Metastatic melanoma is the deadliest of the skin cancers; when malignant melanoma metastasizes to the brain, it is a death sentence for most patients. The mechanisms that govern early metastatic growth and interactions of metastatic cells with the brain’s microenvironment are still shrouded in mystery.
Now, a Tel Aviv University study shows a new way of detecting brain micrometastases months before they transform into malignant and inoperable growths. According to the research, micro-tumor cells hijack astrogliosis, the brain’s natural response to damage or injury, to support metastatic growth. This knowledge may lead to the detection of brain cancer in its first stages and permit early intervention, the university said in a statement.
The study was led by Dr. Neta Erez of the Department of Pathology at TAU’s Sackler Faculty of Medicine and published in Cancer Research.
Erez and her team used mouse models to study and follow the spontaneous metastasis of melanoma in the brain. She and her partners went over all the stages of metastasis: the initial discovery of melanoma in the skin, the removal of the primary tumor, the micrometastatic dissemination of cancer cells across the body, the discovery of a tumor and eventual death.
Imaging techniques used today cannot detect micrometastases. Melanoma patients whose initial melanoma was removed may believe that everything is fine for months, or years, following the initial procedure.
Yet after the removal of the primary tumor, micrometastatic cells travel across the body to the brain or other organs, and are undetectable at the micro level. These cells learn to communicate with cells in their new microenvironment in the brain — cells which are, at first, hostile to them. But eventually a tumor appears. And then it generally is too late for treatment.
Erez calls the period of the initial growth of disseminated micrometastatic cells in distant organs the “black box” of metastasis. “We believe that we have found the tools to characterize this black box,” said Erez. “And this is key to developing therapeutic approaches that may prevent brain metastatic relapse.”
Every organ in the body has a defense system — cells — that detect intruders and are triggered when there is tissue damage, like from a stroke or a viral infection. Once activated, these cells induce an inflammatory response.
“At the earliest stages of metastasis, we already see astrogliosis and inflammation. The brain perceives the micrometastatic invasion as tissue damage, activating inflammation — its natural defense mechanism,” Erez said. “We found that the inflammation unfortunately gets hijacked by tumor cells that are able to grow faster and penetrate deeper because the blood vessels in the brain are more permeable than in any other part of the body. We found that all of this happens very early on.”
Erez is currently studying detailed molecular pathways in the brain’s biological response to find a way to block the metastases. “We’re hoping to develop the detection tools for humans that we developed in mice,” said Erez. “We’re also trying to find molecular targets that will allow us to prevent metastasis rather than trying to treat it.”