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Spontaneous regression of advanced cancer: identification of a unique genetically determined, age-dependent trait in mice.

ABSTRACT: We have established and studied a colony of mice with a unique trait of host resistance to both ascites and solid cancers induced by transplantable cells. One dramatic manifestation of this trait is age-dependent spontaneous regression of advanced cancers. This powerful resistance segregates as a single-locus dominant trait, is independent of tumor burden, and is effective against cell lines from multiple types of cancer. During spontaneous regression or immediately after exposure, cancer cells provoke a massive infiltration of host leukocytes, which form aggregates and rosettes with tumor cells. The cytolytic destruction of cancer cells by innate leukocytes is rapid and specific without apparent damage to normal cells. The mice are healthy and cancer-free and have a normal life span. These observations suggest a previously unrecognized mechanism of immune surveillance, which may have potential for therapy or prevention of cancer.

SUBMITTER: Cui Z

PROVIDER: S-EPMC164507 | biostudies-literature | 2003 May

REPOSITORIES: biostudies-literature

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Spontaneous regression of advanced cancer: identification of a unique genetically determined, age-dependent trait in mice.

Cui Zheng Z Willingham Mark C MC Hicks Amy M AM Alexander-Miller Martha A MA Howard Timothy D TD Hawkins Gregory A GA Miller Mark S MS Weir Holly M HM Du Wei W DeLong Cynthia J CJ

Proceedings of the National Academy of Sciences of the United States of America 20030430 11

We have established and studied a colony of mice with a unique trait of host resistance to both ascites and solid cancers induced by transplantable cells. One dramatic manifestation of this trait is age-dependent spontaneous regression of advanced cancers. This powerful resistance segregates as a single-locus dominant trait, is independent of tumor burden, and is effective against cell lines from multiple types of cancer. During spontaneous regression or immediately after exposure, cancer cells ...[more]

PMID: 12724523

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Project description:ImportancePrevious studies have shown an association between actual age at menarche and risk of all-cause mortality; however, the results are inconsistent, and no study has analyzed the joint associations between genetic susceptibility and actual age at menarche with the risk of mortality in prospective cohorts.ObjectivesTo investigate joint associations of actual age and genetically determined age at menarche with risk of all-cause mortality.Design, setting, and participantsThis prospective cohort study was conducted using data from the UK Biobank population across the United Kingdom from March 13, 2006, to October 1, 2010. A total of 264 546 women aged between 39 and 71 years with actual menarcheal age were included in this study; 246 676 of these women had genetic data available. Actual age at menarche was obtained from the touchscreen questionnaire at recruitment from 2006 to 2010. Genetically determined age at menarche was assessed by a genetic risk score. Statistical analysis was performed from August 22 to December 12, 2019.ExposureAge at menarche.Main outcomes and measuresA multivariable Cox proportional hazards regression model was used to assess associations of actual or genetically determined age at menarche with risk of all-cause mortality.ResultsThe mean (SD) age of the study population at baseline was 56.4 (8.0) years, and the mean (SD) age at menarche included in the analyses was 13.0 (1.6) years. During a median of 9.0 years (range, 8.3-9.7 years) of follow-up, 7761 deaths were documented among the women with actual age at menarche, and 7054 deaths were documented among the women with genetically determined age at menarche. Both the actual age at menarche and the genetically determined age at menarche showed a U-shaped association with the risk of all-cause mortality (lowest actual age [<12 years] vs reference age [15 years]: hazard ratio [HR], 1.16 [95% CI, 1.07-1.26]; highest actual age [≥16 years] vs reference age [15 years]: HR, 1.17 [95% CI, 1.05-1.31]; P < .001 for quadratic trend; genetic risk score [GRS] of 1 vs reference score [GRS of 4]: HR, 1.10 [95% CI, 1.01-1.19; GRS of 6 vs reference score [GRS of 4]: HR, 1.09 [95% CI, 1.00-1.18]; P = .03 for quadratic trend). Significant interactions were also found between actual age at menarche and genetically determined age at menarche with all-cause mortality (HR of mortality associated with age of menarche <12 year was 1.24 [95% CI, 1.10-1.40] in the GRS of 1 group and 1.44 [95% CI, 1.21-1.72] in the GRS of 6 group; P = .001 for interaction). Women with mismatch of actual age and genetically determined age at menarche had the highest mortality risks; participants with the lowest genetic risk score and the highest age at menarche had an HR of 2.12 (95% CI, 1.58-2.83), and participants with the highest GRS and the lowest age at menarche had an HR of 1.44 (95% CI, 1.21-1.72).Conclusions and relevanceThe results suggest that both actual age and genetically determined age at menarche exhibit U-shaped associations with all-cause mortality. Women with mismatch of actual age and genetically determined age at menarche may have the highest risk of all-cause mortality.

