Obesity-induced thymic involution and cancer risk

Lagou, Maria K.; Karagiannis, George S.

doi:10.1016/j.semcancer.2023.04.008

Cited by 8 publications

(5 citation statements)

References 373 publications

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“…Among thymic disorders, age-dependent involution is the most well-characterized thymic pathology 120 , and as such, served as the primary focus for demonstrating our pipeline's utility. Additionally, the thymus is vulnerable to acute involution 9,121,122 , from factors like chemo/radiotherapy 123 , infections 121 , sexual steroids 124,125 , pregnancy 126,127 , and obesity 32,128 . Therefore, our pipeline may be utilized to offer insights in studies aimed at dissecting the molecular mechanisms and reversing thymic involution.…”

Section: Discussionmentioning

confidence: 99%

“…Mouse Gender and Strain Selection. Due to established gender-related differences in the development of T cells [31][32][33][34] , it is generally not recommended to pool together male and female mice in studies related to thymic functions. When compared to males for example, aged female mice tend to have higher numbers of TEC, including the AIRE + mTEC subpopulation, which is critical for the process of negative selection 31,33 .…”

Section: Methods Animal Subjectsmentioning

confidence: 99%

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Morphometric Analysis of the Thymic Epithelial Cell (TEC) Network Using Integrated and Orthogonal Digital Pathology Approaches

Lagou,

Argyris,

Vodopyanov

et al. 2024

Preprint

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The thymus, a central primary lymphoid organ of the immune system, plays a key role in T cell development. Surprisingly, the thymus is quite neglected with regards to standardized pathology approaches and practices for assessing structure and function. Most studies use multispectral flow cytometry to define the dynamic composition of the thymus at the cell population level, but they are limited by lack of contextual insight. This knowledge gap hinders our understanding of various thymic conditions and pathologies, particularly how they affect thymic architecture, and subsequently, immune competence. Here, we introduce a digital pathology pipeline to address these challenges. Our approach can be coupled to analytical algorithms and utilizes rationalized morphometric assessments of thymic tissue, ranging from tissue-wide down to microanatomical and ultrastructural levels. This pipeline enables the quantitative assessment of putative changes and adaptations of thymic structure to stimuli, offering valuable insights into the pathophysiology of thymic disorders. This versatile pipeline can be applied to a wide range of conditions that may directly or indirectly affect thymic structure, ranging from various cytotoxic stimuli inducing acute thymic involution to autoimmune diseases, such as myasthenia gravis. Here, we demonstrate applicability of the method in a mouse model of age-dependent thymic involution, both by confirming established knowledge, and by providing novel insights on intrathymic remodeling in the aged thymus. Our orthogonal pipeline, with its high versatility and depth of analysis, promises to be a valuable and practical toolset for both basic and translational immunology laboratories investigating thymic function and disease.

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Section: Discussionmentioning

confidence: 99%

Section: Methods Animal Subjectsmentioning

confidence: 99%

Morphometric Analysis of the Thymic Epithelial Cell (TEC) Network Using Integrated and Orthogonal Digital Pathology Approaches

Lagou,

Argyris,

Vodopyanov

et al. 2024

Preprint

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“…In order to reduce the incidence of cancer, the discovery of risk factors in precancerous lesions is particularly important. So far, prospective studies have identified several factors that can interfere with cancer risk (Kliemann et al, 2023;Lagou and Karagiannis, 2023;Wang et al, 2023). For example, processed food intake and obesity can influence changes in a range of cancer risk indicators.…”

Section: Introductionmentioning

confidence: 99%

A two-sample Mendelian randomization analysis: causal association between chemokines and pan-carcinoma

Cui,

Song,

Fan

et al. 2023

Front. Genet.

