Comparative Analysis of Combustible and Electronic Cigarette Exposure in KRAS-Mutant Lung Cancer
The increasing prevalence of electronic cigarette use, particularly among younger demographics, has prompted urgent investigation into its long-term health implications. While combustible cigarette smoke (CCS) is a well-established carcinogen, the oncogenic potential of electronic cigarette vapor (ECV) remains underexplored. A recent study led by Dr. Moghaddam et al. at The University of Texas MD Anderson Cancer Center provides a rigorous comparative analysis of CCS and ECV exposure in a KRAS-mutant lung adenocarcinoma (KM-LUAD) mouse model.
Experimental Design and Exposure Protocol
To simulate real-world exposure scenarios, researchers employed a genetically engineered CCSPCre/LSL-K-rasG12D mouse model, which induces tumorigenesis specifically in the airway epithelium. Mice were exposed to either room air (control), CCS, or ECV for 2 hours daily, 5 days per week, over an 8-week period.
The SCIREQ Integrated Cigarette Smoking Robot was used for CCS exposure. The robot administered three puffs per minute using 3R4F research cigarettes, up to 24 cigarettes per session. For ECV exposure, the same robot was adapted to deliver vaporized nicotine (72 mg/mL) diluted in propylene glycol and vegetable glycerin, replicating typical e-cigarette formulations.
This automated system ensured reproducibility and accurate dosing, validated by serum cotinine levels exceeding 3.08 ng/mL—an established threshold distinguishing smokers from non-smokers.
Key Findings
Tumor Burden
Only CCS exposure significantly increased lung tumorigenesis, with:
- Increased tumor count and area compared to both ECV and control groups.
- Adenocarcinoma-like lesions predominant in CCS-exposed mice
- Elevated markers of proliferation (Ki67), angiogenesis (ERG), and apoptosis (CC3) in CCS-exposed lungs.
Immune Modulation
Both CCS and ECV induced a pro-tumor immunosuppressive phenotype, characterized by:
- Reduced the presence of effector cytotoxic T cells
- Increased CD4⁺ FoxP3⁺ regulatory T cells
- Elevated IL-10 immunosuppressive marker expression and reduced NOS2, ARG1, and IFNG transcripts
However, ECV exposure led to a monocytic-dominant myeloid response, contrasting with the granulocytic profile seen in CCS-exposed mice, potentially explaining the differential tumorigenic outcomes.
Microbiome and Metabolome Alterations
Both exposures disrupted lung and gut microbiota. Metabolomic profiling revealed important changes in host and microbial metabolism, with a distinct metabolic impact:
- CSS exposure was associated with oxidative stress, inflammation, and lipid dysregulation in the lungs
- ECV exposure leads to mitochondrial lipid changes and increased microbial indole derivatives
Conclusion
This study reveals that electronic cigarette vapor, while less tumorigenic under the tested regimen than combustible cigarette smoke, still fosters an immunosuppressive and metabolically altered lung microenvironment.
E-cigarettes are not benign alternatives; their immunomodulatory and microbiome-disrupting effects warrant further investigation.
Future studies should explore longer exposure durations, varied nicotine concentrations, and additional genetic backgrounds to fully elucidate ECV’s oncogenic potential.
July, 2025
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