Glivec and Sutent shrink tumors but could also make them more aggressive and mobile

A new study suggests that cancer drugs that shrink tumors by cutting off their blood supply may end up helping them to spread.

Drugs such as Glivec and Sutent reduce the size of tumors but could also make them more aggressive and mobile, it is claimed.

A little-studied group of cells called pericytes that provide structural support to blood vessels act as “gatekeepers” to pen in cancer, scientists have discovered.

Pericytes are wiped out by some advanced cancer drugs that prevent the growth of tumor-nourishing blood vessels, the research shows.

As a result tumors find it easier to “metastasise”, or spread around the body.

Tests on mice showed that both Glivec and Sutent depleted pericytes by 70% while metastasis rates tripled.

Glivec, the brand name of the drug imatinib, and Sutent (sunitinib) have both been shown in trials to increase patient survival by a significant degree.

However, the research raises the possibility that ultimately they might help cancers become more deadly. Metastasis to vital organs such as the liver or brain is the chief reason why people die from cancer.

The US scientists, whose work is reported in the journal Cancer Cell, began by removing pericytes from breast cancer tumors in genetically engineered mice.

They saw a 30% decrease in tumor volumes over 25 days, but also a three-fold increase in the number of secondary tumors growing in the animals’ lungs.

“If you just looked at tumor growth, the results were good,” said lead researcher Professor Raghu Kalluri, from Harvard Medical School in Boston.

“But when you looked at the whole picture, inhibiting tumor vessels was not controlling cancer progression. The cancer was, in fact, spreading.”

A closer look revealed a five-fold percentage increase in oxygen-starved “hypoxic” areas in tumors lacking pericytes.

Cancer cells respond to oxygen deprivation by launching genetic survival programmes, said Prof. Raghu Kalluri. They become more mobile, passing through leaky blood vessel walls, and begin to behave like treatment-resistant stem cells.

Smaller tumors appeared to be shedding more cancer cells into the blood than larger tumors with a good supply of pericytes, the study showed.

The next step was to conduct experiments with Glivec and Sutent.

Glivec works through a number of pathways, one of which is to target a blood vessel growth-promoting protein called PDGFR beta. Sutent also targets PDGFR beta as well as a range of other growth-promoters called VEGFR proteins.

Mice with primary tumors were treated with both drugs. The same result was found: with the loss of pericytes, metastasis increased three-fold.

“We showed that a big tumor with good pericyte coverage is less metastatic than a smaller tumour of the same type with less pericyte coverage,” said Prof. Raghu Kalluri.

To see how relevant the findings were to patients, the scientists went on to examine 130 human breast cancer samples.

Samples with low numbers of pericytes in tumor blood vessel networks correlated with the most deeply invasive cancers, distant cancer spread, and five and 10-year survival rates lower than 20%.

Some assumptions about cancer must now be revisited, Prof. Raghu Kalluri believes.

“We must go back and audit the tumor and find out which cells play a protective role versus which cells promote growth and aggression,” Prof. Raghu Kalluri said.

“Not everything is black and white. There are some cells inside a tumor that are actually good in certain contexts.”