Less is more

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New research indicates that inhibition of the Notch pathway paradoxically increases endothelial cell proliferation and tumor vascular density but inhibits tumor growth.

When it comes to angiogenesis and tumour growth, less might in fact be more. Research by Gavin Thurston and colleagues and Minhong Yan and colleagues indicates that inhibition of the Notch pathway paradoxically increases endothelial cell proliferation and tumour vascular density but inhibits tumour growth.

The two groups examined the role of Delta-like ligand 4 (DLL4), a ligand for the Notch receptor, using mouse xenograft models. Thurston and colleagues activated or inhibited Notch signalling in the tumour stroma by enforced retroviral expression of either DLL4 or DLL4 fused to the Fc region of immunoglobulin G1 (DLL4–Fc), respectively, in rat C6 glioma cells. Yan and colleagues generated a neutralizing DLL4 antibody (YW152F) that blocked the interaction of Notch with DLL4 but not with other Notch ligands.

Thurston and colleagues subcutaneously implanted the C6 glioma cells that expressed either DLL4 or DLL4–Fc in mice. Tumours derived from C6 DLL4–Fc cells showed increased vascular density but were smaller than control C6 tumours. By contrast, C6 DLL4 tumours had slightly decreased vascular density and were the same size as control tumours. Furthermore, systemic adenoviral delivery of DLL4–Fc at the time C6 glioma cells were implanted in mice decreased tumour size by about 70%, and a polyclonal antibody to DLL4 also inhibited tumour growth. Similarly, Yan and colleagues used their YW152F antibody in several different mouse tumour models. The size of xenograft tumours derived from one non-small-cell lung cancer and two colon cancer cell lines remained static after treatment with YW152F, and YW152F also slowed the growth of a melanoma cell line in mouse mammary fat pads.

Furthermore, the groups show that the inhibition of DLL4 reduced the growth of mouse tumours derived from either a human fibrosarcoma cell line or a leukaemia cell line, both of which are resistant to anti-vascular endothelial growth factor (anti-VEGF) therapy. Interestingly, Yan and colleagues also show that YW152F was only modestly effective against xenograft tumours derived from lung carcinoma cells, as was anti-VEGF, but a combination of the two significantly inhibited tumour growth.

Why is increased vasculature in response to Notch pathway inhibition associated with decreased tumour growth? Thurston and colleagues showed that C6 DLL4–Fc tumours had a sevenfold increase in hypoxia, and most of the vessels in these tumours were not perfused, indicating that the vessels are not functional. Similarly, Yan and colleagues found that treatment with anti-DLL4 antibodies led to defective endothelial cell differentiation and reduced perfusion.

Both groups confirmed that the DLL4–Notch pathway is vascular-specific and that DLL4 inhibition in mice was relatively well tolerated. Yan and colleagues showed that the pathway is important during active vascularization rather than in normal vessel maintenance, and Thurston and colleagues show that DLL4 is upregulated in tumour versus normal vessels. These data indicate that the inhibition of DLL4 could be a valid therapeutic strategy, even for tumours that are resistant to anti-VEGF therapy.

Sarah Seton-Rogers

References

Noguera-Troise, I. et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444, 1032–1037 (2006) | Article | PubMed |
Ridgway, R. et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444, 1083–1087 (2006) | Article | PubMed |