Redefining the role(s) of endothelial αvβ3-integrin in angiogenesis

Abstract

For nearly two decades now, the RGD (Arg-Gly-Asp)-binding αvβ3-integrin has been a focus of anti-angiogenic drug design. These inhibitors are well-tolerated, but have shown only limited success in patients. Over the years, studies in β3-integrin-knockout mice have shed some light on possible explanations for disappointing clinical outcomes. However, studying angiogenesis in β3-integrin-knockout mice is a blunt tool to investigate β3-integrin's role in pathological angiogenesis. Since establishing our laboratory at University of East Anglia (UEA), we have adopted more refined models of genetically manipulating the expression of the β3-integrin subunit. The present review will highlight some of our findings from these models and describe how data from them have forced us to rethink how targeting αvβ3-integrin expression affects tumour angiogenesis and cancer progression. Revisiting the fundamental biology behind how this integrin regulates tumour growth and angiogenesis, we believe, is the key not only to understanding how angiogenesis is normally co-ordinated, but also in success with drugs directed against it.

Complementary, Selective PET Imaging of Integrin Subtypes α5β1 and αvβ3 Using 68Ga-Aquibeprin and 68Ga-Avebetrin

“…Thus, 68 Ga-aquibeprin and 68 Ga-avebetrin are recommendable for a wide variety of in vivo studies, for example, on the roles and interplay of integrins a 5 b 1 and a v b 3 in angiogenesis and tumor progression, as well as their temporal expression patterns during myocardial infarction healing. Necessity for such work is evident not only from a complete lack of in vivo data on integrin a 5 b 1 expression in humans, but also from the still unclear role of integrin a v b 3 in angiogenesis, cancer development, and metastasis (23).…”

“…On the other hand, a v b 3 integrin expression is not restricted to endothelial cells during angiogenesis, but it is also frequently presented on the surface of tumor cells or macrophages. Altogether, collected evidence suggests that a v b 3 integrin is neither strictly necessary for angiogenesis, nor is its expression a reliable biomarker for angiogenic activity (23).…”

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

“…The complexity by which ␣v␤3 regulates angiogenesis is illustrated by the fact that this receptor may exhibit both pro-and anti-angiogenic functions (7)(8)(9)(10)(11)(12)(13)(14)(15). Studies suggest that the distinct biological responses stimulated by binding to ␣v␤3 may depend on many factors, including the mechanical and biochemical features of the particular ligands, the cell types within which ␣v␤3 is expressed, as well as the concentration and manner by which the ligands are presented to the receptor (7-9, 24 -27).…”

“…These unexpected findings provide evidence of a negative role for the VEGF/VEGFR signaling during new vessel development (6). Similarly, studies have provided evidence for both a positive and a negative role for integrin ␣v␤3 in angiogenesis (7)(8)(9). For example, multiple pro-angiogenic roles have been proposed for ␣v␤3 as cyclic arginine-glycine-aspartic acid (RGD)-containing peptides and antibodies targeting this integrin inhibit angiogenesis in animal models (10 -12).…”

“…Interestingly, distinct ␣v␤3 ligands may stimulate opposing biological outcomes (7)(8)(9)(10)(11)(12)(13)(14)(15). For example, certain NC1 domains of collagen may bind ␣v␤3 and induce pro-apoptotic responses, whereas binding of other ␣v␤3 ligands may promote cell growth and survival (19 -22).…”