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  • [Clin Cancer Res.]구강암치료 효과에 영향 없이 방사선유도 구내 점막염의 회복을 촉진하는 Smad7 : 이종이식 마우스 모델 연구

    Smad7 Promotes Healing of Radiotherapy-Induced Oral Mucositis without Compromising Oral Cancer Therapy in a Xenograft Mouse Model.

    University of Colorado Anschutz Medical Campus / Xiao-Jing Wang*

  • 출처
    Clin Cancer Res.
  • 등재일
    2019 Jan 15
  • 저널이슈번호
    25(2):808-818. doi: 10.1158/1078-0432.CCR-18-1081. Epub 2018 Sep 5.
  • 내용

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    Abstract
    PURPOSE:
    We previously reported preventive and therapeutic effects of Smad7, a multifunctional protein, on radiotherapy (RT)-induced mucositis in mice without promoting human oral cancer cell survival or migration in vitro. The current study aims to determine whether a Smad7-based biologic can treat existing oral mucositis during radiotherapy for oral cancer and whether this treatment compromises RT-induced cancer cell killing in neighboring oral cancer.

    Experimental Design: We transplanted human oral cancer cells into the tongues of mice and applied craniofacial irradiation to simultaneously kill tumor cells and induce oral mucositis, thus modeling RT and mucositis in oral cancer patients. We topically applied a recombinant human Smad7 protein fused with the cell-penetrating Tat tag (Tat-Smad7) to the oral mucosa of tumor-bearing mice post RT when oral mucositis began to develop.

    RESULTS:
    Topically applied Tat-Smad7 penetrated cells in both the oral mucosa and oral cancer, attenuating TGFβ and NF-κB signaling as well as inflammation at both sites. Tat-Smad7 treatment alleviated oral mucositis with reductions in DNA damage and apoptosis in keratinocytes, but increased keratinocyte proliferation compared with vehicle-treated mucositis lesions. In contrast, adjacent oral cancer exposed to Tat-Smad7 did not show alterations in proliferation or direct DNA damage, but showed increased oxidative stress damage and apoptosis compared with tumors treated with vehicle.

    CONCLUSIONS:
    Our results suggest that short-course Tat-Smad7 application to oral mucositis promotes its healing but does not compromise the cytotoxic effect of RT on oral cancer and has context-specific effects on oral mucosa versus oral cancer.

     


    Author information

    Luo J#1,2, Bian L#2,3,4, Blevins MA5, Wang D2,4, Liang C2, Du D2, Wu F1,2, Holwerda B6, Zhao R5, Raben D7, Zhou H8, Young CD9,4, Wang XJ9,4.
    1
    State Key Laboratory of Oral Diseases, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, P.R. China.
    2
    Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
    3
    Department of Pathology, the First Affiliated Hospital of Kunming Medical University, Kunming, P.R. China.
    4
    Allander Biotechnologies, LLC, Aurora, Colorado.
    5
    Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
    6
    Mtibio, Las Vegas, Nevada.
    7
    Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
    8
    State Key Laboratory of Oral Diseases, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, P.R. China. xj.wang@ucdenver.edu zhouhm@scu.edu.cn Christian.Young@allanderbiotech.com.
    9
    Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. xj.wang@ucdenver.edu zhouhm@scu.edu.cn Christian.Young@allanderbiotech.com.
    #
    Contributed equally

  • 편집위원

    구강암 치료를 위한 방사선에 의한 구강점막염에 대한 분자생물학적인 규명은 활발하긴 했으나, 단일 유전자에 의한 조절에 대한 연구는 미흡했음. 이에 대해, 단일 유전자로서의 Smad7의 전임상적 효과를 규명한 논문이라고 사료됨

    2019-02-26 09:21:27

  • 편집위원

    구강암 치료를 위한 방사선에 의한 구강점막염에 대한 분자생물학적인 규명은 활발하긴 했으나, 단일 유전자에 의한 조절에 대한 연구는 미흡했음. 이에 대해, 단일 유전자로서의 Smad7의 전임상적 효과를 규명한 논문이라고 사료됨

    2019-02-26 09:21:36

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