Carcinogenesis
· 2025 Dec · PMID 41451921
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Chimeric antigen receptor (CAR-T) cell therapy has been widely used in haematological malignancies and has achieved remarkable results. However, two major toxicities of CAR-T-cell therapy, cytokine release syndrome and i...Chimeric antigen receptor (CAR-T) cell therapy has been widely used in haematological malignancies and has achieved remarkable results. However, two major toxicities of CAR-T-cell therapy, cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, have been reported in many studies and often require hospitalization. There is evidence that CAR-T-cell therapy is being increasingly used clinically, so it is important to pay attention to its serious adverse events that may be life-threatening. In this review, we provide a detailed discussion of the clinical manifestations, classification, risk factors, and management and treatment of serious adverse events to provide theoretical support for clinicians to manage such cases. Although the clinical application of CAR-T cells continues to expand, adverse events associated with CAR-T-cell therapy are inevitable. With the identification of risk factors and the application of various new therapeutic approaches, the incidence and severity of these adverse events can be effectively controlled.
Carcinogenesis
· 2025 Nov · PMID 41420324
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Prostate cancer (PCa) is the fourth most commonly diagnosed malignancy worldwide and remains a major clinical challenge due to its heterogeneous course and lack of reliable prognostic biomarkers. Mitochondrial ribosomal...Prostate cancer (PCa) is the fourth most commonly diagnosed malignancy worldwide and remains a major clinical challenge due to its heterogeneous course and lack of reliable prognostic biomarkers. Mitochondrial ribosomal protein L23 (MRPL23) has recently emerged as a potential contributor to cancer progression, but its role in prostate cancer remains poorly understood. Formalin-fixed, paraffin-embedded (FFPE) tissue samples from 67 PCa patients who underwent radical prostatectomy were analyzed. MRPL23 expression was assessed by immunohistochemistry using a semi-quantitative immunoreactive scale (IRS). Clinicopathological data were collected for correlation analysis. Survival outcomes were evaluated using Kaplan-Meier curves and Cox proportional hazards models. MRPL23 expression differed significantly across all tissue types, with higher levels in prostate cancer tissues compared with normal epithelium, and the highest expression observed in lymph node metastases (P < .001). High MRPL23 expression was associated with shorter overall survival (P = .003) and remained an independent prognostic factor in the multivariate analysis (HR 3.99, 95% CI 1.63-9.77, P = .002). Complementary TCGA analysis confirmed elevated MRPL23 mRNA levels in prostate adenocarcinomas compared with normal tissues (P = .01) and demonstrated that high expression predicted shorter disease-free survival (10-year DFS: 75.98% versus 92.92%, log-rank P = .01). MRPL23 is a potential prognostic biomarker in prostate cancer, linked to aggressive tumor behavior and poor outcomes. Its expression in metastatic tissue suggests a role in disease progression, while TCGA data confirm its prognostic value for recurrence risk. MRPL23 may also serve as a therapeutic target in advanced PCa.
Wu Q, Li Z, He X
… +6 more, Yu S, Zhang M, Mo H, He S, Li J, Ni W
Carcinogenesis
· 2025 Dec · PMID 41411308
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Long non-coding RNAs (lncRNAs) serve as pivotal regulators of diverse physiological activities through their interactions with different biomolecules, and their aberrant expression frequently contributes to tumorigenesis...Long non-coding RNAs (lncRNAs) serve as pivotal regulators of diverse physiological activities through their interactions with different biomolecules, and their aberrant expression frequently contributes to tumorigenesis and malignant progression. Emerging evidence has demonstrated that certain lncRNAs contain open reading frames that can generate useful short peptides, which influence cancer-related physiological and pathological pathways via diverse mechanisms. In this research, we identified that the lncRNA LRRC75A-AS1 encodes a conserved peptide consisting of 102 amino acids, designated as LRRC75A-AS1-ORF3. Notably, this peptide acts independently of the non-coding RNA itself to suppress anti-tumor immune responses and promote colorectal cancer progression. Mechanistically, LRRC75A-AS1-ORF3 is localized in the mitochondria, where it induces mitophagy, thereby eliminating cytosolic mitochondrial DNA (mtDNA) and downregulating the cGAS-STING signaling pathway. Our findings reveal a previously uncharacterized mechanism by which LRRC75A-AS1-ORF3 impairs anti-tumor immunity, thereby presenting a novel immunotherapeutic target for colorectal cancer treatment.
