Vessel pruning or healing: endothelial metabolism as a novel target?

Abstract

Introduction: Antiangiogenic drugs were originally designed to starve tumors by cutting off their vascular supply. Unfortunately, when these agents are used as monotherapy or in combination with chemotherapy, they provide only modest survival benefits in the order of weeks to months in most cancer patients. Strategies normalizing the disorganized tumor vasculature offer the potential to increase tumor perfusion and oxygenation, and to improve the efficacy of radio-, chemo- and immunotherapy, while reducing metastasis. Areas covered: This review discusses tumor vascular normalization (TVN) as an alternative strategy for anti-angiogenic cancer treatment. We summarize (pre)-clinical strategies that have been developed to normalize tumor vessels as well as their potential to enhance standard therapy. Notably, we describe how targeting endothelial cell metabolism offers new possibilities for antiangiogenic therapy through evoking TVN. Expert opinion: Several drugs targeting VEGF signaling are now clinically used for antiangiogenic cancer treatment. However, excessive blood vessel pruning impedes perfusion and causes tumor hypoxia, known to promote cancer cell dissemination and impair radio-, chemo- and immunotherapy. Normalized vessels lessen tumor hypoxia, impair cancer cell intravasation and enhance anticancer treatment. New data indicate that targeting endothelial cell metabolism is an alternative strategy of antiangiogenic cancer treatment via promotion of TVN.

Anti-Angiogenics: Their Value in Colorectal Cancer Therapy

“…Hypoxic tumor cells stimulate the overproduction of pro-angiogenic growth factors such as VEGF, inducing an 'angiogenic switch'. This imbalance of growth factors leads to the formation of chaotic tumor blood vessels with a leaky endothelial barrier [9]. Of note, the magnitude of VEGF expression and a high blood vessel density within the tumor tissue are associated with poor prognosis in CRC and many other tumor types [11].…”

“…Growth at the primary tumor site, local tissue infiltration, and distant metastasis of CRC have been demonstrated to be highly dependent on angiogenic vessel formation [9,10]. Hypoxic tumor cells stimulate the overproduction of pro-angiogenic growth factors such as VEGF, inducing an 'angiogenic switch'.…”

“…However, the development of conventional anti-angiogenic drugs revealed that primary or evasive resistance arises as a major problem, and thus the therapeutic efficacy in most patients is limited to a short time frame [12,36]. Preclinical models indicate that drug-induced normalization of the vascular network ('healing' of the chaotic vessel network) within the tumor milieu leads to an improved access of chemotherapeutics and better therapeutic efficacy [9,37,38]. Indeed, shorttime vascular normalization in tumor tissue was also observed in cancer patients treated with anti-angiogenics, but attempts to prolong the state of blood vessel normalization have never been undertaken within clinical trials [9].…”

“…Preclinical models indicate that drug-induced normalization of the vascular network ('healing' of the chaotic vessel network) within the tumor milieu leads to an improved access of chemotherapeutics and better therapeutic efficacy [9,37,38]. Indeed, shorttime vascular normalization in tumor tissue was also observed in cancer patients treated with anti-angiogenics, but attempts to prolong the state of blood vessel normalization have never been undertaken within clinical trials [9]. Thus, investigations on the capability of anti-angiogenic drugs to induce prolonged and sustained vascular normalization in combination with other therapeutic strategies such as chemo-, radio-, or immunotherapy are warranted.…”

Notch signaling and taxis mechanisms regulate early stage angiogenesis: A mathematical and computational model

“…EC metabolism is strongly connected with this cycling dynamics at the tip of sprouts [39], and it is determinant to vascular patterning, pruning and sprouting [40][41][42]. The ability of ECs to rearrange themselves is essential for vessel remodelling [31].…”