Carcinogenesis最新文献

Lifestyle factors such as smoking and alcohol may influence colon cancer (CC) survival, but it is unclear whether their effects vary by tumour-infiltrating immune biomarkers. This study examined CC-specific survival by smoking and alcohol status, stratified by immune cell density, in a large population-based cohort. The study included 661 individuals who underwent surgery for stage II or III CC between 2004 and 2008 within two Health and Social Care (HSC) Trusts in Northern Ireland. Representative formalin-fixed, paraffin-embedded (FFPE) tumour blocks were retrieved, and immunohistochemistry (IHC) was performed on tissue microarrays constructed from both the central tumour and the invasive margin. Cox proportional hazards models were used to assess CC-specific survival, adjusting for key clinical and demographic confounders. Ever smoking, compared to never smoking, was associated with poorer CC-specific survival among individuals with lower densities of CD3+, CD4+ and FOXP3+ tumour-infiltrating immune cells. Among those with higher CD8+ cell density in the central tumour, ever smoking was linked to worse outcomes. Similar patterns were seen in the invasive margin, although these were not all statistically significant. No significant associations were observed between alcohol use and survival across any immune biomarker subgroups. Smoking was associated with poorer survival among patients with CC, and this association appears to be modified by the density of tumour-infiltrating immune cells.

The DNA mismatch repair (MMR) system plays a critical role in maintaining genomic integrity and preventing tumorigenesis. Although MutS homolog 2 (MSH2) is a key component of the MMR system and is dysregulated in human hepatocellular carcinoma (HCC), the molecular mechanism of MSH2 in the process of HCC development under chronic inflammatory conditions remains unclear. To investigate the function of MSH2 in inflammation-associated hepatocarcinogenesis, we treated hepatocyte-specific Msh2-knockout (Msh2 KO) mice with 0.02% thioacetamide for 30 weeks to induce chronic liver inflammation and examined their phenotype. Msh2 KO mice exhibited higher liver tumor incidence than wild-type mice, with no major differences in inflammation or fibrosis. Whole-exome sequencing analysis revealed that genetic alterations with defective MMR-associated signatures were increased in Msh2 KO tumors, though no common cancer driver genes were identified. Transcriptome analysis revealed enrichment of cell cycle-related gene sets, including the G2M checkpoint and E2F targets. Functional assays further demonstrated that MSH2 downregulation impaired ATM-CHK2-mediated DNA damage response and promoted cell cycle acceleration. MSH2 exerts its tumor-suppressive effects in hepatocytes not only through canonical MMR but also by regulating the cell cycle via the ATM-CHK2 axis.

Colorectal cancer (CRC) is one of the deadliest cancer types and is characterized by a complex tumor microenvironment (TME), which includes cancer and immune cells engaging in intricate signaling crosstalk. TME is dependent on the CRC stage and contributes to cancer aggressiveness and therapy resistance. It has been established that tumor-associated immune cells can support cancer progression. However, the underlying mechanisms are not fully elucidated. Here, we provide evidence that communication between CRC and immune cells, particularly tumor-associated macrophages (TAMs), occurs through the release of soluble factors and extracellular vesicles (EVs), such as exosomes. Our study reveals that TAMs initially recognize exosomes as foreign entities, triggering a pro-inflammatory response. Over time, however, the contents of these phagocytosed exosomes reprogram the TAMs into an anti-inflammatory, tumor-supportive phenotype. Our data indicate that such a phenotypic transition in CRC TAMs is primarily triggered by the activation of the NF-kB transcription factor, and that inhibiting NF-kB signaling may significantly decrease the tumor-supportive functions of TAMs in CRC. Thus, pharmacologically slowing the transition of CRC TAMs from pro-inflammatory to tumor-supportive states may be a promising strategy to reduce cancer aggressiveness.

Plasma proteins have been reported as predictors and potential targets for reducing colorectal cancer (CRC) risk. However, their potential roles in CRC prognosis remain unexplored. We measured plasma levels of 367 neuro-related proteins in CRC patients from the West China Hospital (WCH) cohort (N=150, median follow-up=46.72 months) via proximity extension assay. The least absolute shrinkage and selection operator (LASSO) penalized Cox regression identified five overall survival (OS) - and eleven disease-free survival (DFS) - associated proteins, and the multi-protein signature for OS prediction was then validated in the UK Biobank (UKB) cohort (N=1,133). To overcome possible effects from confounders, we then employed Mendelian Randomization analysis leveraging protein quantitative trait loci (pQTLs) to investigate associations between genetically determined protein concentration and OS and cancer-specific survival (CSS) of CRC in the UKB. We found that multi-protein signature developed in the WCH cohort (c-index=0.784, 95% CI=0.713-0.855) showed significant discriminative ability in the external UKB cohort (c-index=0.616, 95%CI=0.559-0.673). A significant association between genetically determined PD-L1 and OS (p=0.043, HR=1.53, 95%CI=1.01-2.29) was observed, although we did not find strong evidence for colocalization. Additionally, single-cell and spatial transcriptome analyses illustrated PD-L1 expression localized predominantly to epithelial cells and immune cells (especially myeloid cells) in CRC tissue. The potential interactions of identified proteins were evaluated in the STRING database. Druggability evaluation also supported PD-L1 as a potential therapeutic target for CRC. Taken together, this study established multi-protein signatures for CRC prognosis and identified plasma PD-L1 as a possible biomarker and therapeutic target.

