Metastasis – where cancer cells leave the original tumor and spread to other parts of the body – is responsible for 90% of cancer deaths. Any research that sheds light on it brings us closer to saving millions of lives. Now, a new study of cancer in mice reveals how migrating cancer cells take their first few steps in metastasis.
Image credit: Madeleine Oudin and Jeff Wyckoff
The study shows how tumor cells that have a particular version of the Mena protein – an invasive form called MenaINV – can remodel their cell environment to enable their passage into blood vessels and spread through the body.
In the journal Cancer Discovery, researchers from the David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT) in Cambridge also reveal that breast cancer patients with higher levels of MenaINV have poorer survival.
Senior author Frank Gertler, a professor of biology, says if we could find a way to block MenaINV, perhaps we could stop metastasis. He adds:
“That’s something that I think would be very promising, because we know that when we genetically remove MenaINV, the tumors become nonmetastatic.”
For metastasis to happen, two types of change need to take place: one in the tumor cells and the other in their environment. The study reveals new insights about both of these.
Previous research has already revealed that a structure protein called fibronectin, which forms part of the extracellular matrix or scaffolding that supports cells, is found in particularly high concentrations around the edges of tumors and near blood vessels.
To be able to reach blood vessels, cancer cells move along a “gradient” of fibronectin concentration – from low to high. However, to have “traction” along this gradient, the cells themselves need a way to “grip” onto it. This is where MenaINV comes in.
There is a segment in the MenaINV protein – not present in the normal version – that helps it bind more strongly onto alpha-5 integrin, a receptor protein found on the surface of tumor cells and nearby support cells. This receptor also recognizes fibronectin.
When MenaINV attaches to the receptor, it boosts the binding of fibronectin to the same receptors. This has an interesting effect on fibronectin. Normally, the structure protein is a tangle of fibers, but when it binds to cell surfaces, it stretches out in long bundles.
The stretched-out fibronectin stimulates another extracellular matrix protein – collagen – to organize into stiff threads that radiate from the edges of the tumor. More aggressive tumors typically have this feature – which allows tumor cells to migrate toward blood vessels.
First author Madeleine Oudin, a post-doctoral researcher at the Koch Institute, explains:
“If you have curly, coiled collagen, that’s associated with a good outcome, but if it gets realigned into these really straight long fibers, that provides highways for these cells to migrate on.”
Dr. Oudin and colleagues found that cells in mice with the invasive form of Mena were better able to follow the fibronectin gradient and travel along the collagen pathways toward blood vessels.
In another part of the study, where they looked at data from breast cancer patients, the researchers found that higher levels of MenaINV and fibronectin are linked to metastasis and earlier death. No such link was found with high levels of normal Mena.
In previous work, Prof. Gertler’s team had already developed antibodies that can detect normal and invasive Mena, and they are now preparing to test them on biopsy samples from patients.
The team hopes a test based on these antibodies could help decide if a patient’s tumor is likely to spread or not, and help select the best treatment.
Another avenue that the study opens up is the development of drugs that block MenaINV as a way to stop metastasis.
Preliminary investigations suggest MenaINV plays a similar role in lung and colon cancers as in breast cancer. The team plans to look into this further and also investigate the abnormal protein’s role in other types of cancer.
The researchers also want to find out how cells “choose” between the normal and the invasive form of Mena, and how other proteins in the extracellular matrix might influence cell migration.
Meanwhile, from a study that looks at the process of metastasis a bit further down the line, Medical News Today recently learned how barring exit from blood vessels may offer a way to stop breast cancer spread.