Zhang S, Cai J, Feng Y
… +6 more, Yang M, Li Y, Qu Y, Zhang L, Zheng C, Wang Y
Carcinogenesis
· 2025 Dec · PMID 41388788
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Lung cancer represents the leading cause of cancer-related mortality worldwide, with up to 50% of cases developing brain metastasis during disease progression. Current therapeutic options for brain metastasis remain limi...Lung cancer represents the leading cause of cancer-related mortality worldwide, with up to 50% of cases developing brain metastasis during disease progression. Current therapeutic options for brain metastasis remain limited, resulting in poor clinical outcomes. Previous studies have demonstrated that tumor cell invasion into the brain involves localized activation of astrocytes, with these tumor-associated astrocytes (TAAs) exhibiting either pro-tumor or anti-tumor effects. However, the role of astrocytes during postcolonization stages remains unclear. In this study, employing both a murine model of lung cancer brain metastasis and an in vitro coculture system, we identified the presence of astrocytes within the tumor microenvironment of both clinical specimens and experimental models. Our in vitro experiments revealed that astrocytes significantly enhanced tumor cell survival without affecting proliferation, primarily through inhibition of apoptosis. Mechanistic investigations demonstrated that astrocyte-derived TNF-α mediates this anti-apoptotic effect via activation of the NF-κB signaling pathway in tumor cells. Genetic knockdown of TNF receptor 2 (TNFR2) in tumor cells or pharmacological inhibition of the NF-κB pathway effectively abolished this protective effect. Importantly, TNFR2 knockdown increased intracranial tumor cell apoptosis and prolonged survival in the brain metastasis mouse model. These findings collectively demonstrate that TAAs in lung cancer brain metastasis promote tumor cell survival through a TNFR2-NF-κB-dependent mechanism mediated by TNF-α secretion.
Hu J, Qi Z, Hu S
… +5 more, Xu X, Qin Y, Zhang Y, Yang Q, Cheng P
Carcinogenesis
· 2025 Nov · PMID 41287591
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Endoplasmic reticulum (ER) stress is a key driver of tumor progression and therapeutic resistance. However, the prognostic role of ER stress-related long non-coding RNAs (lncRNAs) in cervical cancer has not been systemat...Endoplasmic reticulum (ER) stress is a key driver of tumor progression and therapeutic resistance. However, the prognostic role of ER stress-related long non-coding RNAs (lncRNAs) in cervical cancer has not been systematically elucidated. In this study, an ER stress-related lncRNA signature was constructed to evaluate patient prognosis and therapeutic responsiveness. Transcriptomic datasets derived from The Cancer Genome Atlas and the Genotype-Tissue Expression project were integrated, leading to the identification of 197 ER stress-associated differentially expressed genes and 1077 co-expressed lncRNAs. A prognostic 8-lncRNA model was developed using univariate/multivariate Cox regression and least absolute shrinkage and selection operator analysis. The model was validated by survival analysis (Kaplan-Meier and receiver operating characteristic curves), immune infiltration profiling (CIBERSORT and single-sample gene set enrichment analysis), and drug sensitivity analysis. Patients classified into the high-risk category showed significantly shorter overall survival (OS) (log-rank P < .001) and higher chemosensitivity to PI3K/mTOR inhibitors, whereas the low-risk group showed high immune activity (CD8+ T-cell infiltration and checkpoint expression) along with improved responsiveness to Wnt pathway inhibitors. The predictive capacity of the model (area under the curve, AUC: 0.806-0.856) exceeded that of conventional clinical parameters. Functional validation further revealed that LIPE-AS1, a representative high-risk lncRNA, promotes cervical cancer cell proliferation, migration, and invasion. These results introduce a novel ER stress-associated lncRNA signature with prognostic and therapeutic value, thus providing a potential basis for personalized immunotherapeutic and chemotherapeutic strategies in cervical cancer.
Chen W, Li J, Cui H
… +8 more, Dai L, Shen Y, Cheng X, He L, Zhuang Q, He M, Song M, Hang D
Carcinogenesis
· 2025 Nov · PMID 41271603
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No studies have examined the association between non-malignant hematologic diseases and the risk of various cancers. To examine the associations between non-malignant hematologic diseases and cancer risk, we performed a...No studies have examined the association between non-malignant hematologic diseases and the risk of various cancers. To examine the associations between non-malignant hematologic diseases and cancer risk, we performed a cohort study and Mendelian randomization analysis. The association between hematologic diseases and incident cancer risk was assessed using time-varying Cox proportional hazards regression with multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). Over a total of 5 031 372 person-years of follow-up in the UK Biobank, 32 589 (6.8%) patients were diagnosed with hematologic diseases, with 2279 incident cancer cases. Multivariable time-varying Cox regression models revealed that any hematologic disease was positively associated with total cancer (HR = 1.19; 95% CI, 1.14-1.24), hematologic cancer (HR = 1.92; 95% CI, 1.69-2.17), and digestive system cancer risks (HR = 1.36; 95% CI, 1.25-1.48). Nine hematologic diseases were associated with higher hematologic cancer risk, and six of the hematologic diseases were also associated with higher risks of four types of digestive system cancer (liver, stomach, esophageal, and small intestine cancers). Mendelian randomization analysis supported the positive association of agranulocytosis with leukemia, coagulation defects and spleen diseases with lymphoma, and unspecified anemia with small intestine cancer. This study indicates that non-malignant hematologic diseases are associated with an increased risk of cancer, particularly cancers in the hematological and digestive systems.