Plastics have become integral to modern life, but their persistence has generated vast quantities of microplastics (MPs, <5 mm) and nanoplastics (NPs, <1 µm) that now contaminate food, water, air, and human tissues. Although not yet classified as carcinogens by the International Agency for Research on Cancer, accumulating experimental and epidemiologic evidence raises concern that MPs may contribute to cancer development. Global plastic production has risen from 2 megatons in 1950 to more than 450 megatons annually in 2022, leaving behind pervasive waste that fragments into MPs and NPs. These particles act as xenobiotics, carrying toxic additives and adsorbed pollutants, provoking oxidative stress, chronic inflammation, DNA damage, and microbiome disruption; all processes central to carcinogenesis. MPs have been detected in human cancers, and animal studies show tissue accumulation, fibrosis, and genomic instability following exposure. Importantly, the proliferation of plastics parallels a global rise in early-onset cancers (diagnosed before age 50), suggesting a possible, though unproven, temporal association. Individuals born after the 1950s plastic boom have experienced continuous MP exposure beginning in utero, potentially predisposing them to carcinogenic pathways later in life. In this review, we integrate human biomonitoring data, experimental findings, and clinical observations to evaluate the emerging hypothesis that chronic MP exposure contributes to cancer risk. While causality has not been established, the biological plausibility and mounting evidence underscore the urgent need for mechanistic and epidemiologic studies to clarify the role of MPs and NPs in cancer development. It also underscores an urgent need for research into causal pathways and preventive mechanisms.

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 (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), 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.

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.

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.

Epidemiological studies have revealed that ionizing radiation is a risk factor for acute lymphoblastic leukemia. Humans can be exposed to radiation via clinical radiotherapies or spaceflight, yet our knowledge of the potential carcinogenic effects of various types of radiation remains incomplete. To address this shortcoming, we analyzed the development of precursor B-cell lymphoma (pBL) in B6C3F1 mice after irradiation with gamma rays or heavy ions (carbon, silicon, argon, or iron ions) followed by array comparative genomic hybridization, whole-exome sequencing, and RNA-sequencing analyses. Heavy-ion irradiation predominantly induced late-onset pBLs. In addition, chromosomal deletions in late-onset pBLs depended on radiation type: gamma-ray-induced pBLs had interstitial deletions of chromosome 8 (del8) affecting the tumor-suppressor gene Cyld, whereas silicon-ion-induced pBLs had interstitial deletions of chromosome 19 (del19) affecting the tumor-suppressor genes Cd274, Pten, and Fas; notably, carbon ions induced both types of pBL and no pBLs harbored these deletions in the argon- or iron-ion-irradiated mice. Late-onset pBLs were classified into two clusters with differential mutation patterns based on their gene-expression profiles, and pBLs with del8 and del19 were classified into different gene-expression clusters. Furthermore, the mutational and transcriptomic profiles of the late-onset del8 pBLs were reminiscent of human activated B-cell-like diffuse large B-cell lymphoma (DLBCL), whereas those of the del19 pBLs resembled germinal center B-cell-like DLBCL. These results establish the molecular signatures in radiation-induced pBLs that depend on radiation type, which will help improve both targeted molecular therapies for patients and risk assessment after exposure.

The identification and classification of carcinogens is critical in cancer epidemiology, necessitating updated methodologies to manage the burgeoning biomedical literature. We introduce the Carcinogen Detection via Transformers (CarD-T) framework, combining transformer-based machine learning with probabilistic analysis to efficiently nominate potential carcinogens from scientific texts. Trained on 60% of established carcinogens, CarD-T correctly identifies all remaining known carcinogens and nominates ∼1600 potential new carcinogens. Comparative assessment against GPT-4 reveals CarD-T's comparable precision (0.896 versus 0.903), and superior recall (0.853 versus 0.757), implying an improved ability to nominate potential carcinogens for further evaluation. CarD-T associates each nominated entity with relevant scientific literature, allowing for additional analysis of conflicting implications over time through a Bayesian probabilistic carcinogen denomination analysis. The framework also provides rich insights into carcinogenesis associated research, revealing significant shifts in research focus on carcinogenic agents over time, from chemical carcinogens to broader categories including biological agents, environmental factors and lifestyle choices. We establish the CarD-T framework as a locally deployable, computationally inexpensive, and robust tool for identifying and nominating potential carcinogens from vast biomedical literature. This framework enhances the agility of public health responses to carcinogen identification, setting a new benchmark for automated, scalable toxicological investigations.