Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma

Abstract

Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) that is associated with elevated interleukin-6 (IL-6) expression, resistance to chemotherapy, and increased mortality. Although bevacizumab (Bev) is a widely used anti-angiogenic agent for EOC, the efficacy of Bev and the role of IL-6 in modulating angiogenesis in OCCC are unknown. We performed tube formation assays using human umbilical vein endothelial cells (HUVEC) cultured in OCCC cell-conditioned medium and using cells directly co-cultured with OCCC cells. We observed that IL-6 inhibition significantly mitigated the ability of Bev to impede tube formation in both cases. Furthermore, IL-6 blockade disrupted the anti-angiogenic efficacy of Bev and its concomitant anti-tumor activity. In addition, IL-6 inhibition resulted in a significant increase in angiopoietin-1 (Ang1) secretion and decreased vascular endothelial growth factor (VEGF) expression. Clinical specimens also exhibited this reciprocal relationship between IL-6 and Ang1 expression. Finally, depletion of Ang1 abrogated the effects of IL-6 inhibition on Bev activity, demonstrating that IL-6 supports the anti-angiogenic activity of Bev by suppressing Ang1 expression and promoting dependence on VEGF for angiogenesis. Altogether, our data suggest that OCCC tumors with high IL-6 levels are candidates for Bev therapy.

Role of human dural fibroblasts in the angiogenic responses of human endothelial cells: An in vitro dural model and the application of lab‐on‐a‐chip for EDAS

“…IL‐8, a chemokine with defining CXC amino acid motif, is known to regulate angiogenesis by modulating endothelial proliferation and survival 33,34 . IL‐6, a proangiogenic factor, has been shown to influence angiogenesis 35,36 . A study has shown that the overexpression of IL‐6 in transgenic mice induces hypervascularization of the cerebellum and enhances the production of vascular endothelial growth factor (VEGF) by tumor cells 36 .…”

“…33,34 IL-6, a proangiogenic factor, has been shown to influence angiogenesis. 35,36 A study has shown that the overexpression of IL-6 in transgenic mice induces hypervascularization of the cerebellum and enhances the production of vascular endothelial growth factor (VEGF) by tumor cells. 36 CCLs, a family of chemokines with two adjacent cysteines (CC motif), include CCL-2 and CCL-5.…”

Randomized, double-blind, placebo-controlled, crossover trial of oral doxycycline for epistaxis in hereditary hemorrhagic telangiectasia

“…An increased susceptibility to infections has been observed in mice with HHT mutations, possibly due to defects in phagocytic activity, alterations in leukocyte recruitment, and a reduction in proinflammatory cytokines, including IL-6 [43]. However, IL-6 has also been found to enhance anti-angiogenic therapy in certain diseases, such as ovarian cancer, by suppressing ANG-1 expression and promoting dependence on VEGF for angiogenesis [44]. Thus, the higher IL6 levels among responders at baseline may have supported the anti-angiogenic properties of doxycycline, leading to an improvement in epistaxis.…”

Convection-Enhanced Delivery of Antiangiogenic Drugs and Liposomal Cytotoxic Drugs to Heterogeneous Brain Tumor for Combination Therapy

“…The antiangiogenic effect is reflected by the reduction of blood vessel diameter. Although blood vessels shirk significantly in response to the antiangiogenic drugs [ 66 ], both the vessel diameter and length can change [ 67 ]. Disappointingly, there is no such model to define the relationship between the changes in morphological characteristics of microvasculature and the antiangiogenic drug concentration.…”

“… is the surface area of the microvasculature wall, defined as , where and are the mean radius and mean length of the blood vessels, respectively. Studies using microscopy imaging demonstrated that antiangiogenic drugs can not only successfully lead to the shrinkage of microvasculature, but also reduce the blood vessel length [ 66 , 67 ]. However, given there is no kinetic model to describe the relationship between the concentration of antiangiogenic drugs and the radius and length of blood vessels, it is further assumed that only the vessel radius reduces in response to the antiangiogenic drugs.…”