Radiation-Induced Dedifferentiation of Head and Neck Cancer Cells Into Cancer Stem Cells Depends on Human Papillomavirus Status.
Radiation-Induced Dedifferentiation of Head and Neck Cancer Cells Into Cancer Stem Cells Depends on Human Papillomavirus Status.
复制标题
DOI：
10.1016/j.ijrobp.2016.01.005
复制
发表时间：
2016-04-01
期刊：
影响因子：
--
通讯作者：
Pajonk F
中科院分区：
文献类型：
--
作者：
Vlashi E;Chen AM;Boyrie S;Yu G;Nguyen A;Brower PA;Hess CB;Pajonk F
人乳头瘤病毒(HPV-16)是头颈部鳞状细胞癌(HNSCCs)患者最重要的预后因素之一。与HPV阴性的HNSCC相比，HPV阳性的HNSCC对放射治疗(RT)有良好的反应，总体存活率(OS)更高。然而，对HPV阳性的HNSCC固有的放射敏感性的机制的解释仍然难以捉摸。回顾了162名HNSCC患者的队列记录，他们的预后与他们的HPV状态相关。利用一组表达肿瘤干细胞(CSCs)报告基因的HPV阳性和HPV阴性的HNSCC细胞系，我们通过流式细胞术、体外分生能力测定和体内有限稀释试验鉴定了HPV阳性和HPV阴性的HNSCC细胞系。用不同剂量的辐射处理非CSCs，用流式细胞仪和qRT-PCR检测非CSCs去分化为CSCs后重编程因子的重新表达。HPV阳性的肿瘤患者具有更好的OS和局部区域控制。HPV阳性的HNSCC细胞株具有较低的CSCs数量，这与放射敏感性呈负相关。HPV阴性的HNSCC细胞系由于增强的自发去分化而缺乏层级。与HPV阳性株相比，来自HPV阴性株的非CSCs表现出辐射诱导的去分化增强，RT诱导山中重编程因子的重新表达。支持HPV阳性的HNSCC的良好预后，我们发现HPV阳性的HNSCC具有(1)较低的CSCs频率，(2)RT可以将HNSCC细胞去分化为CSCs，以及(3)放射诱导的去分化取决于肿瘤的HPV状态。
Human papilloma virus (HPV), HPV-16, is one of the most important prognostic factors for patients with head and neck squamous cell carcinomas (HNSCCs). HPV-positive HNSCCs have a favorable response to radiation therapy (RT) and superior overall survival (OS) compared to HPV-negative HNSCCs. However, an explanation for the mechanisms responsible for the inherent radiosensitivity of HPV-positive HNSCC remains elusive. Records of a cohort of 162 HNSCC patients were reviewed and their outcomes were correlated with their HPV status. Using a panel of HPV-positive and HPV-negative HNSCC cell lines expressing a reporter for cancer stem cells (CSCs) we characterized HPV-positive and HPV-negative lines via flow cytometry, sphereforming capacity assays in vitro, and limiting dilution assays in vivo. Non-CSCs were treated with different doses of radiation and the dedifferentiation of non-CSCs into CSCs was investigated via flow cytometry and qRT-PCR for re-expression of reprogramming factors. Patients with HPV-positive tumors have superior OS and local-regional control. HPV-positive HNSCC cell lines have lower numbers of CSCs, which inversely correlates with radiosensitivity. HPV-negative HNSCC cell lines lack hierarchy due to enhanced spontaneous dedifferentiation. Non-CSCs from HPV-negative lines show enhanced radiation-induced dedifferentiation compared to HPV-positive lines, and RT induced re-expression of Yamanaka reprogramming factors. Supporting the favorable prognosis of HPV-positive HNSCCs, we show that HPV-positive HNSCCs have (1) a lower frequency of CSCs, (2) RT can dedifferentiate HNSCC cells into CSCs, and (3) radiation-induced dedifferentiation depends on the HPV status of the tumor.