Resistance to antiangiogenic treatments: A review

Angiogenesis (blood vessel formation) is essential for tissue growth in both normal development and physiology and in some diseases such as inflammation and cancer. Angiogenesis is a hallmark of cancer, however, it took many years to establish its importance. Ever since Judah Folkman’s seminal publications in 1971, that clearly showed cancer angiogenesis-dependence, researchers have been investigating the mechanisms of angiogenesis and how to block them. This search blossomed with the finding of inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathways. These new molecules and monoclonal antibodies showed therapeutic efficacy in both the laboratory and human clinical settings and hopes rose. Unfortunately, the benefits did not reach all the patients and they were short-lived: sooner or later tumors resumed their growth and proliferation and became refractory to further antiangiogenic treatments. Worse, antiangiogenic treatments seemed to increase metastatic risk. The development of treatment resistance is still one of the main causes of failure in cancer therapy. Antiangiogenic treatments are no exception and a deeper knowledge of the mechanisms of resistance is necessary if we intend to delay or eliminate them.Two different mechanisms have been identified: primary or evasive resistance and secondary or adaptive resistance.The existence of these two mechanisms led to the non-mainstream conclusion, now shared by many authors, that there are at least two different angiogenic pathways: one is the canonical VEGF- VEGF receptor (VEGFR) axis and others, which are independent of this axis and not fully known. Primary resistance works exclusively through these independent pathways, while secondary resistance, which initially is VEGF-VEGFR-dependent, switches to the other pathways becoming non-responsive to classical antiangiogenic treatments. For the time being, the clear identification of these other pathways belongs to the realm of hypothesis. However, there is enough experimental evidence supporting their existence. We will discuss this evidence as a central issue in antiangiogenic treatment resistance. Some non-conventional pharmacologic strategies against resistance will also be considered.