Division of Head and Neck Surgery, Department of Otolaryngology, Stanford Cancer Institute, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California.
Department of Otorhinolaryngology-Head and Neck Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea.
Clin Cancer Res. 2018 Feb 1;24(3):674-683. doi: 10.1158/1078-0432.CCR-17-0866. Epub 2017 Dec 5.
Head and neck squamous cell carcinoma (HNSCC) is comprised of heterogeneous populations of cells, and CD271 (NGFR; p75NTR) has been associated with a tumor-initiating cell subpopulation. This study assessed the role of CD271 in modulating metastatic behavior in HNSCC. CD271 was overexpressed in murine and human oral squamous cell carcinoma cells to assess the impact of CD271 activation on the invasive and metastatic phenotype of these cells, using and orthotopic modeling. Treatment with human nerve growth factor (NGF) to activate CD271, as well as shRNA knockdown of the CD271-upregulated expression, was used to assess the mechanism of the CD271-induced invasive phenotype. Relevance of CD271 expression in human HNSCC was evaluated in patient-derived xenografts (PDX) and primary human oral cancers, annotated with clinical behavior characteristics and survival data. Forced expression of CD271 resulted in a more invasive and metastatic phenotype. Slug, an epithelial-to-mesenchymal transition (EMT)-related transcription factor, encoded by , was highly expressed in MOC2-CD271 and HSC3-CD271, compared with respective parental cells. CD271 activation by NGF conferred enhanced invasiveness in CD271-overexpressing cells, which was abrogated by knockdown. In PDXs and primary human HNSCC, CD271 expression correlated with higher expression, greater nodal metastasis, and shorter disease-free survival. Activation of CD271 results in upregulation of /Slug, which, in turn, results in a more invasive phenotype and an enhanced capacity for metastasis to regional lymph nodes. These findings point to CD271 as a promising, therapeutic target for oral cancer metastasis. .
头颈部鳞状细胞癌 (HNSCC) 由异质细胞群体组成，CD271（NGFR；p75NTR）与肿瘤起始细胞亚群有关。本研究评估了 CD271 在调节 HNSCC 转移行为中的作用。在鼠和人口腔鳞状细胞癌细胞中过表达 CD271，以评估 CD271 激活对这些细胞侵袭和转移表型的影响，使用 和原位 模型。用人神经生长因子 (NGF) 处理以激活 CD271，以及用 shRNA 敲低 CD271 上调的 表达，用于评估 CD271 诱导的侵袭表型的机制。在患者来源的异种移植物 (PDX) 和原发性人口腔癌中评估 CD271 表达与临床行为特征和生存数据的相关性。CD271 的强制表达导致更具侵袭性和转移性表型。Slug，一种由 编码的上皮-间充质转化 (EMT) 相关转录因子，在 MOC2-CD271 和 HSC3-CD271 中表达高于相应的亲本细胞。NGF 对 CD271 的激活赋予了 CD271 过表达细胞更强的侵袭能力，而 敲低则削弱了这种能力。在 PDX 和原发性人 HNSCC 中，CD271 表达与更高的 表达、更多的淋巴结转移和更短的无病生存期相关。CD271 的激活导致 /Slug 的上调，进而导致侵袭表型增加，并增强向区域淋巴结转移的能力。这些发现表明 CD271 是口腔癌转移有前途的治疗靶点。
