Published online 13 October 2009 | Nature 461, 854-855 (2009) | doi:10.1038/461854b

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Cancer metastasis scrutinized

Researchers shift focus to catch secondary tumours.

BOSTON

Most cancer research has focused on blocking primary-tumour growth, even though cancer cells that cut loose from tumours and invade other tissues account for 90% of cancer-associated deaths.

Metastatic melanoma cells (left) invade pancreatic tissue (right).Richard Lee/NCI

But at the first conference on Frontiers in Basic Cancer Research, hosted by the American Association for Cancer Research last week in Boston, Massachusetts, cancer biologists reported that this focus is changing. Many experts are turning to study the secondary tumours that form when circulating cancer cells infiltrate and colonize other organs — a process known as metastasis.

"The time is now ripe for scientifically deconstructing the process of metastasis in different types of cancer," says Joan Massagué of the Memorial Sloan-Kettering Cancer Center in New York City.

At the conference, Daniel Haber of the Massachusetts General Hospital in Charlestown described a microfluidic chip that can detect vanishingly rare tumour cells circulating in the bloodstream. This technique, he says, could identify rogue cancer cells long before metastases form.

And using a novel genetically engineered mouse model of lung cancer, Tyler Jacks of the Massachusetts Institute of Technology in Cambridge and his postdoc Monte Winslow found that a transcription factor called Nkx2-1 is a metastatic suppressor, specific to lung cancer, that is active in primary tumours but shut off in secondary cancers. "This is probably the closest thing you have to taking metastasis from a patient," says Winslow.

Whether a metastatic cancer cell triggers a new tumour is "a big if", says Massagué. What's more likely, he says, is that these cells reseed the same tumour from which they originated. Massagué presented data from mice showing that the circulating cells express genes allowing them to infiltrate tissues. But the primary tumours from which the cells came release signals to attract them back, so if they don't land in a new organ they return home and aggravate tumour growth there. "The tumour is selecting for the worst of its children," says Massagué. He is testing whether these tissue-adapted metastatic cells account for the high rates of relapse seen following many cancer therapies.

Robert Weinberg of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, linked metastatic cells to cancer stem cells — rare cells thought to fuel primary-tumour growth — through a common molecular transformation called the epithelial-mesenchymal transition. Weinberg says that this transition allows the metastatic cells to become both motile and self-renewing. Many aggressive secondary tumours might form from newly converted cancer stem cells, he notes, overturning the standard dogma that stem cells generate non-stem cells.

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Meanwhile, Sijin Liu of Tufts University School of Medicine in Boston reported one of the first drug compounds that can directly block metastasis, in a mouse model of breast cancer. Liu showed that inhibiting the ROCK signalling pathway with a small molecule led to around 35% fewer metastases, as well as decreasing the mass of the resulting secondary tumours by nearly 80%.

Until such therapies exist, however, understanding primary tumours remains a major route to indirectly mitigating metastasis, Jacks says. "It could be that we will enter an era of cancer management," he says, "in which our understanding of how tumours advance through these early stages will present us with preventative strategies to block the emergence of later lesions." 

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