Research reported in Nature Nanotechnology found that there are four main steps required.
Scientists report the direct visualization of the critical series of steps required for cancer cells to metastasize. Their findings confirm how the drug Avastin blocks the prerequisite formation of new blood vessels to a fused body of new micrometastases, permanently inhibiting their growth.
Frank Winkler, Ph.D., and colleagues at the Ludwig-Maximilians University of Munchen and the Max Planck Institute for Neurobiology published their research in Nature Medicine in a paper titled “Real-time imaging reveals the single steps of brain metastasis formation.”
They used two-photon microscopy and fluorescence markers to follow the fate of single cancer cells in real time and over an extended period as they formed large metastases in the brain of a mouse model. “Essentially, we were able to monitor the stages of metastasis formation live,” comments co-author Yvonne Kienast.
Observations over a number of weeks showed that metastasis formation required four steps. Firstly, circulating tumor cells need to get trapped at a fork in the blood-vessel network. “In contrast to previous reports, intravascular growth is not sufficient to induce a metastasis,” Dr. Winkler stresses. The cells then need to escape out of the blood vessels into the surrounding tissue and stick to the outer surface of the vessel, where micrometastases of 4–50 cells can develop. The fourth, most critical step, involves neighboring micrometastases fusing together and the growth of new blood vessels into the resulting mass. Without angiogenesis into the fused cancer bodies, even strongly proliferating metastases will eventually die off.
“Each one of the steps can go awry,” Dr. Winkler adds. “Cells may not get out of the circulation, may fail to adhere to the outer vessel wall, or be unable to induce angiogenesis.” Having used the mouse model to demonstrate how Avastin blocks the critical angiogenesis step, Dr. Winkler’s team plans to determine the effects of other cancer drugs on the single steps of metastasis formation.
“In the future, our new mouse model can be used to investigate the behavior of tumor cells that do not normally metasta¬size to the brain, which should help to gain further insight into the organ specificity of metastasis formation,” the authors conclude.
“The ability to observe metastasis as a process rather than simply an endpoint has provided new insights into brain-metastasis formation and an opportunity to experimentally address unanswered questions of metastasis research. This knowledge can be used to better tailor therapies in the future: The essential steps of the metastatic cascade should be the primary targets, the inefficient steps might be the easiest to inhibit, and the dead ends of metastasis formation can be ignored.”