Reduced Progenitor Function and Altered Immune Landscape Contribute to Field Cancerization of Lung Adenocarcinoma.
Reduced Progenitor Function and Altered Immune Landscape Contribute to Field Cancerization of Lung Adenocarcinoma.
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祖细胞功能降低和免疫景观改变导致肺腺癌局部癌化。
DOI：
10.1164/rccm.202303-0585le
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发表时间：
2023
影响因子：
24.7
通讯作者：
Ghosh,Moumita
中科院分区：
文献类型：
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作者：
Assante,Alexis;Lkhagvadorj,Khosbayar;Clambey,EricT;Danhorn,Thomas;Merrick,DanielT;Keith,RobertL;New,MelissaL;Degregori,James;Miller,YorkE;Ghosh,Moumita
“现场癌变”是指在整个器官中具有组织学正常或癌前表现的非癌相关组织中存在致癌过程。了解这些过程的性质可以为早期致癌提供有价值的线索（1）。长期暴露于致癌物，遗传和表观遗传改变，祖细胞突变和扩散是少数已知的驱动这种效应的机制（2，3）。在肺部，吸烟者的中心气道现场癌变已被证实会导致鳞状细胞癌（2，3）。然而，周围肺的场效应引起的腺癌（ADC）没有得到很好的定义。这一领域的研究使用了肺切除标本，并通过比较肿瘤、肿瘤相邻和未受累肺组织之间的分子差异来评估场效应（4-6）。这种方法有局限性，因为它评估了一个先进的领域，已经引起了癌症，缺乏与肺从类似的受试者没有癌症的比较，不能容纳纵向分析癌前病变。因此，为了确定癌前病变的最早期变化，我们采取了不同的方法，并收集了胸部计算机断层扫描（CT）检测到的不确定结节的高危个体的外周肺刷检。使用导航支气管镜检查从结节对侧的肺以及结节区域获得鞘刷。结节部位的分析因先前为临床目的收集的活检出血而复杂化。因此，我们主要集中在对侧部位，在那里可以获得更干净的外周气道标本。我们假设，恶性结节对侧（对侧/恶性[C/M]）与良性结节对侧（对侧/良性[C/B]）肺中的细胞和分子差异将允许识别与癌症发展相关或允许癌症发展的非常早期的变化，并允许在患有或不患有癌症的受试者之间进行比较（图1A）。其中一些结果以前以摘要的形式报道过（7）。共入组了43例受试者（23例C/M和20例C/B）。平均年龄为6967.3岁。超过90%的参与者是男性和白色。两组的当前吸烟者和既往吸烟者分布相似（C/M组为40%当前吸烟者和43%既往吸烟者，C/B组为45%当前吸烟者和45%既往吸烟者）。C/M组中4例受试者和C/B组中2例受试者从不吸烟。肺功能检查显示，C/M组中患有慢性阻塞性肺疾病的受试者（FEV 1/FVC比值，，70%）多于C/B组（52% vs. 43%），但差异无显著性。两组之间CT检测到的肺气肿发生率也相似（40% vs. 46%）。本报告中所有肺癌受试者均具有ADC。我们最初的特点是细胞类型存在于外周刷免疫染色的细胞离心涂片，显示72.3617。上皮细胞占27.768。2%是免疫细胞。上皮细胞的比例包括28.965。3%角蛋白（K）51基底，11.466。5%Scgb1a11俱乐部，34.368。6%乙酰化微管蛋白阳性（ACT 1）纤毛，和2.461。6%的肺泡表面活性蛋白C1 II型细胞，所有主要细胞类型存在于外周气道。在C/M和C/B肺之间未检测到细胞类型的显著差异。根据Konda及其同事描述的方法，使用三维类器官形成试验来确定上皮祖细胞的功能（8）。五个C/M之间的比较
“Field cancerization” refers to the presence of oncogenic processes in non–cancer-associated tissues with either histologically normal or premalignant appearances throughout the organ. Understanding the nature of these processes can provide valuable clues to early carcinogenesis (1). Prolonged exposure to carcinogens, genetic and epigenetic alterations, progenitor cell mutations, and dispersal are among the few known mechanisms that drive this effect (2, 3). In the lung, field cancerization in smokers is well established for central airways leading to squamous cell cancer (2, 3). However, the field effect of the peripheral lung that gives rise to adenocarcinoma (ADC) is not well defined. Studies in this area have used lung resection specimens and assessed the field effect by comparing molecular differences between tumor, tumor-adjacent, and uninvolved lung tissues (4–6). This approach has limitations because it evaluates an advanced field that has given rise to cancer, lacks comparison with lungs from similar subjects without cancer, and cannot accommodate longitudinal analysis of premalignant lesions. Thus, to identify the earliest changes in the premalignant field, we took a different approach and collected peripheral lung brushings from high-risk individuals with indeterminate nodules detected by chest computed tomography (CT). Navigational bronchoscopy was used to obtain sheathed brushings from the lungs contralateral to the nodule as well as in the nodule area. Analysis of the nodule site was complicated by bleeding from the previous biopsies collected for clinical purposes. Thus, we focused mainly on the contralateral sites, where a cleaner specimen of peripheral airway can be obtained. We hypothesized that cellular and molecular differences in the lungs contralateral to a malignant nodule (contra/malignant [C/M]) versus contralateral to a benign nodule (contra/benign [C/B]) would allow identification of very early changes associated with or permissive of the development of cancer and permit comparison between subjects with or without cancer (Figure 1A). Some of these results were reported previously in the form of an abstract (7).A total of 43 subjects (23 C/M and 20 C/B) were enrolled. The average age was 6967.3 years. Over 90% of participants were male and White. Both groups had similar distributions of current and former smokers (40% current and 43% former smokers for the C/M group vs. 45% current and 45% former smokers for the C/B group). Four subjects in the C/M group and two in the C/B group were never smokers. Pulmonary function testing showed that more subjects from the C/M group had chronic obstructive pulmonary disease (FEV1/FVC ratio,, 70%) than in the C/B group (52% vs. 43%), but the difference was not significant. The rate of emphysema detected by CT was also similar between the two groups (40% vs. 46%). All subjects with lung cancer in this report had ADC. We initially characterized cell types present in the peripheral brushings by immunostaining of cytospins that showed 72.3617. 6% of these cells were epithelial and 27.768. 2% were immune cells. Proportions of epithelial cells included 28.965. 3% keratin (K) 5 1 basal, 11.466. 5% Scgb1a1 1 club, 34.368. 6% acetylated tubulin–positive (ACT 1) ciliated, and 2.461. 6% surfactant protein C 1 alveolar type II cells, all the major cell types present in the peripheral airways. No significant differences in cell types were detected between C/M and C/B lungs. A three-dimensional organoidforming assay was used to determine the function of epithelial progenitor cells according to methods described by Konda and colleagues (8). Comparisons between five C/M …