The mechanism may have implications for all types of cancer, as well as other diseases of the immune system. Though the study is preclinical, it provides a rationale for the development of new cancer treatments.
“To design innovative treatments against diseases like cancer, researchers need to identify potential vulnerabilities in how the disease develops. Dr. Fabbri and his colleagues have accomplished that goal,” said Brent Polk, chairman of the Keck School’s Department of Pediatrics and director of The Saban Research Institute of Children’s Hospital Los Angeles.
“In this study, we discovered a completely new mechanism used by cancer to develop, grow and spread,” said Fabbri, a researcher at the Children’s Center for Cancer and Blood Diseases at Children’s Hospital. “But what is even more exciting is that now we have identified a key mechanism used by cancer cells to grow and disseminate, and therefore we can develop new drugs that can fight tumors by entering this newly identified breach in cancer’s fortress. Finally, we show that this mechanism involves TLR8, a fundamental receptor of the immune system, suggesting that the implications of this discovery may extend to other diseases, such as autoimmune and inflammatory diseases.”
Scientists have shown that small fragments of RNA, called micro-RNA or miRNA, are present in the blood of cancer patients at different levels than in healthy patients, and this has led to the conclusion that miRNAs are excellent biomarkers for the diagnosis of cancer since they can differentiate a cancer-bearing patient from a healthy one.
Cancer cells release miRNAs both into their surrounding micro-environment and into the circulation. This is the first report showing that a previously unknown cross-talk between cancer cells and immune cells, mediated by cancer cell-released miRNAs, represents a mechanism for the growth and spread of cancer cells.
“This study reveals a new function of microRNA, which we show binds to a protein receptor,” said Carlo Croce, director of Ohio State University’s Human Cancer Genetics program, where the study was performed. “This tells us that some cancer-released microRNAs can bind and activate a receptor in a hormone-like fashion, and this has not been seen before.”
Fabbri, Croce and their colleagues demonstrated that lung cancer cells are able to secrete miRNAs inside small vesicles called exosomes. The surrounding immune cells, which are normally present in the tumor, are able to capture and engulf these exosomes and the miRNAs contained in them.
The researchers found that two miRNAs contained in the exosome (called miR-21 and miR-29a) are able to bind to a receptor called toll-like receptor 8 (TLR8). Once miRNA binds to TLR8 in the immune cells, it activates the receptor and causes the release of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a), resulting in proliferation and increased metastatic potential of the cancer cells. The study also showed that immune cells within a tumor may be unable to destroy cancer cells and may actually be necessary for their growth and dissemination.
The clinical implications of this discovery are significant since identifying a previously unknown mechanism used by cancer cells provides a new opportunity for therapeutic intervention. Developing drugs that interfere with the cancer cell’s ability to release this miRNA-mediated signal to the surrounding immune cells may effectively interfere with the ability of cancer to grow and spread.
“As new technology allows researchers to ‘peel the onion’ back on how cancer cells actually grow and spread, discoveries such as the one described by Dr. Fabbri and his colleagues help us put this complex puzzle together and offer us new paths to launch attacks on the basic mechanisms that control the deadly behavior of these cells,” Stuart Siegel, professor of pediatrics at the Keck School and director of the Children’s Center for Cancer and Blood Diseases, said. “We hope to take advantage of these discoveries to develop more effective treatments for cancer in children and adults.”
University of Southern California Los Angeles, CA 90089