School of Life Sciences, Anhui Medical University, Hefei 230032, China; The First Clinical Medical College of Anhui Medical University, Hefei 230032, China; Henan International Joint Laboratory of Non-coding RNA and Metabolism in Cancer, Henan Provincial Key Laboratory of Long Non-coding RNA and Cancer Metabolism, Translational Research Institute of Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Zhengzhou, Henan, China.
The First Clinical Medical College of Anhui Medical University, Hefei 230032, China.
Int Immunopharmacol. 2024 Oct 25;140:112803. doi: 10.1016/j.intimp.2024.112803. Epub 2024 Aug 1.
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.
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.
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.
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.
肺纤维化（PF）导致肺部纤维结缔组织过度沉积，增加了肺癌的风险，这是由于成纤维细胞（FBs）活性增强所致。成纤维细胞介导的胶原纤维沉积形成了肿瘤样微环境，为肿瘤发生奠定了基础。临床上，已经观察到许多由肺纤维化引起的肺癌病例。近年来，对核苷酸点突变的研究取得了显著进展，与基因表达相比，核苷酸点突变提供了更详细的见解，为临床研究提供了新的视角。
我们首先采用孟德尔随机化确定 PF 诱导的肺癌早期属于小细胞肺癌（SCLC）。随后，通过伪时间序列分析确定肺神经内分泌细胞（PNECs）为具有致癌潜能的细胞簇。我们根据细胞代谢将 FBs 分为四组，然后分析 FBs 与 PNECs 之间的细胞通讯以及 PNECs 细胞内途径的变化。此外，我们还研究了与 PF 显著相关的 FBs 的特征基因组，并探讨了 FBs 对 PF 微环境中免疫细胞的影响。最后，我们探索了预防 PF 向肺癌进展的策略。
揭示了 PF 组织中具有致癌潜能的细胞的遗传特征，其特征是 Achaete-Scute Family BHLH Transcription Factor 1（ASCL1）、Homeobox B2（HOXB2）、Teashirt Zinc Finger Homeobox 2（TSHZ2）、Insulinoma-associated 1（INSM1）上调，以及 RE1 Silencing Transcription Factor（REST）活性降低。具有高糖酵解和低三羧酸（TCA）循环特征的 FBs 在 PF 进展中发挥关键作用。PF 的微环境类似于肿瘤微环境，为癌细胞的发生提供了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，该位点的突变增加了补体因子 B（CFB）的表达，补体途径的过度激活是导致肺纤维化患者发生肺癌的关键因素。确保充足的营养供应和身体功能是预防从肺纤维化向肺癌进展的有效措施之一。
CFB 通过诱导大量单核细胞/巨噬细胞在肺部的积累和极化，促进肺癌的发生，同时降低肺纤维化患者的身体适应性，从而推动疾病的进展。
