Cancers use body's own defences to resist drugs

CANCER RESEARCH UK scientists have discovered that tumours are able to recruit part of the body's defence system to protect them from the effect of a drug designed to block the supply of blood to the tumour.

The research, published in The Journal of Clinical Investigation, showed that white blood cells called macrophages, normally a key part of the body's defence mechanism against disease, are recruited in large numbers by tumours and reduce the effects of an experimental drug called combretastatin-A4P (CA4P).

This is a type of drug called a vascular disrupting agent (VDA) as it rapidly and selectively blocks blood vessels in tumours causing widespread tumour death.

Research groups in Sheffield, led by Professors Claire Lewis and Gillian Tozer - working with Professor Michele De Palma and colleagues in Milan - showed that after treatments with CA4P, tumours in mice begin to release a protein called CXCL12. This recruits these white blood cells from the bloodstream into the treated tumour where they then help to block the effect of the drug on the blood vessels and to encourage tumour growth.

But this effect can be stopped. By blocking the receptor for CXCL12 on these white blood cells, so stopping their recruitment by the tumour, treatment with CA4P was significantly better at slowing tumour growth than when the VDA was used alone.

Professor Claire Lewis, a Cancer Research UK-funded scientist at the University of Sheffield, said: "We know that drugs that block blood vessels in tumours have a really damaging effect on the cancer, but this is often only short-lived and tumours start to re-grow.

"By expanding our research into what prompts macrophages to drive a tumour's re-growth after therapy we should now be able to find ways of blocking their effects and making such treatments more effective."

Professor Malcolm Reed, Head of Surgical Oncology at the University of Sheffield, commented: "This exciting work provides valuable insights into the possible mechanism which may result in a cancer becoming resistant to treatment with chemotherapy. This has the potential to help develop new approaches to improve treatment for patients."

CA4P is an experimental type of drug that targets only the blood vessels that supply cancer cells. It is currently in trials for a number of cancers to find out the best dose and how effective it is.

Dr Julie Sharp, senior science information manager at Cancer Research UK, said: "This exciting area of research provides a critical insight into how cancers are able to use the body's own defences for their own survival. Cancer Research UK is funding further research into how these white blood cells are helping to resist anti-cancer drugs. By tackling this challenge of treatment resistance we will help more people beat their disease."