Human breast tumours' 'microenvironment' primes them for metastasis

The environment within primary breast tumours can 'empower' cells that break free and enter the bloodstream to successfully invade other organs, researchers report in the 4th April Cell, a publication of Cell Press.

Specifically, through studies of hundreds of human breast tumours, the researchers found evidence that the cytokine TGFbeta in the tumour microenvironment primes breast cancer cells for metastasis to the lungs, one of the most common sites for the spread of breast and other cancers. TGFbeta signalling is often activated within tumours as a natural response to the oxygen starved and inflammatory conditions that come with tumour progression.

'The microenvironment of a tumour is not just cancer cells, but all other cell types that congregate there,' said Joan Massague of Memorial Sloan-Kettering Cancer Centre in New York. In recent years, he said, increasing attention has been paid to the impact those other body cells can have on the tumour locally, through their affects on blood vessel growth, the ability of cancer cells to enter the circulation, and so on.

'Our study shows that it doesn't end there,' he said. 'The cancer cells can come out with instructions that serve them in the long run.'

The research team analysed the expression of all 20,000 genes in the human genome within hundreds of primary breast tumours. Those tumours fell within two classical groups based on whether their oestrogen receptor status was positive or negative (ER+ or ER-). In both tumour groups, the researchers found that about 40 percent of the tumours bore the genetic signature of TGFbeta's influence.

They found that TGFbeta exposure didn't seem to make any difference to the risk of cancer spread in ER+ tumours. In ER- tumours, however, TGFbeta correlated markedly with an increased risk for metastasis to the lung, but not to bone. In other words, Massague said, 'context matters.'

The researchers continued to dig, ultimately uncovering the 'fascinating biology' behind that correlation. They found that the TGFbeta exposure in ER- tumours leads to an increase in a second cytokine within the tumour cells, called angiopoietin-like 4 (ANGPTL4). Once those cells escape the tumour and lodge in the lungs, ANGPTL4 disrupts the connections between cells in the thin capillaries there. That separation of cell-cell contacts allows the cancer cells to cross the vessel wall and pass into the lung proper, Massague said.

The findings suggest that TGFbeta, or perhaps even better ANGPTL4, might serve as targets for drugs aimed at preventing the spread of breast cancer to the lungs. The TGFbeta signature could also offer a means of predicting those breast cancer patients at particularly high risk for developing metastatic lung cancer so that they might be monitored more closely and treated more aggressively with existing drugs.

Massague said he suspects the new findings are but one example of a more general cancer phenomenon.

'Entering and colonising an organ requires of a tumour cell a number of special abilities,' he said. After all, 'our bodies are not made up of cells that are allowed to go anywhere as tumour cells [sometimes] manage to do. We've shown that factors within primary tumours can act on cancer cells to enhance their ability' to selectively spread to other tissues.