The treatment of cancer focuses on reduces tumor burden by killing tumor cells. However, the remains of these cells killed by chemotherapy simultaneously creates tumor cell debris that may stimulate inflammation and tumor growth. As a result, conventional cancer therapy may inherently be a double-edged sword.
This discovery, by researchers from Harvard Medical School and the Institute of Systems Biology, was published in the November 30, 2017 online issue of The Journal of Experimental Medicine.
The study also shows that a family of molecules called resolvins can suppress this unwanted inflammatory response, suggesting new ways to enhance the effectiveness of existing cancer therapies.
Cytotoxic cancer treatment designed to kill tumor cells may be a double-edged sword that directly contributes to tumor progression and relapse…
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, Ph.D, at the Department of Anesthesiology, Perioperative and Pain Medicine, Department of Oral Medicine, Infection and ImmunityBrigham and Women’s Hospital, Harvard Medical School.
Based in these results, Serhan and colleagues decided to investigate whether tumor cell debris can stimulate tumor growth. In addition to Serhan, the research team was led by Mark Kieran from the Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Sui Huang from the Institute of Systems Biology in Seattle, and Dipak Panigrahy from the Beth Israel Deaconess Medical Center, Harvard Medical School. Megan Sulciner is the paper’s lead author along with co-lead authors Molly Gilligan and Dayna Mudge.
Sulciner and her team 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,” Panigrahy noted.
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,” Kieran explaned.
Resolvins are molecules generated from ω-3 PUFA (Omega-3 polyunsaturated fatty acids) precursors and can orchestrate the timely resolution of inflammation in model systems.
Since dysregulation of pro-resolving mediators is associated with diseases of prolonged inflammation, designing pharmacological mimetics of naturally occurring pro-resolving mediators offers exciting new targets for drug design.
“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 antiinflammatory mediators,” Huang said
“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 concluded.
Last Editorial Review: November 30, 2017
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