Epigenetic Status Determines Metastasis

What makes cancer so deadly? Cancer cells that leave the parent tumor and travel to distant areas in the body, where they might develop into daughter tumors known as metastases. While most primary tumors can be properly treated, metastases pose the actual threat. Oncologists believe that metastases cause more than 90% of all cancer deaths in solid tumors.

For decades, researchers have been striving to understand and prevent the spread of tumor cells. However, the processes that allow a cancer cell to persist in a distant organ and eventually expand into a metastasis remain mostly unclear.

Cancer cells spread throughout the body via the blood and lymphatic systems. Scientists at the DKFZ and Heidelberg University have now developed a method for observing the behavior of migratory cancer cells in mice soon after they arrive in the metastatic organ—in this case, the lung.

The researchers, led by the two first authors, Moritz Jakab and Ki Hong Lee, revealed that once in the metastatic organ, some tumor cells exit the blood artery and enter a resting condition. Other cancer cells begin to divide within the blood vessel and spread into metastases.

Endothelial cells, which line the inside of all blood arteries, regulate the delicate fate of metastasizing tumor cells. They release Wnt signaling pathway components that encourage tumor cell departure from blood vessels and so commence latency. When the researchers turned off the Wnt factors, latency disappeared.

What distinguishes latent from developing metastasizing cancer cells?

“At this point, we asked ourselves the question: Why do some cancer cells immediately form a metastasis, while others fall into a kind of sleep?” according to Moritz Jakab.

The dormant and metastasizing cancer cells differed neither genetically nor in many other molecular features. However, the researchers discovered a tiny distinction: the methylation of DNA differed between the two cell types. Tumor cells with less methylated DNA were more susceptible to Wnt factors, leading to extravasation from the blood vessel and subsequent latency. The highly methylated cancer cells, on the other hand, did not respond to Wnt factors, remained in the blood vessel, and quickly began to metastasize.

To test this theory, the researchers looked at the DNA methylation state of distinct tumor cell lines. Indeed, they discovered that this was directly related to their metastatic potential.

“These findings are unexpected and may have far-reaching implications for tumor detection and treatment. The study’s findings could, for example, aid in the use of specific methylation patterns as biomarkers to predict for patients how high the load of dormant cancer cells is, and thus how likely the patient is to relapse following successful primary tumor treatment,” says senior author Hellmut Augustin. “But first we need to study whether natural human tumors behave in the same way as the employed cell lines or experimental tumors.”