Researchers have identified a natural immune process in mice that stops cancer cells, which have escaped from their original tumor, from forming tumors in other body areas.
Metastatic disease, which occurs when cancer spreads from its original site to different body regions, is responsible for the majority of cancer-related deaths. Although scientists have some knowledge of how cancer cells leave the main tumor to establish new ones, the reasons why some of these escaped cells develop into tumors—sometimes many years later—while others do not remains largely unclear.
Recently, a research group from the Montefiore Einstein Comprehensive Cancer Center (MECCC), a National Cancer Institute-designated center, found a natural immune mechanism in mice that inhibits the growth of escaped cancer cells into tumors in other parts of the body. Their results were published today in the journal Cell.
“The prevention or treatment of metastases is the biggest challenge in cancer research,” explained study leader Julio Aguirre-Ghiso, Ph.D., director of the Cancer Dormancy Institute at MECCC. “We believe our findings could lead to new treatments aimed at preventing or managing metastatic disease.” The study’s co-first authors include Erica Dalla, Ph.D., a former student, and Michael Papanicolaou, Ph.D., a postdoctoral researcher in Dr. Aguirre-Ghiso’s lab.
The Role of Dormancy in Cancer
Cells that move from the main tumor and contribute to new metastatic tumors are known as disseminated cancer cells (DCCs). Some DCCs act aggressively, quickly forming tumors in new tissue, while others remain in a dormant or inactive state.
“The mystery of why some DCCs can lie dormant in tissues for decades without causing metastasis has puzzled scientists, and we believe we’ve uncovered the answer,” Dr. Aguirre-Ghiso stated, who is also a professor of cell biology, oncology, and medicine, as well as the Rose C. Falkenstein Chair in Cancer Research at Albert Einstein College of Medicine.
Metastatic breast cancer, along with various other cancers, often spreads to the lungs. In their study involving three mouse models of metastatic breast cancer, Dr. Aguirre-Ghiso and his team found that when breast cancer DCCs reach the air sacs (alveoli) in the lungs, they are kept dormant by immune cells known as alveolar macrophages.
Insight into the Immune System
“Alveolar macrophages serve as the lungs’ first line of defense, protecting the organ from bacteria and harmful agents like environmental toxins,” Dr. Aguirre-Ghiso explained. These specialized macrophages appear early in embryonic development and remain in lung tissue throughout life.
“Our research reveals a new function for these macrophages, as they recognize DCCs, interact with them, and secrete a protein called TGF-β2, which sends signals to the cancer cells, keeping them in a dormant state,” he detailed. “Given that each organ has specific tissue-resident macrophages, it’s possible they also help maintain DCC dormancy in those locations. This is the first time our study has demonstrated that these specialized macrophages actively induce dormancy in DCCs.”
In their investigation, Dr. Aguirre-Ghiso and his colleagues validated the vital role of alveolar macrophages in maintaining DCC dormancy. They discovered that removing these immune cells from the mice markedly increased the number of activated DCCs and led to more metastases in the lungs compared to mice that had normal immune cell levels.
The researchers observed that as DCCs became more aggressive, they developed resistance to the dormancy-promoting signals from alveolar macrophages. This capacity for evasion allows certain DCCs to “wake up” from dormancy and form metastases.
“Understanding how immune cells regulate DCCs could pave the way for innovative anti-metastatic cell therapies and other strategies,” highlighted Dr. Aguirre-Ghiso. For instance, he mentioned the possibility of enhancing macrophage signaling to keep DCCs in a dormant state indefinitely or finding methods to retain the effectiveness of dormancy signals in older DCCs.
