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December 5, 2017

“Resolvin” Cancer Cell Debris: Clearing Every Litter Bit Improves Therapy

  • Conventional cancer therapy can generate a dangerous mess—dying, dead, and disintegrating cancer cells. As the cancer cell debris piles up, it worsens the tumor microenvironment, which becomes proinflammatory and even starts promoting tumor growth. The debris, however, needn’t be left to accumulate like so much roadside trash. It can be cleared away by resolvins, molecules that occur naturally in the body and are currently entering clinical development.

    Tidying up the debris-strewn tumor microenvironment, suggest researchers based at Brigham and Women's Hospital (BWH), could enhance the effectiveness of current cancer therapies and prevent tumor recurrence. These researchers have demonstrated that chemotherapy or radiotherapy is a double-edged sword, killing tumor cells but contributing to the release of proinflammatory cytokines. If the debris is so harmful, the researchers reasoned, perhaps clearing it away would be beneficial.

    The BWH-based team, which included Prof. Charles Serhan, Ph.D., D.Sc., the discoverer of resolvins, put their litter-clearing idea to the test in cell cultures and animal models. The results of this work appeared November 30 in The Journal of Experimental Medicine, in an article entitled “Resolvins Suppress Tumor Growth and Enhance Cancer Therapy.”

    “In this study, we show that tumor cells killed by chemotherapy or targeted therapy (“tumor cell debris”) stimulate primary tumor growth when coinjected with a subthreshold (nontumorigenic) inoculum of tumor cells,” wrote the article’s authors. “Debris-stimulated tumors were inhibited by antiinflammatory and proresolving lipid autacoids, namely resolvin D1 (RvD1), RvD2, or RvE1.”

    The authors noted that tumor cell debris triggers macrophage proinflammatory cytokine release after phosphatidylserine exposure. But debris clearance, the authors added, can be enhanced by the resolvins, which promote macrophage phagocytosis. This effect was observed in multiple tumor types.

    In this study, the BWH-based team administered a variety of therapeutic drugs to lab-cultured cancer cells and collected the resulting debris. When co-injected into mice with a small number of nongrowing cancer cells, the debris stimulated tumor formation. A similar test treated mice with the chemotherapy drugs such as cisplatin and vincristine to generate debris in vivo, supporting the conclusion that the debris helped surviving cancer cells form tumors. The researchers concluded that a lipid called phosphatidylserine stimulated immune cells to produce a "cytokine storm" when exposed to the cancerous cells and caused the growth.

    "Dead and dying tumor cells are an underappreciated component of the tumor microenvironment that may promote tumor progression," said Charles Serhan, Ph.D.

    Next, the researchers focused on the body's own resolvins, which act as stop signals to end or "resolve" the inflammation. Resolvins counter the debris-stimulated proinflammatory cytokines and stimulate the immune system, including white blood cells called macrophages ("the big eaters"), to remove or "mop up" the debris. Resolvins are biosynthesized by the body from omega-3 essential fatty acids. Resolvins are a new approach to turn off inflammation in the human body to prevent a cytokine storm rather than blocking a single proinflammatory factor

    Treating mice with small amounts of resolvins inhibited the subsequent therapy-stimulated tumor growth and prevented cancer cells from spreading. Resolvin treatment enhanced the activity of several cytotoxic therapies against a variety of tumor types resulting in tumor regression. Clinical developments using resolvins as potential therapeutic approaches are already in progress for several inflammatory and neurodegenerative diseases.

    "Stimulating the clearance of tumor cell debris via specialized pro-resolving mediators represents a new approach to prevent tumor growth and recurrence," the authors concluded.

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