Sayed Ibrahim M, Chakraborty Anirban, Inouye Kaili, Dugan Leanne, Tocci Stefania, Advani Ira, Park Kenneth, Gaboyan Samvel, Kasaraneni Nikita, Ma Benjamin, Hazra Tapas K, Das Soumita, Crotty Alexander Laura E
Department of Pathology, University of California, San Diego, CA, 92093, USA.
Department of Biomedical and Nutritional Sciences, Zuckerberg College of Health Sciences, University of Massachusetts Lowell, Lowell, MA, 01854, USA.
Arch Toxicol. 2025 Mar;99(3):1223-1236. doi: 10.1007/s00204-024-03932-x. Epub 2025 Jan 9.
E-cigarettes (E.cigs) cause inflammation and damage to human organs, including the lungs and heart. In the gut, E.cig vaping promotes inflammation and gut leakiness. Further, E.cig vaping increases tumorigenesis in oral and lung epithelial cells by inducing mutations and suppressing host DNA repair enzymes. It is well known that cigarette (cig) smoking increases the risk of colorectal cancer (CRC). To date, it is unknown whether E.cig vaping impacts CRC development. A mouse model of human familial adenomatous polyposis (CPC-APC) was utilized wherein a mutation in the adenomatous polyposis coli (APC) gene, CDX2-Cre-APC, leads to the development of colon adenomas within 11-16 weeks. Mice were exposed to air (controls), E.cig vaping, cig, or both (dual exposure). After 4 weeks of 2 h exposures per day (1 h of each for dual exposures), the colon was collected and assessed for polyp number and pathology scores by microscopy. Expression of inflammatory cytokines and cancer stem cell markers were quantified. DNA damage such as double-strand DNA breaks was evaluated by immunofluorescence, western blot, and gene-specific long amplicon qPCR. DNA repair enzyme levels (NEIL-2, NEIL-1, NTH1, and OGG1) were quantified by western blot. Proliferation markers were assessed by RT-qPCR and ELISA. CPC-APC mice exposed to E.cig, cig, and dual exposure developed a higher number of polyps compared to controls. Inflammatory proteins, DNA damage, and cancer stemness markers were higher in E-cig, cig, and dual-exposed mice as well. DNA damage was found to be associated with the suppression of DNA glycosylases, particularly with NEIL-2 and NTH1. E.cig and dual exposure both stimulated cancer cell stem markers (CD44, Lgr-5, DCLK1, and Ki67). The effect of E.cigs on polyp formation and CRC development was less than that of cigs, while dual exposure was more tumorigenic than either of the inhalants alone. E.cig vaping promotes CRC by stimulating inflammatory pathways, mediating DNA damage, and upregulating transcription of cancer stem cell markers. Critically, combining E.cig vaping with cig smoking leads to higher levels of tumorigenesis. Thus, while the chemical composition of these two inhalants, E.cigs and cigs, is highly disparate, they both drive the development of cancer and when combined, a highly common pattern of use, they can have additive or synergistic effects.
电子烟会导致人体器官发炎和损伤，包括肺部和心脏。在肠道中，吸电子烟会加剧炎症并导致肠漏。此外，吸电子烟会通过诱导突变和抑制宿主DNA修复酶，增加口腔和肺上皮细胞的肿瘤发生。众所周知，吸烟会增加患结直肠癌（CRC）的风险。迄今为止，尚不清楚吸电子烟是否会影响结直肠癌的发展。我们使用了一种人类家族性腺瘤性息肉病（CPC-APC）小鼠模型，其中腺瘤性息肉病基因（APC）发生突变，即CDX2-Cre-APC，会在11至16周内导致结肠腺瘤的形成。将小鼠暴露于空气（对照组）、吸电子烟、吸烟或两者同时暴露（双重暴露）。每天暴露2小时，持续4周（双重暴露时每种各1小时）后，收集结肠，通过显微镜检查评估息肉数量和病理评分。对炎性细胞因子和癌症干细胞标志物的表达进行定量分析。通过免疫荧光、蛋白质印迹和基因特异性长扩增子定量聚合酶链反应（qPCR）评估双链DNA断裂等DNA损伤情况。通过蛋白质印迹对DNA修复酶水平（NEIL-2、NEIL-1、NTH1和OGG1）进行定量分析。通过逆转录定量聚合酶链反应（RT-qPCR）和酶联免疫吸附测定（ELISA）评估增殖标志物。与对照组相比，暴露于电子烟、香烟和双重暴露的CPC-APC小鼠长出的息肉更多。在暴露于电子烟、香烟和双重暴露的小鼠中，炎性蛋白、DNA损伤和癌症干性标志物也更高。发现DNA损伤与DNA糖基化酶的抑制有关，特别是与NEIL-2和NTH1有关。电子烟和双重暴露均会刺激癌细胞干细胞标志物（CD44、Lgr-5、双皮质素样激酶1（DCLK1）和Ki-67）。电子烟对息肉形成和结直肠癌发展的影响小于香烟，而双重暴露比单独任何一种吸入物更具致瘤性。吸电子烟通过刺激炎症途径、介导DNA损伤和上调癌症干细胞标志物的转录来促进结直肠癌的发生。至关重要的是，将吸电子烟与吸烟相结合会导致更高水平的肿瘤发生。因此，虽然这两种吸入物，即电子烟和香烟的化学成分截然不同，但它们都会促使癌症发展，而且当两者结合使用时（这是一种非常常见的使用模式），它们可能会产生相加或协同作用。
