机构:[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.医技科室病理科昆明医科大学附属第一医院[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]School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China[9]Henan Key Laboratory for Esophageal Cancer Research and Department of Pathology of Basic Medical College, Zhengzhou University,Zhengzhou, Henan, P.R. China.
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 TGF beta and NF-kappa B 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.
基金:
Marsico Endowment fund for research; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DE024659, DE015953]; National Nature Science Foundation of ChinaNational Natural Science Foundation of China [81772898]; China Scholarship CouncilChina Scholarship Council [201506240122, 201606240201]; [T32 CA174648]
第一作者机构:[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.
共同第一作者:
通讯作者:
通讯机构:[*1]University of Colorado Anschutz Medical Campus, 12800 East 19th Avenue, Mailstop 8104, Aurora, CO 80045.[*2]State Key Laboratory of Oral Diseases, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, No. 14, Sec. 3, Renmin Road South, Chengdu, Sichuan 610041, P.R. China.[*3]Allander Biotechnologies, LLC, 12635 E. Montview Blvd #100, Aurora, CO 80045
推荐引用方式(GB/T 7714):
Luo Jingjing,Bian Li,Blevins Melanie A.,et al.Smad7 Promotes Healing of Radiotherapy-Induced Oral Mucositis without Compromising Oral Cancer Therapy in a Xenograft Mouse Model[J].CLINICAL CANCER RESEARCH.2019,25(2):808-818.doi:10.1158/1078-0432.CCR-18-1081.
APA:
Luo, Jingjing,Bian, Li,Blevins, Melanie A.,Wang, Dongyan,Liang, Chao...&Wang, Xiao-Jing.(2019).Smad7 Promotes Healing of Radiotherapy-Induced Oral Mucositis without Compromising Oral Cancer Therapy in a Xenograft Mouse Model.CLINICAL CANCER RESEARCH,25,(2)
MLA:
Luo, Jingjing,et al."Smad7 Promotes Healing of Radiotherapy-Induced Oral Mucositis without Compromising Oral Cancer Therapy in a Xenograft Mouse Model".CLINICAL CANCER RESEARCH 25..2(2019):808-818