How a sleeping cancer awakens and metastasizes

COLD SPRING HARBOR, N.Y., Sept. 27, 2018 /PRNewswire/ -- Scientists at Cold Spring Harbor Laboratory (CSHL) have determined one of the ways in which cancers in remission can spring back into action. This knowledge has inspired a new treatment idea designed to prevent cancer recurrence and metastasis.

Even after successful cancer treatment, dormant, non-dividing cancer cells that previously detached from the original tumor may still exist elsewhere in the body. If awakened, these cells can proliferate and grow into metastatic tumors. A CSHL team studying metastasis to the lungs has now identified signals accompanying inflammation that can awaken dormant cancer cells, as well as a way of blocking those signals.

Whether inflammation can directly cause cancer recurrence, and if so how, has not been clear. In their new research, the team demonstrates that sustained lung inflammation, including that caused by tobacco smoke exposure, can cause dormant breast and prostate cancer cells that have traveled to the lungs to awaken and begin to divide. These cells can now form a metastasis in the lungs.  Metastasis accounts for the bulk of lethality from most common cancers. 

The team, led by Associate Professor Mikala Egeblad, showed that sustained lung inflammation induced white blood cells called neutrophils to awaken nearby dormant cancer cells in an extraordinary way. 

Neutrophils can vanquish their prey by expelling their DNA into the space beyond the cell membrane. Laced with toxic enzymes, this expelled DNA forms a gauzy, net-like trap (called neutrophil extracellular traps, or NETs) that can kill a pathogen.

The new research shows that sustained lung inflammation causes the formation of NETs near dormant cancer cells. Two enzymes in the NETs, called NE (neutrophil elastase) and MMP9 (matrix metalloproteinase 9), interact with a protein in tissue called laminin. In sequence, first NE then MMP9 make cuts in laminin proteins. This changes the protein's shape, exposing a new surface, called an epitope.

This epitope, when recognized by dormant cancer cells nearby, spurs signaling that awakens the cancer cells.

The team created an antibody to block the epitope exposed on the laminin proteins.  In mice, this prevented the reawakening of dormant cancer cells nearby. Work has begun to optimize the antibody and compare it with other approaches to interfere with NETs, with the hope of eventually conducting trials in people.

For a list of funding sources that support this work, visit http://www.cshl.edu/how-a-sleeping-cancer-awakens-and-metastasizes

Citation: Albrengues J et al, "Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice" appears online in Science, September 28, 2018.

About Cold Spring Harbor Laboratory

Founded in 1890, Cold Spring Harbor Laboratory has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. Home to eight Nobel Prize winners, the private, not-for-profit Laboratory employs 1,100 people including 600 scientists, students and technicians. For more information, visit www.cshl.edu

SOURCE Cold Spring Harbor Laboratory

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