Idiopathic Pulmonary Fibrosis (IPF) is characterized by progressive, often fatal loss of lung function due to overactive collagen production and tissue scarring. IPF patients have a sevenfold-increased risk of developing lung cancer. The COVID-19 pandemic has increased the number of patients with lung diseases, and infection can worsen prognoses for those with chronic lung diseases and disease-associated cancer. Understanding the molecular pathogenesis of IPF associated lung cancer is imperative for identifying diagnostic biomarkers and targeted therapies that will facilitate prevention of IPF and progression to lung cancer. To understand how IPF-associated fibroblast activation, matrix remodeling, epithelial- mesenchymal transition, and immune modulation influences lung cancer predisposition, we developed a mouse model to recapitulate the molecular pathogenesis of pulmonary fibrosis-associated lung cancer using the bleomycin and Lewis Lung Carcinoma models. We demonstrate that development of pulmonary fibrosis-associated lung cancer is likely linked to increased abundance of tumor-associated macrophages and a unique gene signature that supports an immune-suppressive microenvironment through secreted factors. Not surprisingly, pre-existing fibrosis provides a pre-metastatic niche and results in augmented tumor growth, and tumors associated with bleomycin-induced fibrosis are characterized by a dramatic loss of cytokeratin expression, indicative of epithelial-to-mesenchymal transition. Implications: This characterization of tumors associated with lung diseases provides new therapeutic targets that may aid in the development of treatment paradigms for lung cancer patients with pre-existing pulmonary diseases.

中文翻译：

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小鼠特发性肺纤维化相关肺癌的分子发病机制建模

特发性肺纤维化 (IPF) 的特点是由于胶原蛋白生成过度活跃和组织疤痕导致肺功能逐渐丧失，通常是致命的。IPF 患者患肺癌的风险增加七倍。COVID-19 大流行增加了肺部疾病患者的数量，而感染可能会恶化慢性肺部疾病和疾病相关癌症患者的预后。了解 IPF 相关肺癌的分子发病机制对于确定有助于预防 IPF 和进展为肺癌的诊断生物标志物和靶向治疗至关重要。为了了解 IPF 相关成纤维细胞激活、基质重塑、上皮-间质转化和免疫调节如何影响肺癌易感性，我们开发了一种小鼠模型，使用博莱霉素和 Lewis 肺癌模型来概括肺纤维化相关肺癌的分子发病机制。我们证明，肺纤维化相关肺癌的发展可能与肿瘤相关巨噬细胞丰度的增加以及通过分泌因子支持免疫抑制微环境的独特基因特征有关。毫不奇怪，预先存在的纤维化提供了转移前的生态位并导致肿瘤生长增加，而与博莱霉素诱导的纤维化相关的肿瘤的特征是细胞角蛋白表达的急剧丧失，表明上皮到间质的转变。意义：与肺部疾病相关的肿瘤的这一特征提供了新的治疗靶点，可能有助于为患有既往肺部疾病的肺癌患者开发治疗范例。