**3.1 JAM proteins regulate endothelial angiogenesis**

As already alluded to, JAM proteins are highly expressed on endothelial cells and have been crucially implicated in the control of barrier function and cell motility. In the context of cancer, however, endothelial cells assume a new importance via the development of neovascularisation sites to support growing tumours (Hanahan & Folkman, 1996). This section will review the evidence currently linking JAM proteins to angiogenesis as a contributory mechanism to cancer progression.

Angiogenesis in response to enhanced growth factor signalling is of particular relevance in tumour microenvironments. A body of work from Naik *et al* has convincingly shown an important role for JAM-A in angiogenesis induced by basic fibroblast growth factor (bFGF). Specifically, bFGF signalling facilitates the disassembly of an inhibitory complex between JAM-A and αvβ3 integrin, permitting JAM-A-dependent activation of MAP kinase which leads to endothelial tube formation, a surrogate for angiogenesis (Naik *et al*., 2003). JAM-A has also been shown to activate extracellular signal-related kinase (ERK) signalling in response to bFGF, facilitating endothelial migration (Naik *et al*., 2003) in a matrix-specific context (Naik & Naik, 2006). *In vivo*, JAM-A expression has been linked with the very early stages of murine embryonic vasculature development (Parris *et al*., 2005), and although deletion of JAM-A appears to be dispensable for vascular tree development, homozygous JAM-null mice were found to be incapable of supporting FGF-2-induced angiogenesis in isolated aortic ring assays (Cooke *et al*., 2006). In the context of tumour neovascularisation, others have reported reduced angiogenesis in a model of pancreatic carcinoma in JAM-Anull mice (Murakami *et al*., 2010).

Other JAM family members appear to contribute similarly to angiogenesis; with functional blockade of JAM-C being shown to decrease aortic ring angiogenesis and block angiogenesis in hypoxic vessels of the murine retina (Lamagna *et al*., 2005; Orlova *et al*., 2006). Furthermore, soluble JAM-C shed into the serum of patients with inflammatory conditions (presumably following cleavage by ADAM enzymes) was noted to induce endothelial tube formation in a Matrigel model (Rabquer *et al*., 2010). An interesting dichotomy, however, is that amplification of JAM-B in a trisomy-21 mouse model of Down's syndrome has been linked with reductions in VEGF-induced angiogenesis and thus anti-tumour effects in a lung carcinoma model in these mice (Reynolds *et al*., 2010).

Taken together, these studies illustrate that by influencing angiogenic functions in endothelial cells, JAMs may indirectly influence the ability of tumours to survive and progress. While there appears to be a consensus that JAMs –A and –C activate signalling cascades that promote angiogenesis, it is possible that clear roles for the other family members in the regulation of angiogenesis will also emerge in time. It is tempting to speculate that pharmacological antagonism of JAMs will show promise as an option for blocking tumour progression, similar to the VEGF-A-neutralizing antibody bevacizumab (avastin) (Van Meter & Kim, 2010).
