Vascular-disrupting agents are a relatively new class of anti-cancer compound that selectively disrupt the blood supply to tumours, causing tumour cell death. The lead compound in this series is combretastatin A4 phosphate (CA4P), a pro-drug that is de-phosphorylated in vivo to its active form. Trials of CA4P in combination with anti-angiogenic agents are underway. However, the long-term utility of drugs of this class is limited by rapid re-growth of the tumour vasculature from blood vessels remaining at the periphery of the tumour. Understanding the mechanisms that induce this vascular re-growth is an important step towards improving the efficacy of vascular-disrupting agents in this series.

Abigail Welford of the University of Sheffield Medical School, Sheffield, UK, Daniela Biziato of San Raffaele Scientific Institute, Milan, Italy and their colleagues have now shown in mouse models that infiltration of tumours with macrophages that express the gene TIE2, which encodes a cell-surface receptor that binds angiopoietin, limits tumour injury by CA4P. TIE2-expressing macrophages (TEMs) are a strongly pro-angiogenic subset of tumour-associated macrophages (TAMs). Welford, Biziato and their colleagues first injected CA4P or saline into mammary tumour-bearing female FVB/MMTV-PyMT transgenic mice, and found, as expected, that tumours from the mice that had been injected with CA4P were the more necrotic and hypoxic. CA4P-treated tumours were also infiltrated by more TIE2-expressing macrophages than control tumours. Infiltration by these cells but not by other types of TAM increased 24 hours after CA4P injection. TEMs in both CA4P-treated and untreated tumours were found to express the pro-angiogenic matrix metalloprotease MMP9. The chemokine CXCL12, known to be up-regulated in hypoxic conditions, was also found to be over-expressed in all tumours, and the receptor for this chemokine, CXCR4, was expressed in all tumour-associated macrophages. CXCR4 was expressed more strongly in TEMs than other TAMs and more strongly still in those that had been treated with CA4P.

The researchers then used AMD-3100, a compound known to inhibit the binding of CXCL12 to its receptor, to investigate the role of this chemokine system in TEM infiltration of tumour cells, using the subcutaneous N202 mouse model of mammary tumours. When injected with CA4P, however, his inhibitor – which alone has no effect on tumours – significantly reduced tumour infiltration by TEMs but not by other types of macrophage. Tumours injected with both AMD-3100 and CA4P also became more necrotic than those only injected with CA4P, and the combination of drugs inhibited tumour growth significantly more than CA4P alone. Welford and Biziato then specifically eliminated TEM cells in transgenic mice using ganciclovir in a conditional suicide-gene based strategy, finding that CA4P-induced tumour necrosis was markedly stronger in mice that had undergone this process than in those without TEM cell depletion.

Taken together, these results indicate that TEMs rapidly infiltrate murine tumours that are treated with the vascular-disrupting agent CAP4; that this protects those tumours against vascular damage, hypoxia and necrosis; and that interfering with TEM recruitment will increase tumour damage. Although these results cannot explain the mechanisms through which TEMs protect tumours completely, the researchers suggest that if, as is likely, these results are applicable to human cancers, developing compounds that target TEMs should be a useful strategy for increasing the effectiveness of CA4P and other vascular-disrupting anti-tuimour agents.

Article: Welford, A.F., Biziato, D., Coffelt S.B. and nine others (2011). TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice. J. Clin. Invest., published online ahead of print 1 April 2011. doi: 10.1172/JCI44562