During space missions, astronauts are continuously exposed to extraterrestrial radiation that differs in quality and dose rate compared with terrestrial radiation. As such, astronauts are considered special radiation wor...During space missions, astronauts are continuously exposed to extraterrestrial radiation that differs in quality and dose rate compared with terrestrial radiation. As such, astronauts are considered special radiation workers and are subject to a unique set of standards in place of the Occupational Safety and Health Administration standards that cover terrestrial radiation workers. To accurately estimate and communicate the risk of cancer from space radiation to astronauts and mission managers to facilitate decision-making, the NASA Space Cancer Risk (NSCR) model was developed and has been used operationally at NASA since 2013. The Life Span Study (LSS) of the atomic bomb survivor cohort serves as a key foundational dataset for NSCR that enables quantification of health risks from space radiation. Here, we provide a description of how LSS data and models are currently used within the NSCR model and discuss future perspectives for utilizing this robust dataset to improve risk estimation.
Eighty years have passed since the atomic bombings (A-bombing) of Hiroshima and Nagasaki in August 1945. Survivors represent an unparalleled and irreplaceable human cohort for comprehensively studying the long-term carci...Eighty years have passed since the atomic bombings (A-bombing) of Hiroshima and Nagasaki in August 1945. Survivors represent an unparalleled and irreplaceable human cohort for comprehensively studying the long-term carcinogenic effects of radiation exposure. This review provides a pathological perspective on A-bomb radiation-related solid cancers. Key findings underscore the persistent nature of radiation-induced carcinogenesis: an increased risk of solid cancers has been evident for over 10 years post-bombing and continues to persist. Epidemiological data consistently demonstrate a linear dose-response relationship, with the risk of all solid cancers increasing by ∼40%-50% per Gy, notably without an apparent threshold. The phenomenon of multiple primary cancers is significantly affected by A-bomb radiation, suggesting a systemic predisposition. At a molecular level, evidence points to long-lasting genomic instability, characterized by constitutive activation of the DNA damage response in non-neoplastic epidermis of proximally exposed survivors. This persistent genomic disruption is a critical contributing factor to tumorigenesis. Furthermore, radiation-associated cancers exhibit distinct molecular features. For instance, specific gene fusions are prevalent in thyroid cancer, while HER2 and c-MYC co-amplifications are observed in breast cancer, and gene expression alterations are noted in gastric cancer, often differing from sporadic cases. Research into biomarkers, such as cdkn1a in a rat model of thyroid carcinogenesis, shows promise for identifying radiation effects from the early pre-cancerous phase. This comprehensive analysis highlights the profound and enduring impact of A-bomb radiation on human carcinogenesis. The insights derived from this unique cohort are profoundly relevant for understanding and mitigating global radiation health risks.
Wang K, Chen Y, Li X
… +6 more, Li X, Zhai Y, Yang Y, Li H, Wang Y, Gao M
Carcinogenesis
· 2025 Nov · PMID 41230881
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This study developed a prognostic nomogram for hepatoid adenocarcinoma of the stomach (HAS) using clinicopathological data from 61 surgically treated patients (First Affiliated Hospital of Zhengzhou University, 2013-2025...This study developed a prognostic nomogram for hepatoid adenocarcinoma of the stomach (HAS) using clinicopathological data from 61 surgically treated patients (First Affiliated Hospital of Zhengzhou University, 2013-2025) and externally validated it with 20 cases from Henan Cancer Hospital. Multivariate Cox regression identified TNM stage, CA125, Ki67, and primary tumor location as independent predictors of overall survival (OS). These factors were integrated into a nomogram and internally validated via bootstrap resampling. Compared to the TNM staging system, the nomogram demonstrated superior predictive performance, as indicated by lower Akaike (160.947 versus 168.746) and Bayesian Information Criterion values (169.391 versus 170.857). The bootstrap-corrected concordance index (C-index) for the nomogram was 0.800 (95% CI: 0.729-0.880), significantly outperforming the TNM system (0.653, 95% CI: 0.559-0.746; P = .001); the external validation C-index was 0.754 (95% CI: 0.638-0.870). Time-dependent C-index and calibration curves confirmed superior discriminative ability and accuracy, while decision curve analysis indicated clinical utility. Patients stratified as high-risk by the nomogram had significantly worse OS versus low-risk groups in both training (P < .0001) and validation cohorts (P = .02). This tool enables risk stratification to guide personalized HAS management.
