Anti-angiogenic Therapy in Cancer: Downsides and New Pivots for Precision Medicine

Abstract

Primary solid tumors originate close to pre-existing tissue vasculature, initially growing along such tissue blood vessels, and this phenomenon is important for the metastatic potential which frequently occurs in highly vascularized tissues. Unfortunately, preclinic and clinic anti-angiogenic approaches have not been very successful, and multiple factors have been found to contribute to toxicity and tumor resistance. Moreover, tumors can highlight intrinsic or acquired resistances, or show adaptation to the VEGF-targeted therapies. Furthermore, different mechanisms of vascularization, activation of alternative signaling pathways, and increased tumor aggressiveness make this context even more complex. On the other hand, it has to be considered that the transitional restoration of normal, not fenestrated, microvessels allows the drug to reach the tumor and act with the maximum efficiency. However, these effects are time-limited and different, depending on the various types of cancer, and clearly define a specific “normalization window.” So, new horizons in the therapeutic approaches consist on the treatment of the tumor with pro- (instead of anti-) angiogenic therapies, which could strengthen a network of well-structured blood vessels that facilitate the transport of the drug.

Anti‐angiogenic effect of quercetin and its 8‐methyl pentamethyl ether derivative in human microvascular endothelial cells

“…The imbalance among the molecules that coordinate the neoangiogenesis is often the cause of inflammatory, immune, infectious and malignant disorders . The newly formed blood vessels are fenestrated, permeable, tortuous and heterogeneous both in their structure and efficiency of perfusion . Aberrant angiogenesis , in fact, is responsible for several ocular diseases, such as choroidal subretinal neovascularization, retinopathy of prematurity, proliferative diabetic retinopathy and retinoblastoma .…”

“…In phase I‐ or II‐ clinical trials for cancer treatment, soluble decoy receptors, ligands sequesters, kinase activity inhibitors, several angiogenesis inhibitors were administered after their approval by the United States Food and Drug Administration . Unfortunately, serious side effects were observed with the currently available anti‐angiogenic drugs, which limited their continuous use . For these reasons, a growing interest in identifying natural health‐safe products is emerging.…”

“…38 The newly formed blood vessels are fenestrated, permeable, tortuous and heterogeneous both in their structure and efficiency of perfusion. 43 Aberrant angiogenesis, in fact, is responsible for several ocular diseases, such as choroidal subretinal neovascularization, retinopathy of prematurity, proliferative diabetic retinopathy 4 and retinoblastoma. 44,45 The VEGF family (VEGFA, VEGFB, VEGFC, VEGFD and placental growth factor [PlGF]) and their cognate receptors are the leading molecular players in angiogenesis.…”

“…Results are shown as per cent of control for total length and branch point, respectively anti-angiogenic drugs, which limited their continuous use. 43 For these reasons, a growing interest in identifying natural health-safe products is emerging. These novel phytochemicals contain a variety of anti-angiogenic compounds, which could be used for developing anti-angiogenic drugs.…”

Neem Leaf Glycoprotein Restrains VEGF Production by Direct Modulation of HIF1α-Linked Upstream and Downstream Cascades

“…Targeting VEGF by many agents, including anti-VEGF monoclonal antibodies, have been developed showing promising effect in vitro, but their effects in vivo settings or in cancer patients are limited due several adverse effects, such as hypertension, gastrointestinal-perforation, bleeding, impairment of wound healing etc. (18). On the other hand, several plant based natural molecules or anti-oxidants show promises in reducing VEGF but their mechanisms are largely unknown.…”