2 ligand angiopoietin (Ang-1) led to suppression of CSC markers, suggesting that the Ang-1/Tie-2 signaling pathway functions as an autocrine loop for the maintenance of prostate CSCs. More importantly, we found that Tie-2 High prostate cancer cells are more adhesive than the Tie-2 Low population to both osteoblasts and endothelial cells. Moreover, only the Tie-2 High , but not the Tie-2 Low cells developed tumor metastasis in vivo when injected at a low number. Taken together, our data suggest that Tie-2 may play an important role during the development of prostate tumor metastasis.