Tissue-engineered models of lung cancer premalignancy

Lung cancer is the leading global cause of cancer-related deaths. Although smoking cessation is the best preventive action, nearly 50% of all lung cancer diagnoses occur in people who have already quit smoking. Research into treatment options for these high-risk patients has been constrained to rodent models of chemical carcinogenesis, which are time-consuming, expensive, and require large numbers of animals. Here we show that embedding precision-cut lung slices within an engineered hydrogel and exposing this tissue to a carcinogen from cigarette smoke creates an in vitro model of lung cancer premalignancy. Hydrogel formulations were selected to promote early lung cancer cellular phenotypes and extend PCLS viability up to six weeks. In this study, hydrogel-embedded lung slices were exposed to the cigarette smoke derived carcinogen vinyl carbamate, which induces adenocarcinoma in mice. At six weeks, analysis of proliferation, gene expression, histology, tissue stiffness, and cellular content revealed that vinyl carbamate induced the formation of premalignant lesions with a mixed adenoma/squamous phenotype. Two putative chemoprevention agents were able to freely diffuse through the hydrogel and induce tissue-level changes. The design parameters selected using murine tissue were validated with hydrogel-embedded human PCLS and results showed increased proliferation and premalignant lesion gene expression patterns. This tissue-engineered model of human lung cancer premalignancy is the starting point for more sophisticated ex vivo models and a foundation for the study of carcinogenesis and chemoprevention strategies.

肺癌是全球癌症相关死亡的首要原因。尽管戒烟是最佳的预防措施，但近50%的肺癌诊断病例发生在已戒烟的人群中。针对这类高风险患者的治疗研究受限于化学致癌的啮齿动物模型，此类模型耗时漫长、成本高昂，且需大量动物。本研究中，我们将精密切割的肺切片嵌入至工程化水凝胶中，并将该组织暴露于香烟烟雾中的致癌物质，从而创建了一种体外肺癌前病变模型。选用的水凝胶配方旨在促进早期肺癌细胞表型的形成，并延长肺切片的存活时间至六周。在本研究中，水凝胶包裹的肺切片被暴露于香烟烟雾衍生的致癌物质乙烯亚胺中，该物质能在小鼠中诱导腺癌的发生。六周后，对增殖、基因表达、组织学、组织硬度和细胞含量进行分析，发现乙烯亚胺诱导了具有混合腺瘤/鳞状表型的癌前病变的形成。两种潜在的化学预防剂能够自由扩散通过水凝胶并诱导组织层面的变化。使用小鼠组织选定的设计参数，经水凝胶包裹的人类肺切片验证后，结果显示增殖和癌前病变基因表达模式有所增加。此人工构建的人肺癌前病变组织工程模型，是构建更复杂体外模型的开端，也是研究致癌机制和化学预防策略的基础。