背景:肺纤维化(PF)导致肺中纤维结缔组织的过度沉积,由于成纤维细胞(FBs)的活性增强,增加了肺癌的风险。成纤维细胞介导的胶原纤维沉积创造了肿瘤样的微环境,为肿瘤发生奠定基础。临床上,已观察到许多由肺纤维化引起的肺癌病例。近年来,核苷酸点突变的研究,它提供了比基因表达更详细的见解,取得了重大进展,为临床研究提供新的视角。
方法:我们最初采用孟德尔随机化来确定PF诱导的肺癌的初始阶段属于小细胞肺癌(SCLC)。随后,肺神经内分泌细胞(PNEC)通过假时间序列分析鉴定为具有致癌潜力的细胞簇.我们根据细胞代谢将FBs分为四组,然后分析了FB和PNEC之间的蜂窝通信,以及PNEC细胞内途径的变化。此外,我们检查了与PF显着相关的FBs的特征基因组,并研究了FBs对PF微环境中免疫细胞的影响。最后,我们探索了防止PF进展为肺癌的策略.
结果:揭示了PF组织中具有致癌潜能的细胞的遗传特征,以Achaete-Scute家族BHLH转录因子1(ASCL1)上调为特征,HomeoboxB2(HOXB2),Teashirt锌指Homeobox2(TSHZ2),胰岛素瘤相关1(INSM1),RE1沉默转录因子(REST)的活性降低。以高糖酵解和低三羧酸(TCA)循环为特征的FBs在PF的发展中起着关键作用。PF的微环境类似于肿瘤微环境,为癌细胞的发生提供有利的免疫抑制环境。在树突状细胞中,rs9265808是从肺纤维化进展为肺癌的易感位点,该基因座的突变增加了补体因子B(CFB)的表达,补体通路的过度激活是导致肺纤维化患者肺癌发展的关键因素。确保充足的营养供应和身体机能是防止肺纤维化进展为肺癌的有效措施之一。
结论:CFB通过诱导肺中大量单核细胞/巨噬细胞的积累和极化促进肺癌的发生,通过降低肺纤维化患者的身体素质来驱动疾病进展。
BACKGROUND: Pulmonary fibrosis (PF) leads to excessive deposition of fibrous connective tissue in the lungs, increasing the risk of lung cancer due to the enhanced activity of fibroblasts (FBs). Fibroblast-mediated collagen fiber deposition creates a tumor-like microenvironment, laying the foundation for tumorigenesis. Clinically, numerous cases of lung cancer induced by pulmonary fibrosis have been observed. In recent years, the study of nucleotide point mutations, which provide more detailed insights than gene expression, has made significant advancements, offering new perspectives for clinical research.
METHODS: We initially employed Mendelian randomization to ascertain that the initial stage of lung cancer induced by PF belongs to small cell lung cancer (SCLC). Subsequently, pulmonary neuroendocrine cells (PNECs) were identified by using pseudo-time series analysis as cell clusters with carcinogenic potential. We categorized FBs into four groups according to their cellular metabolism, and then analyzed the cellular communication between FBs and PNECs, as well as changes in intracellular pathways of PNECs. Additionally, we examined the characteristic genome of FBs which is significantly associated with PF and investigated the impact of FBs on immune cells in the PF microenvironment. Finally, we explored strategies for preventing the progression from PF to lung cancer.
RESULTS: The genetic features of cells with carcinogenic potential in PF tissues were revealed, characterized by upregulation of Achaete-Scute Family BHLH Transcription Factor 1 (ASCL1), Homeobox B2 (HOXB2), Teashirt Zinc Finger Homeobox 2 (TSHZ2), Insulinoma-associated 1 (INSM1), and reduced activity of RE1 Silencing Transcription Factor (REST). FBs characterized by high glycolysis and low tricarboxylic acid (TCA) cycling played a key role in the progression of PF. The microenvironment of PF resembles the tumor microenvironment, providing a conducive immunosuppressive environment for the occurrence of cancer cells. In dendritic cells, rs9265808 is a susceptibility locus for progression from pulmonary fibrosis to lung cancer, mutations at this locus increase the expression of Complement Factor B (CFB), and excessive activation of the complement pathway is a crucial factor leading to lung cancer development in patients with pulmonary fibrosis. Ensuring adequate nutritional supply and physical function is one of the effective measures to prevent progression from pulmonary fibrosis to lung cancer.
CONCLUSIONS: CFB promotes lung cancer occurrence by inducing the accumulation and polarization of a large number of monocytes/macrophages in the lungs, driving disease progression by reducing the physical fitness of patients with pulmonary fibrosis.