Project description:BackgroundFacet joint (FJ) osteoarthritis (FJOA) is a widely prevalent spinal disorder but its pathogenesis remains unclear, largely due to the difficulties in conducting longitudinal human studies and lack of spontaneous-FJOA animal models for mechanistic investigations. This study aimed to investigate whether spontaneous FJOA occurs in mice bearing mutant NFAT1 (nuclear factor of activated T cells 1) transcription factor.MethodsThe lumbar FJs of 50 NFAT1-mutant mice and of 50 wild-type control mice, of both sexes, were examined by histopathology, quantitative gene expression analysis, semiquantitative immunohistochemistry, and a novel FJOA scoring system for semiquantitative assessment of the histopathologic changes at 2, 6, 12, and 18 months of age. Age-dependent and tissue-specific histopathologic and gene or protein expression changes were analyzed statistically.ResultsFJs in NFAT1-mutant mice displayed significantly increased expression of specific catabolic genes (p < 0.05) and proteins (p < 0.001) in cartilage and synovium as early as 2 months of age, followed by early osteoarthritic structural changes such as articular surface fissuring and chondro-osteophyte formation at 6 months. More severe cartilage lesions, osteophytes, subchondral bone changes, synovitis, and tissue-specific molecular alterations in FJs of NFAT1-mutant mice were observed at 12 and 18 months. Osteoarthritic structural changes were not detected in FJs of wild-type mice at any ages, although age-related cartilage degeneration was observed at 18 months. The novel FJOA scoring system had high intraobserver and interobserver reproducibility (correlation coefficients: r > 0.97). Whole-joint FJOA scoring showed significantly higher OA scores in FJs of NFAT1-mutant mice compared with wild-type mice at all time points (p = 0.0033 at 2 months, p = 0.0001 at 6 months, p < 0.0001 at 12 and 18 months).ConclusionsThis study has identified the NFAT1-mutant mouse as a novel animal model of spontaneous FJOA with age-dependent and slowly progressing osteoarthritic features, developed the first FJOA scoring system, and elucidated the molecular mechanisms of NFAT1 mutation-induced FJOA.Clinical relevanceThis murine FJOA model resembles the features of human FJOA and may provide new insights into the pathogenesis of and therapeutic strategies for FJOA in humans.

Project description:BackgroundResults from observational studies indicate an association between circulating levels of mammalian target of rapamycin (mTOR)-dependent circulating proteins and the risk of multiple sclerosis (MS). However, a causal association has not been fully elucidated. Mendelian randomization (MR) is used to overcome limitations inherent to observational studies, assess the causal association, and minimize bias due to confounding and reverse causation.MethodsTo explore the causal association between seven mTOR-dependent proteins (AKT, RP-S6K, eIF4E-BP, eIF4A, eIF4E, eIF4G, and PKC-α) and MS, we obtained summary statistics from the genome-wide association study (GWAS) meta-analysis of the International Multiple Sclerosis Genetics Consortium (47,429 patients and 68,374 controls) and the INTERVAL study (genetic associations with 2994 plasma proteins from 3301 healthy individuals). MR analyses were conducted using inverse variance weighted, weighted median estimator, and MR-Egger regression methods/models. Sensitivity analyses were performed to ensure the reliability of the findings. Single nucleotide polymorphisms (SNPs) that are independent (r2 < 0.01) and strongly associated to minerals (p < 1e-5) were selected as instrumental variables.ResultsThe results of the MR analyses revealed that among the seven mTOR-dependent proteins selected for study, the circulating level of PKC-α (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.82-0.98; P = 0.017) and RP-S6K (OR 1.12, 95% CI 1.00-1.25; P = 0.045) were associated with MS risk and that there was no sign of pleiotropy or heterogeneity. PKC-α was negatively related to MS, while RP-S6K was positively related to MS. No significant causation was found between the other proteins studied (AKT, eIF4E-BP, eIF4A, eIF4E, eIF4G) and MS.ConclusionMolecules in the mTOR signaling pathway may bidirectionally regulate the occurrence and development of MS. PKC-α is a protective factor, while RP-S6K is a risk factor. Further explorations of pathways underlying the association between mTOR-dependent proteins and MS are required. PKC-α and RP-S6K might be used as future therapeutic targets for screening high-risk individuals and potentially improving opportunities for targeted prevention strategies.

Dataset Information

Spontaneous regression of advanced cancer: identification of a unique genetically determined, age-dependent trait in mice.

Publications

Spontaneous regression of advanced cancer: identification of a unique genetically determined, age-dependent trait in mice.

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