Exploring the co-morbid relationship between Alzheimer's disease and lung cancer in the 5xFAD transgenic mouse model

Abstract

Background: Alzheimer's disease (AD) and lung cancer are leading causes of mortality among the older population. Epidemiological evidence suggests an antagonistic relationship between them, whereby patients with AD exhibit a reduced risk of developing cancer and vice versa. However, the precise mechanism by which AD antagonizes lung cancer progression warrants further elucidation.

Methods: To this end, we established a co-morbidity model using 5xFAD transgenic mice induced with the carcinogen urethane. We visualized and quantified surface lung tumor colonies, assessed pathological parameters associated with lung cancer and AD using histopathological analysis, and employed single-cell sequencing and molecular pathological analyses to explore the mechanisms by which AD confers resistance to lung cancer.

Results: Our findings revealed a significant reduction in lung tumor incidence in the AD group compared with that in the wild-type (WT) group. The results indicated a close association between AD-induced inhibition of lung tumor progression and iron homeostasis imbalance and increased oxidative stress. Moreover, greater CD8⁺ T cytotoxic lymphocyte and effector natural killer cell infiltration in the lung tumor tissues of AD mice and enhanced CD8⁺ T cytotoxic lymphocyte-mediated killing of target cells may be the primary factors contributing to the inhibition of lung tumor growth in the presence of AD.

Conclusion: This study identified essential mechanisms through which AD suppresses lung tumorigenesis, thereby providing targets for potential therapeutic interventions in these diseases.

Keywords

Alzheimer's disease / CD8⁺ T cell / ferroptosis / lung cancer / single-cell transcriptomics

References

[1] GBD. Dementia forecasting collaborators, estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the global burden of disease study 2019. Lancet Public Health. 2019; 7(2022): e105-e125.

[2] Siegel RL, Miller KD, Fuchs HE, et al. CA cancer. J Clin. 2022; 72(2022): 7-33.

[3] Jia J, Wei C, Chen S, et al. The cost of Alzheimer's disease in China and re-estimation of costs worldwide. Alzheimers Dement. 2018; 14: 483-491.

[4] GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders. A systematic analysis for the global burden of disease study 2016. Lancet Neurol. 2016; 18: 459-480.

[5] Musicco M, Adorni F, Di Santo S, et al. Inverse occurrence of cancer and Alzheimer disease: a population-based incidence study. Neurology. 2013; 81: 322-328.

[6] Ren RJ, Huang Q, Xu G, et al. Association between Alzheimer's disease and risk of cancer: a retrospective cohort study in Shanghai, China. Alzheimers Dement. 2022; 18: 924-933.

[7] Roe CM, Behrens MI, Xiong C, Miller JP, Morris JC. Alzheimer disease and cancer. Neurology. 2005; 64: 895-898.

[8] Lu KP. Pinning down cell signalling, cancer and Alzheimer's disease. Trends Biochem Sci. 2004; 29: 200-209.

[9] Lanni C, Masi M, Racchi M, Govoni S. Cancer and Alzheimer's disease inverse relationship: an age-associated diverging derailment of shared pathways. Mol Psychiatry. 2021; 26: 280-295.

[10] Aramillo Irizar P, Schäuble S, Esser D, et al. Transcriptomic alterations during ageing reflect the shift from cancer to degenerative diseases in the elderly. Nat Commun. 2018; 9: 327.

[11] Melkoumian ZK, Peng X, Gan B, Wu X, Guan JL. Mechanism of cell cycle regulation by FIP200 in human breast cancer cells. Cancer Res. 2005; 65: 6676-6684.

[12] Chao DL, Sanchez CA, Galipeau PC, et al. Cell proliferation, cell cycle abnormalities, and cancer outcome in patients with Barrett's esophagus: a long-term prospective study. Clin Cancer Res. 2008; 14: 6988-6995.

[13] Wang W, Bu B, Xie M, Zhang M, Yu Z, Tao D. Neural cell cycle dysregulation and central nervous system diseases. Prog Neurobiol. 2009; 89: 1-17.

[14] Sanchez-Valle J, Tejero H, Ibáñez K, et al. A molecular hypothesis to explain direct and inverse co-morbidities between Alzheimer's disease, glioblastoma and lung cancer. Sci Rep. 2017; 7: 4474.

[15] Seo J, Park M. Molecular crosstalk between cancer and neurodegenerative diseases cell. Mol Life Sci. 2020; 77: 2659-2680.

[16] Tirosh I, Izar B, Prakadan SM, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 2016; 352: 189-196.

[17] Guo X, Zhang Y, Zheng L, et al. Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat Med. 2018; 24: 978-985.

[18] Chung W, Eum HH, Lee HO, et al. Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer. Nat Commun. 2017; 8: 15081.

[19] Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018; 36: 411-420.

[20] Milošević D, Medeiros AS, Stojković Piperac M, et al. The application of uniform manifold approximation and projection (UMAP) for unconstrained ordination and classification of biological indicators in aquatic ecology. Sci Total Environ. 2022; 815: 152365.

[21] Wu T, Hu E, Xu S, et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2: 100141.

[22] Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013; 14: 7.

