Vascular Integrins: Therapeutic and Imaging Targets of Tumor Angiogenesis

Abstract

Cells, including endothelial cells, continuously sense their surrounding environment and rapidly adapt to changes in order to assure tissues and organs homeostasis. The extracellular matrix (ECM) provides a physical scaffold for cell positioning and represents an instructive interface allowing cells to communicate over short distances. Cell surface receptors of the integrin family emerged through evolution as essential mediators and integrators of ECM-dependent communication. In preclinical studies, pharmacological inhibition of vascular integrins suppressed angiogenesis and inhibited tumor progression. alpha(V)beta(3) and alpha(V)beta(5) were the first integrins targeted to suppress tumor angiogenesis. Subsequently, additional integrins, in particular alpha(1)beta(1), alpha(2)beta(1), alpha(5)beta(1), and alpha(6)beta(4), emerged as potential therapeutic targets. Integrin inhibitors are currently tested in clinical trials for their safety and antiangiogenic/antitumor activity. In this chapter, we review the role of integrins in angiogenesis and present recent advances in the use of integrin antagonists as potential therapeutics in cancer and discuss future perspectives.

β1 Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy

“…Due to their expression on tumor cells and endothelium, a large body of preclinical and clinical work on αvβ 3 /β 5 integrin inhibition indicates substantial tumor cell death in a variety of tumor entities, such as glioblastoma and lung cancer, in addition to providing imaging possibilities prior and during the course of therapy. Most importantly, all studies accomplished to date come to the same conclusion: monotherapeutic anti-integrin approaches are by far less efficient alone than in combination with chemotherapy and, particularly, radiotherapy, a strategy in line with modern multimodal treatment regimes (11,22,47).…”

“…Targeting the epidermal growth factor receptor using inhibitory antibodies caused significant improvement of both locoregional tumor control and overall survival of patients with HNSCC (7). In addition to transmembrane growth factor receptors, recent studies provide evidence for integrins as potential cancer targets (8)(9)(10)(11)(12). Similar to other integrin receptors, β 1 integrins are overexpressed in various tumor entities, including HNSCCs (13,14), and have been described as strong promoters of HNSCC development and tumorigenesis and essential determinants of tumor cell resistance to therapy (15).…”

Nonproteolytic Properties of Murine Alternatively Spliced Tissue Factor: Implications for Integrin-Mediated Signaling in Murine Models

“…As the levels of masTF rise during pancreatic cancer progression (Figure 1), it is worth noting that αvβ3-the integrin known to interact with hasTFplays a particularly major role in pancreatic cancer pathobiology. The αvβ3 dimer, a major RGD receptor, is perceived to exert its tumor-promoting effects through adhesion-mediated modulation of tumor cell invasiveness and proliferative/migratory capacity, as well as promoting metastatic neovascularization: compared with normal microvessels, metastatic microvessels express higher levels of this integrin (43). However, αvβ3 is also expressed in PDAC cells and was reported to play a significant adhesion-independent role in pancreatic cancer (44).…”

18F-FPPRGD2 and 18F-FDG PET of Response to Abraxane Therapy

“…Integrins are composed of a family of heterodimeric glycoproteins responsible for the regulation of cellular activation, migration, proliferation, survival, and differentiation (13). One of the most important members of this receptor class is integrin a v b 3 , which is preferentially expressed on several types of cancer cells, including melanoma, glioma, and ovarian and breast cancers (14).…”