Can controlled systems ever truly simulate natural environments? Do animals on a farm behave the same way as they would in their natural habitat? Probably not. So, perhaps it should come as no surprise that tumour xenografts and spontaneously arising tumours respond in different ways to angiogenic stress, as Marianna Ruzinova et al. and Hashmat Sikder et al. both report in the October issue of Cancer Cell. Id proteins are negative regulators of basic helix–loop–helix transcription factors and are essential for angiogenesis and growth of tumour xenografts — however, the role of Id proteins in spontaneous tumours was not known until now.

Ruzinova et al. studied spontaneous tumour development in Pten+/− mice and observed that loss of Id genes does not curtail the rate of growth of hyperplastic lymphoid lesions or uterine carcinomas. Sikder et al. used carcinogenic chemicals to induce spontaneous tumour growth in Id1 −/− mice and these mice actually had a higher incidence of skin tumours than wild-type controls.

So, loss of Id did not inhibit the growth rate of spontaneous tumours, but what was the effect on the neovasculature and tumour histology? Ruzinova et al. observed that both Id1 and Id3 are overexpressed in the vasculature of the lymph and uterine tumours that develop in Pten+/− mice. These tumours become necrotic and undergo haemorrhage in an Id-mutant background. Pheochromocytomas, which do not normally overexpress Id in their vasculature, were not affected by reduced Id dosage.

Previous studies in xenografts showed that reduction of Id dosage severely stunted neovascularization, but in the more physiologically relevant Pten+/− model, tumour vasculature was impaired in a different way — anastomosing networks of enlarged, irregularly shaped blood vessels, Hif-1α overexpression and increased vascular permeability were all observed. By contrast, Sikder et al. did not observe defects in angiogenesis in their Id−/− mouse model — vessel density and calibre were similar to that of Id+/+ mice, although whether these tumour vessels normally express Id genes was not established.

Xenograft vascularization relies on bone-marrow-derived circulating endothelial precursors (BM-CEPs). Ruzinova et al. showed that in Pten+/− mice BM-CEPs contribute to the vasculature of uterine carcinomas and restore functionality, but do not contribute to the neovessels of lymphoid hyperplasias, demonstrating that dependence on the requirement for these precursors varies with tumour type.

But what are the downstream targets of Id? Ruzinova and colleagues compared gene-expression profiles of endothelial cells from tumours that developed in the Pten+/−Id1+/+ mice and Pten+/−Id1−/− mice and found that Id1 controls expression of several angiogenesis-associated factors, including α6 and β4 integrins, matrix metalloproteinase 2 and fibroblast growth factor receptor 1. Expression of thrombospondin-1, previously found to be upregulated in Id1−/− mouse embryonic fibroblasts, was not upregulated in the vasculature of Id1−/− spontaneous tumours. Sikder and colleagues showed that loss of Id1 caused loss of expression of the chemokine receptor Cxcr4 by a T cell subgroup that is involved in tumour immunosurveillance. This prevented homing of these cells to the skin, leaving skin tumour development unchecked.

These data challenge the long-held view that tumours cannot grow beyond a limited size under severe angiogenic stress, and highlight the need to use mouse models of spontaneous tumours in further studies.