Expression of Angiopoietin-1, Angiopoietin-2, and Tie2 Genes in Normal Ovary with Corpus luteum and in Ovarian Cancer

Abstract

Objective: The recent discovery of angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) has provided novel and important insights into the molecular mechanisms of blood vessel formation. Ang1 and Ang2 bind with similar affinity to the endothelial cell tyrosine kinase receptor Tie2. Our purpose was to assess the potential role of the Ang/Tie2 system in physiological and pathological angiogenesis in the ovary. Methods:Ang1, Ang2, and Tie2 gene expression in 14 normal ovaries with corpus luteum (CL) and in 19 cases of ovarian cancer were analyzed by polymerase chain reaction of RNA after reverse transcription. The level of each gene expression was presented by the relative yield of each gene to the β₂-microglobulin gene, respectively. Furthermore, cellular distribution of Ang1 and Ang2 mRNA was examined by in situ hybridization, and localization of Tie2 was studied by immunochemistry. Results: The Ang1, Ang2, and Tie2 gene expression in normal ovary with CL ranged from 0.18 to 1.06 (median 0.54), 0.31–2.64 (median 1.01), and 0.10–0.47 (median 0.20), respectively. The expression of these same genes in ovarian cancer ranged from 0.06 to 0.75 (median 0.14), 0.69–1.59 (median 1.12), and 0.04–0.35 (median 0.15), respectively. Ang1 gene expression in normal ovary with CL was significantly higher than that in ovarian cancer (p = 0.0004). The gene expression levels of Ang2 and Tie2 were statistically the same in both groups. There was a significant correlation between Ang1 gene expression and Tie2 gene expression in normal ovary with CL (r = 0.619, p = 0.018). No such significant correlation was found in ovarian cancer. Moreover, Ang2 gene expression showed no significant correlation with the Tie2 gene expression either in normal ovary with CL or in ovarian cancer. Transcripts for Ang1 were observed in CL cells and endothelial cells around CL, and in tumor cells and endothelial cells at the periphery of tumor invasion. Ang2 transcripts were expressed in the same patterns. Tie2 expression was positive primarily in the endothelial cells around CL and in those at the periphery of tumor invasion. Conclusion: Our results indicate that there is a difference in the Ang/Tie2 gene expression between physiological and pathological angiogenesis in the ovary. This finding may aid in the development of new therapeutic interventions for ovarian cancer.

The blood vessels development, morphogenesis and blood circulation are three ontologic groups highly up-regulated in porcine oocytes before in vitro maturation

“…ANGPT2 modulates angiogenesis in a cooperative manner with another important angiogenic factor, VEGF [14][15]. Furthermore, Hata et al (2002) suggested that there is a difference in the angiopoietin/Tie2 gene expression between physiological and pathological angiogenesis in the ovary [16]. Angiopoietin-like proteins (ANGPTLs) are a family of proteins structurally similar to the angiopoietins.…”

Angiogenic Switch of Angiopietins-Tie2 System and Its Prognostic Value in Bladder Cancer

“…Elevated Tie2 levels were detected in breast, gastric, and endometrial cancers (35 -37). In contrast, decreased Tie2 level was found in ovarian carcinoma and lung cancer (10,38). Some authors found correlation between Tie2 level and malignancy (e.g., in gastric cancer), whereas others in ovarian cancer did not (11,39).…”

Final results of a phase 3 study of trebananib plus weekly paclitaxel in recurrent ovarian cancer (TRINOVA-1): Long-term survival, impact of ascites, and progression-free survival-2

“…HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PFS-2, time to second progression event; TSST, time to second subsequent treatment. (8) 101 (22) Treatment-emergent adverse events with ≥5% difference in incidence between arms Localized edema 122 (27) One approach to addressing these challenges suggested by the EMA is to assess the durability of treatment effect by evaluating postprogression endpoints such as PFS-2 and time to second subsequent therapy (TSST) [27,30]. The TRINOVA-1 study is among the first to demonstrate that an antiangiogenic therapy significantly delayed the time to second progression (i.e.…”

“…The angiopoietin axis is distinct from the VEGF pathway; angiopoietin 1 (Ang1) and angiopoietin 2 (Ang2) regulate angiogenesis and vascular remodeling by interacting with the endothelial receptor tyrosine kinase, Tie2 [5]. Evidence suggests that the Ang2 pathway plays a role in the pathophysiology of ovarian cancer [6][7][8] and upregulation of Ang2 is correlated with poor prognosis in women with recurrent ovarian cancer [9]. Several antiangiogenic agents that target the VEGF pathway have been shown to improve progression-free survival (PFS) in patients with ovarian cancer; however, a statistically significant improvement in OS has not been demonstrated [10][11][12][13][14][15][16][17][18].…”