OP0022 TIE-2 regulates stemness and metastasis of prostate cancer cells

Abstract

Background Prostate cancer is the most commonly diagnosed male cancer in western countries. Currently, the major treatment challenge for prostate cancer patients is the development of tumour metastasis. Ample evidence supports the idea that tumour 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 prostate tumour metastasis. Here we report the identification of a rare population of prostate cancer cells that express the Tie-2 protein, a tyrosine kinase receptor needed for bone marrow homing and colonisation of haemopoietic stem cells. Notably, this Tie-2-positive population exists exclusively in highly metastatic prostate cancer cell lines. Methods To study the role of Tie-2 in prostate tumour metastasis, we used fluorescence-activated cell sorting to isolate the Tie-2-positive population from a prostate cancer cell line (PC-3). We then used cDNA microarray analysis to characterise the gene expression profile of these cells. Furthermore, we did a cell adhesion assay to examine the ability of the Tie-2-positive cells in adhering to osteoblasts and endothelial cells. We also undertook quiescent staining and a drug sensitivity assay to examine whether Tie-2-positive cells are more quiescent, and thus become resistant to chemotherapeutic drugs. Finally, we injected both Tie-2-positive and Tie-2-negative PC-3 cells intracardiacly into NOD-SCID mice to establish whether Tie-2 expression promotes prostate tumour metastasis in vivo. Findings Data from our study revealed that Tie-2-positive cells express higher level of prostate CSC markers compared with the Tie-2-negative population. Meanwhile, Tie-2-positive cells are highly adhesive to both osteoblasts and endothelial cells, a characteristic necessary for tumour metastasis. We also found that Tie-2-positive cells are more quiescent and resistant to the chemotherapeutic drug cabazitaxel, providing further support that these cells possess CSC-like characteristics. More importantly, we found that Tie-2-positive cells, but not Tie-2-negative cells, developed metastatic tumours in vivo. Interpretation Our data suggest that Tie-2 plays an important part in the development of drug resistance and prostate tumour metastasis. Thus, Tie-2 might be a novel therapeutic target for treatment of patients with advanced prostate cancer.