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Pathway to Prevention

May 21, 2013

mouse tongue exposed to increasing levels of radiationOral mucositis describes deep, often severely inflamed ulcerations of the gums, or mucosa, inside the mouth. These painful sores can arise as a common complication of radiation and/or chemotherapy. It is estimated that up to 40 percent of people with cancer treated with chemotherapy and almost all head and neck cancer patients treated with radiation develop oral mucositis. Few effective treatments are available for the condition, and oral mucositis stands out as an oft-cited cause for interrupting cancer treatment. Indeed, studies estimate that oral mucositis adds on average $18,000 in direct and indirect costs to a patient’s cancer care.

In the April issue of Nature Medicine, NIDCR scientists, grantees, and colleagues add some important new cell-signaling details to guide future prevention strategies for oral mucositis, a common side effect of cancer treatment. They found in mice that certain oral mucosal cells ramp up expression of transforming growth factor b1 (TGF-b1), a much-studied protein with a pro-inflammatory effect in these cells. Importantly, the scientists report that the protein Smad7 naturally targets TGF-b1 and another key signaling pathway to dampen the biological cascade that leads to oral mucositis. They found that a recombinant form of the protein Smad7, when applied topically to mice prior to receiving oral mucositis-inducing levels of radiation to the cranium, resulted in fewer cells undergoing programmed cell death and less infiltration of inflammation-initiating immune cells compared to mice treated with the recombinant protein Palifermin. The latter is approved for preventing oral mucositis in people who receive bone-marrow transplants for hematological cancers, or about 4 percent of those at risk for that specific condition.

The scientists also found in cell studies that Smad7 unblocks the protein Rac1, which is known to be indispensable for oral wound healing. Following up on this lead, they exposed mice in a series of experiments to fractionated or single-high-dose radiation to induce oral mucositis and then treated their lesions with either topical recombinant Smad7 or Palifermin. Those treated with Smad7 had smaller ulcers, less pathological alterations, and, especially in high-dose group, marked wound closure.

The article is titled “Preventive and therapeutic effects of Smad7 on radiation-induced oral mucositis” and is published in the April issue of Nature Medicine. The authors are: Gangwen Han, Li Bian, Fulun Li, Ana Cotrim, Donna Wang, Jian Bo Lu, Yu Deng, Gregory Brid, Anastasia Sowers, James B. Mitchell, J. Silvio Gutkind, Rui Zhao, David Raben, Peter ten Dijke, Yosef Refaeli, Qinghong Zhang, and Xiao-Jing Wang.

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This page last updated: February 26, 2014