A previously unreported mechanism for the growth and spread of cancer has been reported by Muller Fabbri, MD, first author on the paper that recently appeared in the early edition of the Proceedings of the National Academy of Sciences. This mechanism may have implications for all types of cancer as well as other diseases of the immune system. Although the study is preclinical, it provides a rationale for the development of new cancer treatments.
Muller Fabbri, MD, The Saban Research Institute of Children’s Hospital Los Angeles (Photo: Business Wire)
“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, MD, 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 Los Angeles. “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 from a healthy patient. 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 new 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, MD, director of Ohio State’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 of small vesicles, called exosomes, and the surrounding immune cells, that are normally present in the tumor, are able to capture and engulf these exosomes and the miRNAs contained in them. They 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 shows 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 completely new 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.
Stuart Siegel, MD, director of the Children’s Center for Cancer and Blood Diseases commented, “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. We hope to take advantage of these discoveries to develop more effective treatments for cancer in children and adults.”
Fabbri performed the research at Ohio State University in the lab of Carlo M. Croce, MD. He will be continuing this work at the Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles. He is also an assistant professor of Pediatrics and Molecular Biology and Immunology at the Keck School of Medicine of the University of Southern California.
About Children’s Hospital Los Angeles
Children’s Hospital Los Angeles has been named the best children’s hospital in California and among the top five in the nation for clinical excellence with its selection to the prestigious US News & World Report Honor Roll. Children’s Hospital is home to The Saban Research Institute, one of the largest and most productive pediatric research facilities in the United States, is one of America’s premier teaching hospitals and has been affiliated with the Keck School of Medicine of the University of Southern California since 1932. For more information, visit www.CHLA.org.