Idiopathic Pulmonary Fibrosis and Lung Cancer: Finding Similarities within Differences.
Idiopathic Pulmonary Fibrosis and Lung Cancer: Finding Similarities within Differences.
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特发性肺纤维化和肺癌：在差异中寻找相似之处。
DOI：
10.1165/rcmb.2019-0172ed
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发表时间：
2019
影响因子：
6.4
通讯作者：
Gottardi,CaraJ
中科院分区：
文献类型：
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作者：
Reyfman,PaulA;Gottardi,CaraJ
特发性肺纤维化（IPF）和非小细胞肺癌（NSCLC）有着共同的重要风险因素，包括高龄和吸烟。此外，尼达尼布（一种小分子酪氨酸激酶抑制剂）在减缓IPF进展（1）以及治疗NSCLC方面的有效性证据激发了人们的希望，即癌症和纤维化中类似的上皮“转化”特征可能支持将其他癌症疗法重新用于治疗IPF（2，3）。然而，尼达尼布治疗IPF和NSCLC的潜在有效性掩盖了这两种疾病过程的病理生物学差异。尽管NSCLC的发展特征是肺上皮细胞（包括TP 53、KRAS和EGFR）中特征性体细胞遗传学改变的积累，导致恶性克隆扩增并最终转移（4），但没有证据表明体细胞突变、克隆上皮细胞扩增或转移与IPF的生物学相关。尽管存在这些差异，但越来越多的可用于治疗癌症的小分子作为IPF治疗的潜在来源是有吸引力的;然而，如何最好地确定哪些可能提供最有希望的治疗仍然是一个悬而未决的问题。在本期杂志中，Ulke和他的同事们（pp. 713-726）通过对可获得的NSCLC和IPF数据集进行基因集富集分析来解决这个问题（5）。从NSCLC患者与对照受试者相比上调的基因开始，作者确定了一组与IPF共有的92个基因。这些基因在从用博来霉素损伤的小鼠肺或从IPF患者分离的肺泡上皮2型（AT 2）细胞中比从相同患者分离的成纤维细胞更强烈地富集，这可能与NSCLC的上皮起源一致。（基因本体论，基因和基因组的京都百科全书，和Reactome），作者发现NSCLC和IPF最共有的上调基因主要与有丝分裂/细胞周期控制相关。ECT 2（上皮细胞转化-2）是Rho家族GTP酶的一种鸟嘌呤核苷酸交换因子（即激活剂），由于其先前描述的致癌活性以及在胞质分裂和ERK（细胞外信号调节激酶）信号传导中的既定作用，因此选择ECT 2进行进一步分析（6）。作者很好地证实了IPF患者肺泡上皮中ECT 2蛋白的上调，这些细胞似乎是共表达增殖标记物PCNA（增殖细胞核抗原）的大型增生性AT 2细胞。他们还发现，原代AT 2细胞（从博来霉素损伤的小鼠中分离，并表现出ECT 2表达升高）通过流式分析显示出DNA含量增加，以及合成（S期细胞周期蛋白D1表达）。相反，在这些相同的细胞中瞬时敲低ETC 2会减少DNA合成。这些
Idiopathic pulmonary fibrosis (IPF) and non–small cell lung cancer (NSCLC) share important risk factors, including advanced age and cigarette smoking. Moreover, evidence of the efficacy of nintedanib, a small-molecule tyrosine kinase inhibitor, for slowing the progression of IPF (1) as well as for treating NSCLC has fueled hopes that similar epithelial “transformation” profiles in cancer and fibrosis might support the repurposing of other cancer therapies for treatment of IPF (2, 3). However, the potential usefulness of nintedanib for treating IPF and NSCLC belies critical differences in the pathobiology of these two disease processes. Although the development of NSCLC is characterized by the accumulation of characteristic somatic genetic alterations in lung epithelial cells, including in TP53, KRAS, and EGFR, leading to the expansion of malignant clones and ultimately metastasis (4), there is no evidence that somatic mutations, clonal epithelial cell expansion, or metastasis are relevant to the biology of IPF. Despite these differences, the growing array of small molecules available for the treatment of cancer is attractive as a potential source of therapies for IPF; however, how to best determine which ones might offer the most promise remains an open question. In this issue of the Journal, Ulke and colleagues (pp. 713–726) tackle this question by performing a gene set enrichment analysis of publically available NSCLC and IPF data sets (5). Starting with genes that were upregulated in patients with NSCLC compared with control subjects, the authors identified a set of 92 genes that were shared with IPF. These genes were more strongly enriched in alveolar epithelial type 2 (AT2) cells isolated from mouse lungs injured with bleomycin or from patients with IPF than fibroblasts isolated from the same patients, perhaps consistent with the epithelial origins of NSCLC.Using standard gene set analysis databases (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Reactome), the authors found that the upregulated genes that were most shared by NSCLC and IPF were largely associated with mitosis/cell-cycle control. ECT2 (epithelial cell transformation-2), a guanine nucleotide exchange factor (ie, activator) for Rho-family GTPases, was chosen for further analysis because of its previously described oncogenic activity and established roles in cytokinesis and ERK (extracellular-signal–regulated kinase) signaling (6). The authors nicely verified upregulation of ECT2 protein in the alveolar epithelium of patients with IPF, in what appeared to be large hyperplastic AT2 cells coexpressing the proliferation marker PCNA (proliferating cell nuclear antigen). They also found that primary AT2 cells (isolated from bleomycin-injured mice and manifesting elevated ECT2 expression) showed enhanced DNA content by flow analysis, as well as synthesis (S-phase cyclin D1 expression). Conversely, transient knockdown of ETC2 in these same cells reduced DNA synthesis. These