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The majority of cancer deaths are caused by metastatic disease, which occurs when cancer spreads from the primary tumour to other areas of the body. and researchers understand how cancer cells escape the primary location to seed new tumours, it is unclear why some cancer cells produce new tumours decades later and others do not.
A research team at the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Centre (MECCC) has uncovered a natural immunological response in mice that prevents escaping cancer cells from growing into tumours elsewhere in the body. The study was published today in the journal Cell. "Preventing or curing metastases is the most critical challenge in cancer," said study leader Julio Aguirre-Ghiso, Ph.D., director of MECCC's Cancer Dormancy Institute. "We think our findings have the potential to point to new therapies to prevent or treat metastatic disease." The study's co-first authors are Erica Dalla, Ph.D., a former student, and Michael Papanicolaou, Ph.D., a postdoctoral fellow in Dr. Aguirre-Ghiso's lab. Cells that migrate from primary tumors and seed metastatic tumors are called disseminated cancer cells (DCCs). Some DCCs behave aggressively, immediately starting tumors in new tissue, while others remain in a state of suspended animation referred to as dormancy. "It's long been a mystery how some DCCs can remain in tissues for decades and never cause metastases, and we believe we've found the explanation," said Dr. Aguirre-Ghiso, who is also professor of cell biology, of oncology, and of medicine and the Rose C. Falkenstein Chair in Cancer Research at Albert Einstein College of Medicine. Breast cancer and many other types of cancer metastasize to the lungs. In research involving three mouse models of metastatic breast cancer, Dr. Aguirre-Ghiso and colleagues determined that when breast cancer DCCs spread to the lung's air sacs (alveoli), they are kept in a dormant state by immune cells known as alveolar macrophages. "Alveolar macrophages are the lung's first responders, defending the organ against bacteria and dangerous substances like environmental pollutants," said Dr. Aguirre-Ghiso. These specialized macrophages, he notes, appear early in embryonic development and reside within lung tissue for life. "Our findings demonstrate a new role for these macrophages, in which they recognize DCCs and actively interact with them, and--by secreting a protein called TGF-b2--produce signals in the cancer cells that keep them in a dormant state," Dr. Aguirre-Ghiso said. "Since every organ in the body has its own set of tissue-resident macrophages, they may function to keep DCCs in check in those organs as well. Our study has shown for the first time that these specialized macrophages function to actively induce dormancy in DCCs." Confirming the importance of alveolar macrophages in keeping DCCs dormant, Dr. Aguirre-Ghiso and his team found that depleting them in the mice significantly increased the number of activated DCCs and subsequent metastases in their lungs compared to mice with normal levels of the immune cells. As DCCs become more aggressive, the researchers found, they become resistant to the pro-dormancy signals produced by alveolar macrophages. Ultimately, this evasion mechanism enables some DCCs to "wake up" from dormancy and reactivate to form metastases. "Understanding how immune cells keep DCCs in check could lead to new anti-metastatic cell therapies among other strategies," Dr. Aguirre-Ghiso said. For example, he noted, it may be possible to strengthen macrophage signaling so that DCCs never awaken from dormancy or find ways to prevent older DCCs from becoming resistant to dormancy signaling. (ANI)
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