Researchers from Harvard Medical School, Boston, and the Institute for Systems Biology, Seattle, have discovered that the remains of tumor cells killed by chemotherapy or other cancer treatments can actually stimulate tumor growth by inducing an inflammatory reaction. The study also reveals that a family of molecules called resolvins can suppress this unwanted inflammatory response, suggesting new ways to enhance the effectiveness of existing cancer therapies (J Exp Med 2017; doi:10.1084/jem.20170681).
Conventional, radiation- and drug-based cancer therapies aim to kill as many tumor cells as possible, but the debris left behind by dead and dying cancer cells can stimulate the production of proinflammatory cytokines, signaling molecules that are known to promote tumor growth.
“Dead and dying tumor cells are an underappreciated component of the tumor microenvironment that may promote tumor progression,” explained Charles N. Serhan, PhD, Director of the Center for Experimental Therapeutics and Reperfusion Injury at Brigham and Women's Hospital and Professor at Harvard Medical School. Serhan and colleagues therefore decided to investigate whether tumor cell debris can stimulate tumor growth.
Studying Cell Death
Researchers began by killing laboratory-cultured cancer cells with a variety of cytotoxic or targeted drugs and found that the resulting debris stimulated tumor formation when co-injected into mice with a small number of living cancer cells unable to initiate tumor growth on their own. Similarly, treating mice with the chemotherapy drugs cisplatin and vincristine generated tumor cell debris in vivo that enhanced the ability of surviving cancer cells to form tumors.
“Cytotoxic cancer treatment designed to kill tumor cells may be a double-edged sword that directly contributes to tumor progression and relapse because tumor cell debris stimulates the survival and growth of living tumor cells,” explained Dipak Panigrahy, MD, Assistant Professor of Pathology Beth Israel Deaconess Medical Center, Boston.
The researchers discovered that tumor cell debris promotes tumor growth because a lipid called phosphatidylserine, which is exposed on the surface of dead and dying cells, stimulates the production of proinflammatory cytokines by immune cells known as macrophages.
“We reasoned that if drug-generated debris promotes tumor growth, clearance of debris may mitigate this effect,” noted Mark Kieran, MD, PhD, Associate Professor, Pediatrics, Harvard Medical School; Director, Pediatric Medical Neuro-Oncology, Dana-Farber Cancer Institute; and Associate Professor, Pediatrics, Boston Children's Hospital. “Resolvins are a family of endogenous lipid-derived mediators that stimulate the resolution of inflammation by countering proinflammatory cytokines and increasing the uptake of cell debris into macrophages.”
Treating mice with small amounts of resolvins inhibited debris-stimulated tumor growth and prevented cancer cells from metastasizing. Moreover, resolvin treatment enhanced the activity of various cytotoxic therapies against several different types of tumors.
Resolvins are already in clinical development as potential therapeutic approaches for several inflammatory and neurodegenerative diseases. “Targeting the resolvin pathways provides an entirely new, non-toxic, and non-immunosuppressive approach to cancer therapy by increasing the body's natural production of endogenous pro-resolving and anti-inflammatory mediators,” said Sui Huang, MD, PhD, Molecular and Cell Biologist at the Institute for Systems Biology.
“While generation of tumor cell debris throughout treatment may explain an inherent therapeutic limit to conventional cancer therapies, stimulating the clearance of such debris via specialized pro-resolving mediators, such as resolvins, represents a novel approach to preventing tumor growth and recurrence,” Serhan added.