Classical VEGF, Notch and Ang signalling in cancer angiogenesis, alternative approaches and future directions

Abstract

Angiogenesis is the formation of new vessels starting from pre-existing vasculature. Tumour environment is characterized by ‘aberrant angiogenesis’, whose main features are tortuous and permeable blood vessels, heterogeneous both in their structure and in efficiency of perfusion and very different from normal vessels. Therapeutic strategies targeting the three pathways chiefly involved in tumour angiogenesis, VEGF, Notch and Ang signalling, have been identified to block the vascular supply to the tumour. However, phenomena of toxicity, development of primary and secondary resistance and hypoxia significantly blunted the effects of anti-angiogenic drugs in several tumour types. Thus, different strategies aimed to overcome these problems are imperative. The focus of the present review was some principal ‘alternative’ approaches to classic antiangiogenic therapies, including the cyclooxygenase-2 (COX-2) blockade, the use of oligonucleotide complementary to the miRNA to compete with the mRNA target (antimiRs) and the inhibition of matrix metalloproteinases (MMPs). The role of blood soluble VEGFA as a predictive biomarker during antiangiogenic therapy in gastric, ovarian and colorectal cancer was also examined.

Novel noncanonical regulation of soluble VEGF/VEGFR2 signaling by mechanosensitive ion channel TRPV4

“…Our results reinforce TRPV4 as a negative regulator of angiogenesis, most likely by controlling VEGFR2 localization/ activation, indicating that angiogenesis is regulated by a tight co-ordination between mechanical and soluble (growth factor) signaling. In contrast to the current strategy of inhibiting angiogenesis by targeting VEGF and its receptors (1,(3)(4)(5), our study proposes that TRPV4 is an alternate VEGF-independent strategy to target pathologic angiogenic disorders, such as cancer and retinopathy, which are usually characterized by enhanced VEGFR2 expression/activity. Importantly, targeting a negative regulator of angiogenesis, such as TRPV4, could also offer a potential therapeutic mechanism to enhance angiogenesis in conditions such as ischemic heart disease to improve revascularization.…”

Vascular endothelial growth factor (VEGF) impairs the motility and immune function of human mature dendritic cells through the VEGF receptor 2‐RhoA‐cofilin1 pathway

“…In addition, the migration and immune function of mDCs were inhibited by Y27632 and P‐COF1 BP, which could be due to the reduced actin polymerization and disappearance of dendrites . Vascular endothelial growth factor signaling is also transduced by way of several other intracellular signaling pathways, including Erk, p38MAPK, or the serine/threonine protein kinase Akt, leading to increased cell proliferation, survival, permeability, and migration of endothelial cells . It was reported that VEGF can enhance the phosphorylation of Erk1/2, but not those of p38MAPK or Akt in mDCs .…”

Retinoic acid signaling in vascular development

“…For example, in the central nervous system (CNS) neural-derived signals stimulate the formation of a high density vascular plexus and development of a blood-brain barrier (BBB) (R Daneman et al, 2009; Haigh et al, 2003; Stenman et al, 2008). Many of the key factors that orchestrate embryonic vascular development such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), Wnt-β-catenin and Notch, have been identified and their elucidation has facilitated therapies for several diseases, most notably anti-tumor angiogenesis therapies (reviewed in (Adams & Alitalo, 2007; Caporarello et al, 2017; Giacomini et al, 2016; Reis & Liebner, 2013). …”