It has become evident that we cannot understand tumour growth without considering components of the stromal microenvironment, such as the vasculature. At the same time, the tumour phenotype determines the nature of the tumour vasculature. Much research is now devoted to determining the impact of angiogenesis on tumour development and progression, and the reciprocal influences of tumour products on the microvasculature. A more detailed understanding of the complex parameters that govern the interactions between the tumour and vascular compartments will help to improve anti-angiogenic strategies-- not only for cancer treatment, but also for preventing recurrence.

Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signalling pathways are affording demonstrable therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. However, in both preclinical and clinical settings, the benefits are at best transitory and are followed by a restoration of tumour growth and progression. Emerging data support a proposition that two modes of unconventional resistance underlie such results: evasive resistance, an adaptation to circumvent the specific angiogenic blockade; and intrinsic or pre-existing indifference. Multiple mechanisms can be invoked in different tumour contexts to manifest both evasive and intrinsic resistance, motivating assessment of their prevalence and importance and in turn the design of pharmacological strategies that confer enduring anti-angiogenic therapies.The long-standing proposition that induction of chronic angiogenesis is a hallmark of cancer is now solidly grounded in a substantial body of research involving genetic and pharmacological perturbation of elements in the vascular regulatory circuitry. The 'angiogenic switch'1 is increasingly recognized as a rate-limiting secondary event in multistage carcinogenesis 2 , as documented in animal models of cancer and correlated in advanced pre malignant stages, as well as their malignant derivatives, in a growing list of human cancer types. That this acquired capability is functionally important for manifestation of the disease has been further validated by the approval of angiogenesis inhibitors as cancer therapeutics, most notably ones targeting the vascular endothelial growth factor (VEGF) pro-angiogenic signalling pathways 3 . The pioneers of the clinical proof-of-concept for angiogenesis inhibitors are bevacizumab (Avastin, Genentech/Roche), a ligand-trapping monoclonal antibody, and two kinase inhibitors (sorafenib (Nexavar, Bayer) and sunitinib (Sutent, Pfizer)) targeting the VEGF receptor (VEGFR) tyrosine kinases, principally VEGFR2 (also known as KDR). Since March 2008, bevacizumab has been approved for treating patients with late-stage colon cancer, non-small-cell lung cancer and breast cancer, all in combination with chemotherapy. Sorafenib and sunitinib have both been approved for treating renal carcinoma, a highly vascularized (and angiogenic) tumour type. In addition, sunitinib has been approved for treating gastrointestinal stromal tumours, and sorafenib for hepatocel-lular carcinomas3 -6. Numerous ongoing clinical trials seek to expand the applications of each of these VEGF pathway inhibitors, and dozens of other angiogenesis inhibitors (many also targeting VEGF signalling) are being clinically evaluated (see Angiogenesis Inhibitors Therapy URL and clinical trials URLs in Further information). Moreover, two VEGF pathway inhibitors (the RNA aptamer pegaptanib and a Fab derivative of bevacizumab) have been approved for treating the angiogenic (wet) form of macular degeneration 7-9.Many of the demonstrable clinical benefits and side ef...

During carcinogenesis of pancreatic islets in transgenic mice, an angiogenic switch activates the quiescent vasculature. Paradoxically, vascular endothelial growth factor (VEGF) and its receptors are expressed constitutively. Nevertheless, a synthetic inhibitor (SU5416) of VEGF signalling impairs angiogenic switching and tumour growth. Two metalloproteinases, MMP-2/gelatinase-A and MMP-9/gelatinase-B, are upregulated in angiogenic lesions. MMP-9 can render normal islets angiogenic, releasing VEGF. MMP inhibitors reduce angiogenic switching, and tumour number and growth, as does genetic ablation of MMP-9. Absence of MMP-2 does not impair induction of angiogenesis, but retards tumour growth, whereas lack of urokinase has no effect. Our results show that MMP-9 is a component of the angiogenic switch.