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Objective: According to the 2020 data from the World Health Organization (WHO), cancers stand as one of the foremost contributors to global mortality. Revealing novel cancer risk factors and protective factors is of paramount importance in the prevention of disease occurrence. Studies on the relationship between chemokines and cancer are ongoing; however, due to the coordination of multiple potential mechanisms, the specific causal association remains unclear.Methods: We performed a bidirectional Mendelian randomization analysis to explore the causal association between serum chemokines and pan-carcinoma. All data is from the GWAS catalog and IEU Open GWAS database. The inverse-variance weighted (IVW) method is primarily employed for assessing the statistical significance of the findings. In addition, the significance threshold after the multiple hypothesis test (Bonferroni) was 0.0013, and the evidence of a potential association was considered if the p-value < 0.05, but remained greater than Bonferroni’s threshold.Results: The results indicate that CCL1 (odds ratio, OR = 1.18), CCL2 (OR = 1.04), CCL8 (OR = 1.36), CCL14 (Colorectal, OR = 1.08, Small intestine, OR = 0.77, Lung, OR = 1.11), CCL15 (OR = 0.85), CCL18 (Breast, OR = 0.95, Prostate, OR = 0.96), CCL19 (Lung, OR = 0.66, Prostate, OR = 0.92), CCL20 (Lung, OR = 0.53, Thyroid, OR = 0.76), CCL21 (OR = 0.62), CCL22 (OR = 2.05), CCL23 (OR = 1.31), CCL24 (OR = 1.06), CCL27 (OR = 1.49), CCL28 (OR = 0.74), CXCL5 (OR = 0.95), CXCL9 (OR = 3.60), CXCL12 (Breast, OR = 0.87, Small intestine, OR = 0.58), CXCL13 (Breast, OR = 0.93, Lung, OR = 1.29), CXCL14 (Colon, OR = 1.40) and CXCL17 (OR = 1.07) are potential risk factors for cancers. In addition, there was a reverse causal association between CCL1 (OR = 0.94) and CCL18 (OR = 0.94) and breast cancer. Sensitivity analysis results were similar. The results of the other four MR Methods were consistent with the main results, and the leave-one-out method showed that the results were not driven by a Single nucleotide polymorphism (SNP). Moreover, there was no heterogeneity and pleiotropy in our analysis.Conclusion: Based on the two-sample MR Analysis method, we found that chemokines might be upstream factors of cancer pathogenesis. These results might provide new insights into the future use of chemokines as potential targets for cancer prevention and treatment. Our results also provide important clues for tumor prevention, and changes of serum chemokine concentration may be recognized as one of the features of precancerous lesions in future clinical trials.

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“…However, with increasing age, the thymus is involved. The major feature of aged thymus is the reduced TEC numbers (4), which are accompanied by impaired TEC development, which causes severe T cell de ciency (1,5). Despite the crucial roles of TECs in age-related thymus involution, the underlying mechanisms of TEC-associated thymic atrophy have not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Unveiling the Impact of 17β-Estradiol on Thymic Epithelial Cell Proliferation: A miRNA Perspective

Guo,

Chen,

et al. 2023

Preprint

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Background Estrogen signaling and microRNA (miRNA) expression play a pivotal role in thymus involution by regulating thymic epithelial cell (TECs) functions. However, the role of Estrogen on miRNA expression in TECs has not been fully elucidated. Methods Cell proliferation assays, such as the cell-counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) and flow cytometry assays were conducted. Next-generation sequencing (NGS)-based miRNA profiling was performed and validated using Quantitative polymerase chain reaction (qPCR). Additionally, the mechanism of 17β-Estradiol(E2) regulation of miRNA expression in MTEC1 cells was investigated using anti-estrogen ICI 182, 780 and ERα siRNA. Results A total of 3356 candidate miRNAs across the six miRNA libraries were subjected to analysis, among these, 69 miRNAs displayed notable changes in expression patterns, with 33 miRNAs exhibiting downregulation and 36 miRNAs showing upregulation. Further investigation focused on miR-99a-5p, miR-99b-5p, miR-378a-5p, miR-361-5p, miR-16-5p, and miR-22-3p due to their elevated expression levels. Subsequent examination through Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed a significant association between the dysregulated miRNAs and the functional role of cell proliferation. Furthermore, the regulatory impact of E2 on miRNA expression can be modified by the anti-estrogen ICI 182 780 or inhibited by ERαsiRNA in MTEC1 cells. Conclusions E2 canalter miRNA expression in TECs, and this miRNA expression may be closely associated with post-transcriptional regulation of cell proliferation in an ERα-dependent manner. Our data indicated the good performance of these miRNAs as potential biomarkers in E2-related thymic involution in TECs.

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Obesity-induced thymic involution and cancer risk

Cited by 8 publications

References 373 publications

Morphometric Analysis of the Thymic Epithelial Cell (TEC) Network Using Integrated and Orthogonal Digital Pathology Approaches

Morphometric Analysis of the Thymic Epithelial Cell (TEC) Network Using Integrated and Orthogonal Digital Pathology Approaches

A two-sample Mendelian randomization analysis: causal association between chemokines and pan-carcinoma

Unveiling the Impact of 17β-Estradiol on Thymic Epithelial Cell Proliferation: A miRNA Perspective

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