Nakamichi S, von Muhlinen N, Yamada L
… +6 more, Melamed JR, Papp TE, Parhiz H, Weissman D, Horikawa I, Harris CC
Carcinogenesis
· 2025 Nov · PMID 41225668
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Tyrosine kinase (TK) inhibitors improve clinical outcomes in non-small cell lung cancer (NSCLC) with targetable mutations. However, such NSCLC cases account for only about 50% in the western populations. Inhibition of th...Tyrosine kinase (TK) inhibitors improve clinical outcomes in non-small cell lung cancer (NSCLC) with targetable mutations. However, such NSCLC cases account for only about 50% in the western populations. Inhibition of the splicing factor SRSF3 has been reported to be tumor-suppressive in other cancer cell types. This study for the first time explores the tumor-suppressive activity of siRNA knockdown of SRSF3 in NSCLC cells. The cell lines used were A549 (no TK mutation; TP53 wild type), NCI-H1975 (EGFR L858R/T790M; TP53 R273H mutant), NCI-H322 (no TK mutation; TP53 R248L mutant), and NCI-H596 (no TK mutation; TP53 G245C mutant). In all these cell lines, SRSF3 knockdown increased cellular senescence, as indicated by increased senescence-associated β-galactosidase activity and reduced cell proliferation. In A549 cells, increased apoptotic cleavage of caspase-3 and poly(ADP-ribose) polymerase was also observed. A tumor-suppressive p53 isoform, p53β, was shown to be upregulated by SRSF3 knockdown. However, overexpression of p53β did not induce cellular senescence or apoptosis, suggesting that this p53 isoform is not a primary effector of SRSF3 knockdown in NSCLC cells. Gene expression analyses suggested that the SRSF3 knockdown-induced senescence in NSCLC cells may be mediated by the downregulation of TOP2A, UBE2C, or ASPM, which are known oncogenic factors associated with poor patient prognosis. We also generated SRSF3 siRNA-encapsulating lipid nanoparticles as a future therapeutic tool. This study proposes a therapeutic strategy for NSCLC that is independent of the mutation status of TP53 and TK-encoding genes.
Wu R, Wang X, Tian M
… +7 more, Wei X, Wang X, Ye S, Zhang R, Xia Q, Fang R, Rao Q
Carcinogenesis
· 2025 Nov · PMID 41215589
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TFE3-rearranged renal cell carcinoma (TFE3-RCC), an aggressive kidney cancer predominantly affecting pediatric and young adult populations, is driven by Xp11.2 rearranged generating oncogenic TFE3 fusion proteins. Althou...TFE3-rearranged renal cell carcinoma (TFE3-RCC), an aggressive kidney cancer predominantly affecting pediatric and young adult populations, is driven by Xp11.2 rearranged generating oncogenic TFE3 fusion proteins. Although these fusions define the disease, their mechanistic roles remain elusive. Here, lentiviral-mediated overexpression of PRCC-TFE3 or NONO-TFE3 in RCC models triggered nuclear rearranged fusion proteins and significantly accelerated tumor proliferation both in vitro and in vivo. Our integrated RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses mechanistically revealed that TFE3 fusions directly bind to promoters of lysosome and mTOR signaling pathway genes, leading to transcriptional activation of this pathway. Moreover, the fusions aberrantly escaped canonical mTOR signaling pathway regulation and paradoxically hyperactivated phospho-mTOR signaling. Importantly, dual inhibition of the autophagy and mTOR pathways synergistically suppressed tumor growth, exceeding the efficacy of single-agent treatments. These data demonstrate that co-targeting these TFE3-regulated pathways represents a promising therapeutic strategy for this intractable malignancy.
