Miserocchi Giacomo, Cocchi Claudia, De Vita Alessandro, Liverani Chiara, Spadazzi Chiara, Calpona Sebastiano, Di Menna Giandomenico, Bassi Massimo, Meccariello Giuseppe, De Luca Giovanni, Campobassi Angelo, Maddalena Tumedei Maria, Bongiovanni Alberto, Fausti Valentina, Cotelli Franco, Ibrahim Toni, Mercatali Laura
Osteoncology and Rare Tumors Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola 47014, Italy.
Maxillofacial Surgery Unit, Bufalini Hospital, Cesena 47521, Italy.
Cancer Biol Med. 2021 Mar 27;18(2):502-16. doi: 10.20892/j.issn.2095-3941.2020.0482.
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 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.
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.
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.
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.
鳞状细胞癌（SCC）是所有头颈恶性肿瘤中最常见的组织学类型，包括口咽鳞状细胞癌（OSCC），这是一种与不同临床结局相关且与人乳头瘤病毒（HPV）状态有关的肿瘤。转化研究中用于研究OSCC不同病理生理行为的模型很少。本研究提出一种基于胶原蛋白的三维（3D）仿生支架，以模拟肿瘤微环境以及细胞外基质（ECM）与癌细胞之间的相互作用。
我们比较了在普通单层载体和支架上培养的HPV阳性和HPV阴性OSCC细胞系的表型和基因特征。我们还探讨了癌细胞对3D微环境的适应性及其对在细胞系和原代培养物上测试的药物疗效的影响。
HPV阳性和HPV阴性细胞系在3D模型中成功生长，并呈现出不同的胶原纤维组织。3D培养诱导了与上皮-间质转化（EMT）和基质相互作用相关标志物的表达增加，并显示出不同的迁移行为，斑马鱼胚胎异种移植证实了这一点。缺氧诱导因子1α（HIF-1α）和糖酵解标志物的表达表明支架区域内缺氧微环境的形成。此外，3D培养在细胞系和原代培养物中均激活了耐药信号通路。
我们的结果表明，基于胶原蛋白的支架可能是再现OSCC病理生理特征的合适模型。此外，3D结构似乎能够诱导耐药过程，对其进行研究有助于我们更好地理解HPV阳性和HPV阴性OSCC患者的不同临床结局。
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