Moving beyond VEGF for anti-angiogenesis strategies in gynecologic cancer

Abstract

Gynecologic cancer is a major burden in both developed and developing countries. Almost a half million deaths from gynecologic cancer are reported each year. Understanding the molecular biology of cancer is a principle resource leading to the identification of new potential therapeutic targets, which may be parlayed into novel therapeutic options in gynecologic cancer. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase, which plays a pivotal role in many aspects of malignant growth including cancer cell survival, migration, invasion, angiogenesis and metastasis. Various human cancer tissues have demonstrated high expression of FAK or activated FAK, which has been correlated with survival of cancer patients. Among gynecologic cancers, reports have emerged demonstrating that FAK is involved in the pathogenesis of ovarian, endometrial, and cervical cancers. In addition, the polycomb group protein enhancer of Zeste homologue 2 (EZH2), Dll4/notch and EphA2 has also emerged as important regulators of endothelial cell biology and angiogenesis. Herein, we review the role of these new targets in tumor angiogenesis and the rationale for further clinical development.

Figure 1

Molecular pathways of FAK regulation and sites of phosphorylation.

Figure 2

Angiogenesis pathway of FAK, EZH2 and Dll4/Notch in cancer-associated endothelial cells. FAK is stimulated by integrin and Src associated VEGF1 receptor. FAK regulates VEGF transcription, angiogenic cytokines and pericyte migration. VEGF-A promotes EZH2 and Dll4/Notch through VEGF2 receptor. Endothelial cell migration and tube formation are regulated by EZH2. Both EZH2 and Dll4/Notch inhibit vessel maturation.