Kassie F, Wang K, Bang K
… +6 more, Chowdhury MRH, Wang J, Prabhu S, Liang X, Seelig D, Desai P
Carcinogenesis
· 2025 Nov · PMID 41147148
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Although preclinical studies consistently indicate that sulfasalazine (SAS) and disulfiram (DSF) are promising agents for the prevention and treatment of lung cancer, their clinical efficacy is limited. This discrepancy...Although preclinical studies consistently indicate that sulfasalazine (SAS) and disulfiram (DSF) are promising agents for the prevention and treatment of lung cancer, their clinical efficacy is limited. This discrepancy is attributed to the poor bioavailability of the drugs. Therefore, in the present study, we explored whether delivery of lower doses of SAS and DSF in nano self-emulsifying drug delivery systems (Nano-SEDDS) improves their potency and efficacy in suppressing malignant progression of lung tumors. Mice were treated with the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and once lung adenoma developed, high doses of free SAS (250 mg/kg) + DSF (100 mg/kg) or SEDDS formulations containing lower doses of SAS + DSF (40 mg/kg SAS + 8, 16 or 40 mg/kg DSF) were administered by oral gavage, every other day, for 10 weeks. Although the doses of SAS and DSF contained in SAS + DSF-SEDDS were about 6-fold and 3-15-fold lower, respectively, than the doses of the respective free drugs, SAS + DSF-SEDDS was more effective than free SAS + DSF in reducing the multiplicity of bigger lung tumors (≥1 mm). These effects were paralleled by significant reductions in the multiplicity of adenoma with progression and adenocarcinoma histopathological lesions. Also, lung tumors from mice treated with SAS + DSF-SEDDS exhibited an increase in the level of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), lipid peroxidation products. Overall, our results show that the Nano-SEDDS formulation of SAS + DSF is a promising approach to enhance the potency and efficacy of the drugs for lung cancer chemo-interception and treatment.
Carcinogenesis
· 2025 Sep · PMID 41144271
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Medical exposures are the largest source of human-made ionizing radiation received by the general population. Cancer risk assessment for medical radiation is often based on the Life Span Study (LSS) of the Japanese atomi...Medical exposures are the largest source of human-made ionizing radiation received by the general population. Cancer risk assessment for medical radiation is often based on the Life Span Study (LSS) of the Japanese atomic bomb survivors. Various assumptions are required to transfer radiation-related cancer risk estimates from the LSS to medical radiation exposures, including dose and fractionation effects. We compared organ-specific cancer risk coefficients from pediatric medical radiation studies (age, <22 years) with the LSS, controlling for average age at exposure, attained age, or time since exposure. We compared 21 studies (including 5 pooled analyses) of brain, breast, thyroid cancer, and leukemia (the most radiosensitive cancers in children), including 6 low-dose (mean < 100 mGy), 7 moderate-dose (mean = 100 mGy to -<2 Gy) and 8 high-dose (mean = 2+ Gy). The high-dose studies all had lower dose-response estimates than the LSS (ratio range = 1.3-37), as did most of the moderate-dose studies (ratio range = 0.4-9.4). In contrast, the dose-response estimates for the low-dose studies were all higher than the LSS (ratio range = 0.1-0.7). These results do not provide strong support for a dose reduction effectiveness factor of 2 for risk assessment for low-dose medical radiation exposures using the LSS. Whilst there is a clear reduction in risk from high-dose fractionated exposures compared with the LSS, the wide variation in ratios makes it difficult currently to quantify these effects.
Samet JM, Rajaraman P, Pine SR
… +1 more, Shibata T
Carcinogenesis
· 2025 Sep · PMID 41144270
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The year 2025 marks the 80th anniversary of one of the worst human-caused tragedies: the atomic bombings of Hiroshima and Nagasaki, with acute death tolls of approximately 140,000 in Hiroshima and 74,000 in Nagasaki by t...The year 2025 marks the 80th anniversary of one of the worst human-caused tragedies: the atomic bombings of Hiroshima and Nagasaki, with acute death tolls of approximately 140,000 in Hiroshima and 74,000 in Nagasaki by the end of 1945. This editorial provides historical and social context for the articles in this special issue of Carcinogenesis.
Nakamura N, Yamada M, Sakata R
… +3 more, Ohishi W, Tatsukawa Y, Uchimura A
Carcinogenesis
· 2025 Sep · PMID 41144269
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This is a brief review of studies conducted at the Atomic Bomb Casualty Commission and Radiation Effects Research Foundation regarding the possible transgenerational effects of atomic bomb radiation. These include clinic...This is a brief review of studies conducted at the Atomic Bomb Casualty Commission and Radiation Effects Research Foundation regarding the possible transgenerational effects of atomic bomb radiation. These include clinical, epidemiological, and biological studies on birth defect, sex ratio, chromosome aberration, molecular changes, disease prevalence and incidence, and whole genome analysis. Also, future plans are addressed.