Rada Miran, Kapelanski-Lamoureux Audrey, Tsamchoe Migmar, Petrillo Stephanie, Lazaris Anthoula, Metrakos Peter
Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Cancers (Basel). 2022 May 21;14(10):2540. doi: 10.3390/cancers14102540.
Resistance to anti-angiogenic therapy is a major challenge in the treatment of colorectal cancer liver metastases (CRCLMs). Vessel co-option has been identified as a key contributor to anti-angiogenic therapy resistance in CRCLMs. Recently, we identified a positive correlation between the expression of Angiopoietin1 (Ang1) in the liver and the development of vessel co-opting CRCLM lesions in vivo. However, the mechanisms underlying its stimulation of vessel co-option are unclear. Herein, we demonstrated Ang1 as a positive regulator of actin-related protein 2/3 (ARP2/3) expression in cancer cells, in vitro and in vivo, which is known to be essential for the formation of vessel co-option in CRCLM. Significantly, Ang1-dependent ARP2/3 expression was impaired in the cancer cells upon Tie2 or PI3K/AKT inhibition in vitro. Taken together, our results suggest novel mechanisms by which Ang1 confers the development of vessel co-option in CRCLM, which, targeting this pathway, may serve as promising therapeutic targets to overcome the development of vessel co-option in CRCLM.
抗血管生成治疗耐药是结直肠癌肝转移（CRCLM）治疗中的一项重大挑战。血管共选择已被确定为CRCLM中抗血管生成治疗耐药的关键因素。最近，我们发现肝脏中血管生成素1（Ang1）的表达与体内血管共选择CRCLM病变的发展呈正相关。然而，其刺激血管共选择的潜在机制尚不清楚。在此，我们在体外和体内证明Ang1是癌细胞中肌动蛋白相关蛋白2/3（ARP2/3）表达的正调节因子，已知该蛋白对CRCLM中血管共选择的形成至关重要。重要的是，体外抑制Tie2或PI3K/AKT后，癌细胞中Ang1依赖的ARP2/3表达受损。综上所述，我们的结果提示了Ang1促进CRCLM中血管共选择发展的新机制，针对该途径可能成为克服CRCLM中血管共选择发展的有前景的治疗靶点。
