Profiling the Stromal and Vascular Heterogeneity in Patient-derived Xenograft Models of Head and Neck Cancer: Impact on Therapeutic Response.

Margaret Folaron,Mukund Seshadri,Robert L Ferris,Mihai Merzianu,Umamaheswar Duvvuri

doi:10.3390/cancers11070951

Margaret Folaron, Mukund Seshadri + Show 3 more

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https://doi.org/10.3390/cancers11070951

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Abstract

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.

Highlights

Head and neck squamous cell carcinomas (HNSCC) are aggressive epithelial neoplasms that can arise in several sites within the upper aero-digestive tract and exhibit considerable heterogeneity in clinical behavior [1,2]
In this study, using patient-derived xenograft (PDX) models, we examined the impact of human papillomavirus (HPV) on tumor angiogenesis and response of HPV+ and HPV− HNSCC to a microtubule-targeted tumor-vascular disrupting agent (VDA), EPC2407 (CrolibulinTM) that has demonstrated potent antivascular and antitumor activity in experimental models of breast, prostate and brain tumors [12,13,14,15]
The role of antiangiogenic agents and VDAs in the treatment paradigm for HNSCC is unclear. These observations along with our results suggest that p16− head and neck tumors that often harbor p53 mutations and exhibit increased angiogenesis could be more susceptible to vascular-targeted therapies such as VDAs and VEGF inhibitors

Summary

Introduction

Head and neck squamous cell carcinomas (HNSCC) are aggressive epithelial neoplasms that can arise in several sites (e.g., oral cavity, pharynx, larynx) within the upper aero-digestive tract and exhibit considerable heterogeneity in clinical behavior [1,2]. Patients with early stage disease exhibit a favorable response to therapy, a majority of HNSCC patients present with advanced stage disease which is associated with a poor prognosis [2,5]. As such there is a critical need to investigate novel treatment strategies for patients that suffer from these esthetically and functionally debilitating cancers. In this regard, patient-derived xenograft (PDX) models of cancer provide an important platform for understanding disease biology and examining therapeutic activity of novel agents [6,7,8]. Studies by us and others have previously reported on the ability of PDX models of HNSCC to reliably mimic

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