Study points to potential new cancer drug

Scientists have uncovered details of the workings of a protein that both slows the spread of cancer and boosts the efficiency of chemotherapy. The molecule, called histidine-rich glycoprotein (HRG) could therefore prove useful to researchers' efforts to develop anti-cancer drugs. The study, which was partly funded by the EU, is published in the journal Cancer Cell.

EU support for the research came from the TIE2+MONOCYTES ('Tie2-expressing monocytes: Role in tumor angiogenesis and therapeutic targeting') project, a EUR 1.31 million European Research Council (ERC) Starting Grant awarded to one of the authors of the paper, Michele De Palma of the San Raffaele Scientific Institute in Italy.

HRG works by improving the quality of the network of blood vessels supplying the tumour with oxygen and nutrients. Although it sounds counterintuitive, this actually lowers the risk of metastases (where cancer spreads to other parts of the body) and enhances the ability of drugs to attack the tumour.

Like all tissues, malignant tumours rely on oxygen and nutrients for their growth and maintenance, and cancers often engage a range of molecules called blood vessel growth factors to create their own blood supply. For many years, researchers therefore focused on developing anti-cancer drugs that would cut off the tumour's blood supply by blocking the activity of blood vessel growth factors. However, doing this can raise the risk of metastases.

Studies have shown that because tumours grow so fast, their blood vessel networks are poorly constructed and often fail to supply the tumour with sufficient oxygen. It is this lack of oxygen that drives some cancer cells to leave the site of the tumour and set up home in other parts of the body. By aggravating the lack of oxygen in the tumour, drugs that cut off the cancer's blood supply often boosted the potential for metastasis.

Recent years have thus seen a growing interest in drugs that could improve the tumour's blood (and oxygen) supply, thereby encouraging the cancerous cells to stay put. Furthermore, as drugs are often delivered to the tumour via the blood, improving the flow of blood to the cancerous cells also gives chemotherapy greater access to the malignant cells.

In this study, scientists in Belgium, Italy and Sweden reveal that the protein HRG is able to 'normalise' a tumour's blood vessel supply by influencing levels of two different kinds of immune cells.

According to the researchers, most types of cancer lead to inflammation involving cells called tumour-associated macrophages (TAMs). There are two types of TAM; M2 macrophages promote blood vessel growth and moderate the body's immune defences, while M1 macrophages activate immune cells that attack cancerous tumours. Crucially, M1 macrophages do not have the ability to boost blood vessel development.

The new research shows that HRG is able to suppress a protein called placenta growth factor (PlGF). This in turn triggers the transformation of M2 macrophages (which promote tumour growth) into M1 macrophages (which launch an immune system attack on the cancer and so reduce its size).

Because it does not actively promote blood vessel growth, M1 leads to the development of a more conventional blood vessel network in the tumour. This in turn boosts the tumour's blood (and oxygen) supply, reducing the risk of metastasis and enhancing the effects of chemotherapy drugs, which gain better access to the tumour.

"Our study shows that the regulation of tumour-associated inflammation can be utilised to treat cancer and that there is a great potential to develop HRG into a drug for cancer treatment," commented Professor Lena Claesson-Welsh of the Department of Immunology, Genetics and Pathology at Sweden's Uppsala University. "The next step will be to find the binding sites for HRG on macrophages, so they can be used in developing drugs. We are also looking into how HRG levels in the blood change in cancer."

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