Three-dimensional collagen-based scaffold model to study the microenvironment and drug-resistance mechanisms of oropharyngeal squamous cell carcinomas

• 作者: Giacomo Miserocchi Claudia Cocchi Alessandro De Vita Chiara Liverani Chiara Spadazzi Sebastiano Calpona Giandomenico Di Menna Massimo Bassi Giuseppe Meccariello Giovanni De Luca Angelo Campobassi Maria Maddalena Tumedei Alberto Bongiovanni Valentina Fausti Franco Cotelli Toni Ibrahim Laura Mercatali
• 来源期刊: 癌症生物学与医学（英文版）
• 年，卷（期）: 2021,（2）
• 所属期刊栏目: ORIGINAL ARTICLE
• 页码范围: 502-516
• 页数: 15页
• 语种: 英文
• DOI: 10.20892/j.issn.2095-3941.2020.0482

摘要

Objective:Squamous cell carcinoma (SCC) represents the most common histotype of all head and neck malignancies and includes oropharyngeal squamous cell carcinoma (OSCC), a tumor associated with different clinical outcomes and linked to human papilloma virus (HPV) status. Translational research has few available in vitro models with which to study the different pathophysiological behavior of OSCCs. The present study proposes a 3-dimensional (3D) biomimetic collagen-based scaffold to mimic the tumor microenvironment and the crosstalk between the extracellular matrix (ECM) and cancer cells. Methods:We compared the phenotypic and genetic features of HPV-positive and HPV-negative OSCC cell lines cultured on common monolayer supports and on scaffolds. We also explored cancer cell adaptation to the 3D microenvironment and its impact on the efficacy of drugs tested on cell lines and primary cultures. Results:HPV-positive and HPV-negative cell lines were successfully grown in the 3D model and displayed different collagen fiber organization. The 3D cultures induced an increased expression of markers related to epithelial-mesenchymal transition (EMT) and to matrix interactions and showed different migration behavior, as confirmed by zebrafish embryo xenografts. The expression of hypoxia-inducible factor 1α (1α) and glycolysis markers were indicative of the development of a hypoxic microenvironment inside the scaffold area. Furthermore, the 3D cultures activated drug-resistance signaling pathways in both cell lines and primary cultures. Conclusions:Our results suggest that collagen-based scaffolds could be a suitable model for the reproduction of the pathophysiological features of OSCCs. Moreover, 3D architecture appears capable of inducing drug-resistance processes that can be studied to better our understanding of the different clinical outcomes of HPV-positive and HPV-negative patients with OSCCs.