Both preclinical and clinical trials show that anticancer therapies that disrupt the blood supply of a solid tumour are most effective when combined with either radio- or chemotherapy. Jain and colleagues have now found a possible explanation for this result and, surprisingly, it is not that anti-angiogenic factors eradicate the tumour's vasculature, but that they might transiently improve it.

The vascular network feeding a solid tumour is often a mass of highly disorganized and overly large, leaky vessels, leading to an inefficient blood supply and mostly hypoxic tumour tissue. The treatment of solid tumours, such as glioblastoma multiforme, with radiotherapy is hampered by these hypoxic conditions. Jain and colleagues used a mouse orthotopic model of human glioblastoma to assess why combined anti-angiogenic treatment and radiotherapy gives better results.

Initially, the authors combined an antibody (DC101) that inhibits vascular endothelial growth factor receptor 2 (VEGFR2) with γ-radiation and examined tumour growth. Although both treatments together showed an additive response in delaying tumour growth, scheduling radiation treatment 4–6 days after starting treatment with DC101 gave a synergistic response. However, delaying radiotherapy until 8 days after DC101 treatment resulted in loss of this synergy. Jain and co-workers thought that this might be due to a transient improvement in the vascular network, increasing the levels of tumour oxygenation and making the tumour cells more sensitive to radiation.

Analysis of the tumours using in vivo multiphoton microscopy and immunofluoresence indicated that the tumour vasculature did change during the initial stages of treatment with DC101 — the vessels became less tortuous and vessel diameter decreased. These changes correlated with the recruitment of pericytes to the tumour vessels — cells that are associated with stabilized vessels in normal tissues. cDNA microarray data, along with mRNA and protein studies show that angiopoietin-1 expression is selectively increased after treatment with DC101 and that inhibition of the angiopoietin-1 receptor, TIE2, blocked recruitment of the pericytes. In addition, the authors found that the abnormally thick basement membrane often seen in tumour vessels was temporarily reduced. This was not a function of pericyte recruitment, but one of increased matrix-metalloproteinase activity.

Collectively, these results show that blockade of VEGFR2 transiently 'normalizes' the vascular network in tumours and decreases hypoxia, making radiotherapy more effective. The identification of a normalization window in patients might lead to more successful treatments for glioblastoma multiforme and other solid tumours.