Angiopoietins Promote Ovarian Cancer Progression by Establishing a Procancer Microenvironment

• DOI: 10.1016/j.ajpath.2014.05.006
• Publication Date: 2014-07-18T04:31:57Z
• Authors: Melissa K. Brunck...; Yin Xu; Rong Lu; Qin Yu
• Keywords: Ovarian Neoplasms; Neovascularization, Pathologic; Blotting, Western; Fluorescent Antibody Technique; Real-Time Polymerase Chain Reaction; Immunohistochemistry; Receptor, TIE-2; Pathology and Forensic Medicine; Cystadenocarcinoma, Serous; 3. Good health; Mice; 03 medical and health sciences; 0302 clinical medicine; Cell Line, Tumor; Disease Progression; Tumor Microenvironment; Animals; Heterografts; Humans; Female; Neoplasm Invasiveness; Angiopoietins; Cell Proliferation

Despite decades of research, the survival rate of ovarian cancer patients is largely unchanged. Current chemotherapeutic drugs are effective only transiently because patients with advanced disease eventually develop resistance. Thus, there is a pressing need for identifying novel therapeutic targets in ovarian cancer. Mounting evidence suggests that angiopoietins (Angpts) may play an essential role in cancer progression; however, the expression profiles and biological effects of Angpts on ovarian cancer remain largely unknown. Here, we show that, compared with their normal counterparts, expressions of Angpt1, Angpt2, and Angpt4 are increased in ovarian cancer cells and tissues and that human ovarian cancer cells also express the Angpt receptor Tie-2-receptor tyrosine kinase. We show that increased expression of Angpt1, Angpt2, or Angpt4 promotes intraperitoneal growth of ovarian cancers and shortens survival of the experimental mice. We further show, for the first time, that Angpts promote accumulation of cancer-associated fibroblasts and tumor angiogenesis in the ovarian cancer microenvironment, as well as enhance ovarian cancer cell proliferation and invasion in vivo. In addition, we establish a novel function of Angpts in promoting proliferation and invasion and inducing Tie-2 and extracellular signal-regulated kinase 1/2 activation in ovarian cancer-associated fibroblasts. Taken together, these data suggest that the Angpt-Tie-2 functional axis is an important player in ovarian cancer progression and an attractive target for ovarian cancer therapy.