Vascular co‐option and vasculogenic mimicry mediate resistance to antiangiogenic strategies

Abstract

Background:The concept that all the tumors need the formation of new vessels to grow inspired the hypothesis that inhibition of angiogenesis would have led to "cure" cancer. The expectancy that this type of therapy would have avoided the insurgence of resistance was based on the concept that targeting normal vessels, instead of the cancer cells which easily develop new mutations, would have allowed evasion of drug caused selection is, however, more complex as it was made apparent by the discovery of nonangiogenic tumors. At the same time an increasing number of trials with antiangiogenic drugs were coming out as not as successful as expected, mostly because of the appearance of unexpected resistance.Recent Findings: Among the several different mechanisms of resistance to antiangiogenic treatment by now described, we review the evidences that vascular co-option and vasculogenic mimicry by nonangiogenic tumors are effectively two of such mechanisms. We focused on reviewing exclusively the study, both clinical and preclinical, that offer a demonstration that vascular co-option and vasculogenic mimicry are effectively two mechanisms of both intrinsic and acquired resistance. Conclusion:The discovery that vascular co-opting and vasculogenic mimicry are two ways of escaping antiangiogenic treatment, prompts the need for a better understanding of this phenomenon in order to improve cancer treatment.

Antiangiogenic Properties of Axitinib versus Sorafenib Following Sunitinib Resistance in Human Endothelial Cells—A View towards Second Line Renal Cell Carcinoma Treatment

“…However, no statistically significant difference among the three drugs is apparent with regard to progression free survival [ 35 ]. An animal study has revealed blockage of angiogenesis under cabozantinib, whilst tumors become more infiltrative and escape treatment [ 36 ]. These findings point to a mechanism similar to the one shown for sorafenib in counteracting sunitinib resistance by interfering with pathways connected to angiogenesis, but not to cell growth.…”

Vasculogenic Mimicry Formation Predicts Tumor Progression in Oligodendroglioma

“…In other words, patients with VM formation were more likely to suffer from tumor relapse, suggesting that VM may promote tumor progression. It has been reported that chemotherapeutic stress can promote VM, which in turn mediates resistance to anti-angiogenic therapy [35,36]. VM formation has been blamed for the unexpected adverse outcome after anti-angiogenic treatment in the triple-negative breast cancer, uveal melanoma and ovarian cancer [37][38][39].…”

The Anti-VEGF(R) Drug Discovery Legacy: Improving Attrition Rates by Breaking the Vicious Cycle of Angiogenesis in Cancer

“…Alternative mechanisms of tumor vasculature, including intussusceptive microvascular growth (IMG), vasculogenic mimicry, and vascular co-option, are involved in resistance to anti-angiogenic therapies [ 32 , 33 ], but again, anti-angiogenic treatments have been so far provided without evaluating whether the tumors are angiogenic or not or in which proportions a tumor is angiogenic or not angiogenic [ 34 ]. IMG, in which the capillary network increases its complexity by insertion of a multitude of transcapillary pillars, has been observed in different human tumors, including melanoma, colon and breast carcinoma, lymphoma, and glioblastoma [ 32 ].…”