Folaron Margaret, Merzianu Mihai, Duvvuri Umamaheswar, Ferris Robert L, Seshadri Mukund
Department of Oral Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
Department of Pathology and Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
Cancers (Basel). 2019 Jul 6;11(7):951. doi: 10.3390/cancers11070951.
Head and neck squamous cell carcinomas (HNSCC) represent a group of epithelial neoplasms that exhibit considerable heterogeneity in clinical behavior. Here, we examined the stromal and vascular heterogeneity in a panel of patient-derived xenograft (PDX) models of HNSCC and the impact on therapeutic response. Tumor sections from established tumors were stained for p16 (surrogate for human papillomavirus (HPV) infection), stromal (Masson's trichrome) and vascular (CD31) markers. All PDX models retained the HPV/p16 status of the original patient tumor. Immunohistochemical evaluation revealed the presence of multiple vessel phenotypes (tumor, stromal or mixed) in the PDX panel. Vascular phenotypes identified in the PDX models were validated in a tissue microarray of human HNSCC. Treatment with a microtubule targeted vascular disrupting agent (VDA) resulted in a heterogeneous antivascular and antitumor response in PDX models. The PDX with the tumor vessel phenotype that exhibited higher CD31+ vessel counts and leaky vasculature on magnetic resonance imaging (MRI) was sensitive to VDA treatment while the PDX with the stromal vessel phenotype was resistant to therapy. Collectively, our results demonstrate the phenotypic and functional vascular heterogeneity in HNSCC and highlight the impact of this heterogeneity on response to antivascular therapy in PDX models of HNSCC.
头颈部鳞状细胞癌（HNSCC）是一组上皮性肿瘤，其临床行为表现出相当大的异质性。在此，我们研究了一组HNSCC患者来源的异种移植（PDX）模型中的基质和血管异质性及其对治疗反应的影响。对已建立肿瘤的肿瘤切片进行p16（人乳头瘤病毒（HPV）感染的替代指标）、基质（Masson三色染色）和血管（CD31）标志物染色。所有PDX模型均保留了原始患者肿瘤的HPV/p16状态。免疫组织化学评估显示PDX模型组中存在多种血管表型（肿瘤性、基质性或混合性）。在PDX模型中鉴定出的血管表型在人HNSCC组织芯片中得到验证。用一种靶向微管的血管破坏剂（VDA）治疗在PDX模型中导致了异质性的抗血管和抗肿瘤反应。在磁共振成像（MRI）上表现出较高CD31+血管计数和渗漏血管的具有肿瘤血管表型的PDX对VDA治疗敏感，而具有基质血管表型的PDX对治疗耐药。总体而言，我们的结果证明了HNSCC中血管的表型和功能异质性，并突出了这种异质性对HNSCC的PDX模型中抗血管治疗反应的影响。
