A study published in the journal PNAS reveals details of a way the dangerous brain tumours called glioblastomas, resist the effects of antiangiogenic drugs designed to cut off their blood supply.

The researchers describe how the tumours can spread along existing blood vessels in normal tissue.

A process called vessel co-option can lead to compression of those vessels to reduce the oxygen supply available for adjacent tissues and therefore stimulate angiogenesis.

"The treatments designed to starve tumours by pruning away blood vessels have provided little or no survival benefits to patients with glioblastoma, said Rakesh K. Jain, senior author of the report. Because of its ability to circumvent a tumour's need to develop a new blood supply, vessel co-option can confer resistance to antiangiogenic therapy. Unfortunately, this mode of progression is difficult to target because the underlying mechanisms are not fully understood.

To get a better understanding of how cancer cells interact with the vasculature during co-option, Jain and his team followed tumour progression in mouse models of glioblastoma.

Using advanced imaging technology they found that treating existing glioblastomas with the antiangiogenic drug cediranib increased the spread of tumour cells along existing blood vessels and away from the primary tumour mass.

They also presented evidence that this process causes the compression of co-opted vessels by tumour cells, which can trigger hypoxia-induced angiogenesis.

Using the data from these experiments and from previous studies, the investigators developed a mathematical model that takes into account the biological and physical events driving the process of tumour growth and response to antiangiogenic treatment - from the earliest stages of vascular modification, through vessel co-option to secondary angiogenesis.

Designed to integrate events from the cellular and subcellular levels with overall tumour growth, the model's predictions matched the results of several published studies of vessel co-option and further suggested that tumour progression can be more effectively inhibited by combination therapies that block both angiogenesis and co-option.

Jain notes that the possibility that glioblastoma progression can only be stopped by combination therapies, although this may have important clinical implications.

A previous study from his team identified a specific pathway - the Wnt signalling pathway as a regulator of vessel co-option in glioblastoma, suggesting that drugs inhibiting that pathway could block co-option.

The new model also predicts that targeting co-option before using antiangiogenic drugs would be a better strategy than administering both drugs simultaneously.

"With a number of agents that block Wnt signalling in clinical trials, our work provides the rationale for testing the proposed combination for glioblastoma, which is a uniformly fatal disease," said Jain.

Source: Massachusetts General Hospital