Resistance to Anti-angiogenic Therapies: A Mechanism Depending on the Time of Exposure to the Drugs

Abstract

Angiogenesis, the formation of new blood vessels from preexisting one, represents a critical process for oxygen and nutrient supply to proliferating cells, therefore promoting tumor growth and metastasis. The Vascular Endothelial Growth Factor (VEGF) pathway is one of the key mediators of angiogenesis in cancer. Therefore, several therapies including monoclonal antibodies or tyrosine kinase inhibitors target this axis. Although preclinical studies demonstrated strong antitumor activity, clinical studies were disappointing. Antiangiogenic drugs, used to treat metastatic patients suffering of different types of cancers, prolonged survival to different extents but are not curative. In this review, we focused on different mechanisms involved in resistance to antiangiogenic therapies from early stage resistance involving mainly tumor cells to late stages related to the adaptation of the microenvironment.

Keywords: VEGFA; anti-angiogenic treatments; combined therapies; resistance; tumor microenvironment.

FIGURE 1

The physiological angiogenic cascade. Stable vessels (A) undergo a vascular permeability allowing extravasation of plasma proteins (B). MMPs degrate the extracellular matrix liberating growth factors (C). ECs proliferate and migrate (D) and undergo morphogenesis and assemble as lumen-bearing cords (E).

FIGURE 2

The adaptation to anti-angiogenic therapies; a clock ticking mechanism. Immediate-early resistance occuring within minutes to few hours following anti-angiogenic treatment involved angiogenic redundancy, glycosylation of VEGFR2, metabolic adaptation and sequestration of drugs in lysosomes inducing incomplete autophagy. Early resistance occurs during the following days after treatment and involved BMDCs, stromal cells recruitment into the tumor mass and ECs. The heterogeneity of ECs mediates resistance. Finally, within months following therapy, tumors adopt neovascularization strategies and increased lymphangiogenesis triggering metastasis and poor outcome in patients.