[23] Qiu X, Mao Q, Tang Y, et al. Reversed graph embedding resolves complex single-cell trajectories. Nat Methods. 2017; 14: 979-982.

[24] Monzavi SM, Muhammadnejad A, Behfar M, Khorsand AA, Muhammadnejad S, Kajbafzadeh AM. Spontaneous xenogeneic GvHD in Wilms' tumor patient-derived xenograft models and potential solutions. Animal Model Exp Med. 2022; 5: 389-396.

[25] Sarode P, Mansouri S, Karger A, et al. Epithelial cell plasticity defines heterogeneity in lung cancer. Cell Signal. 2020; 65: 109463.

[26] Li Q, Wang R, Yang Z, et al. Molecular profiling of human non-small cell lung cancer by single-cell RNA-seq. Genome Med. 2022; 14: 87.

[27] Ming C, Wang M, Wang Q, et al. Whole genome sequencing-based copy number variations reveal novel pathways and targets in Alzheimer's disease. Alzheimers Dement. 2022; 18: 1846-1867.

[28] Wang Z, Li Z, Zhou K, et al. Deciphering cell lineage specification of human lung adenocarcinoma with single-cell RNA sequencing. Nat Commun. 2021; 12: 6500.

[29] Wang W, Green M, Choi JE, et al. CD8⁺ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019; 569: 270-274.

[30] Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumour microenvironment. Nat Immunol. 2013; 14: 1014-1022.

[31] Baharom F, Ramirez-Valdez RA, Khalilnezhad A, et al. Systemic vaccination induces CD8⁺ T cells and remodels the tumour microenvironment. Cell. 2022; 185: 4317-4332.e15.

[32] Park J, Hsueh PC, Li Z, Ho PC. Microenvironment-driven metabolic adaptations guiding CD8⁺ T cell anti-tumour immunity. Immunity. 2023; 56: 32-42.

[33] Gate D, Saligrama N, Leventhal O, et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease. Nature. 2020; 577: 399-404.

[34] Lai Y, Lu X, Liao Y, et al. Crosstalk between glioblastoma and tumour microenvironment drives proneural-mesenchymal transition through ligand-receptor interactions. Genes Dis. 2024; 11: 874-889.

[35] Tanzi RE. The genetics of Alzheimer disease, cold spring Harb. Pers Med. 2012; 2: a006296.

[36] Landel V, Baranger K, Virard I, et al. Temporal gene profiling of the 5XFAD transgenic mouse model highlights the importance of microglial activation in Alzheimer's disease. Mol Neurodegener. 2014; 9: 33.

[37] Oakley H, Cole SL, Logan S, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006; 26: 10129-10140.

[38] Park MH, Yun HM, Hwang CJ, et al. Presenilin mutation suppresses lung tumourigenesis via inhibition of peroxiredoxin 6 activity and expression. Theranostics. 2017; 7: 3624-3637.

[39] Yun HM, Park MH, Kim DH, et al. Loss of presenilin 2 is associated with increased iPLA2 activity and lung tumour development. Oncogene. 2014; 33: 5193-5200.

[40] Raven EP, Lu PH, Tishler TA, Heydari P, Bartzokis G. Increased iron levels and decreased tissue integrity in hippocampus of Alzheimer's disease detected in vivo with magnetic resonance imaging. J Alzheimers Dis. 2013; 37: 127-136.

[41] Ayton S, Fazlollahi A, Bourgeat P, et al. Cerebral quantitative susceptibility mapping predicts amyloid-beta-related cognitive decline. Brain. 2017; 140: 2112-2119.

[42] Bao WD, Pang P, Zhou XT, et al. Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer's disease. Cell Death Differ. 2021; 28: 1548-1562.

[43] Greenough MA, Lane DJR, Balez R, et al. Selective ferroptosis vulnerability due to familial Alzheimer's disease presenilin mutations. Cell Death Differ. 2022; 29: 2123-2136.

[44] Ma H, Dong Y, Chu Y, Guo Y, Li L. The mechanisms of ferroptosis and its role in Alzheimer's disease. Front Mol Biosci. 2022; 9: 965064.

[45] Chen P, Wu Q, Feng J, et al. Erianin, a novel dibenzyl compound in dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis. Signal Transduct Target Ther. 2020; 5: 51.

[46] Jiang L, Kon N, Li T, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015; 520: 57-62.

[47] Zhang Y, Shi J, Liu X, et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol. 2018; 20: 1181-1192.

[48] Liao P, Wang W, Wang W, et al. CD8⁺ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell. 2022; 40: 365-378.e6.

[49] Piehl N, van Olst L, Ramakrishnan A, et al. Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment. Cell. 2022; 185: 5028-5039.e13.

[50] Kwak M, Kim DJ, Lee MR, et al. Nanowire array chips for molecular typing of rare trafficking leukocytes with application to neurodegenerative pathology. Nanoscale. 2014; 6: 6537-6550.

[51] McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol. 2019; 37: 457-495.

[52] Philip M, Schietinger A. CD8⁺ T cell differentiation and dysfunction in cancer. Nat Rev Immunol. 2022; 22: 209-223.

RIGHTS & PERMISSIONS

2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.