Hiyama Y, Kanda A, Fukazawa T
… +6 more, Tanimoto K, Kojima M, Morihara N, Matsuo H, Hiyama E, Sotomaru Y
Carcinogenesis
· 2025 Dec · PMID 41874974
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Neuroblastoma (NB), a common childhood solid tumor, is the leading cause of childhood cancer deaths. Transgelin (TAGLN) is an actin-binding protein of the calponin family, and it is involved in cell motility and migratio...Neuroblastoma (NB), a common childhood solid tumor, is the leading cause of childhood cancer deaths. Transgelin (TAGLN) is an actin-binding protein of the calponin family, and it is involved in cell motility and migration. The TAGLN gene expression was induced in NB cell lines, such as GOTO, SK-N-SH, and TGW, by gene overexpression using a retroviral Tet-On inducible expression system, and was repressed by RNA interference (RNAi) treatment. TAGLN overexpression repressed cell growth and migration and induced cell arrest and differentiation. On the other hand, RNAi-mediated TAGLN repression activated cell growth. Cells overexpressing TAGLN showed decreased levels of undifferentiated cell markers, such as SOX2, OCT4, KLF4, and ID2. Single-cell analysis after TAGLN overexpression revealed a distinguishable cluster characterized by expression of POSTM, APOE, PDGFRA, IGFBP3, SMAD5, and IGFBP7. In TH-MYCN mice, which have a high frequency of NB development, Tagln overexpression by induction of the murine Tagln gene significantly reduced tumor formation and prolonged survival. In conclusion, these in vitro and in vivo analyses suggest that TAGLN is a candidate tumor suppressor gene in NB.
Tran LM, Edwards PC, Yang W
… +12 more, Zhang QY, Han W, Kovalchuk N, Ding L, Wu X, Fan X, Arredondo A, Merluza RJA, Besselsen DG, Reader JR, Van Winkle LS, Ding X
Carcinogenesis
· 2026 Mar · PMID 41855137
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Many chemical carcinogens in tobacco smoke require bioactivation by cytochrome P450 enzymes. While the roles of P450 enzymes in carcinogenesis have been demonstrated in vivo using several individual carcinogens at relati...Many chemical carcinogens in tobacco smoke require bioactivation by cytochrome P450 enzymes. While the roles of P450 enzymes in carcinogenesis have been demonstrated in vivo using several individual carcinogens at relatively high doses, no data has been reported on their contributions to carcinogenesis induced by tobacco smoke, a complex mixture of >4000 compounds. The present study aims to address this important knowledge gap, using mice deficient in the expression of enzymes of the Cyp2abfgs gene subfamilies, which are known to bioactivate multiple chemical carcinogens in tobacco smoke. Male and female wild-type (WT) and Cyp2abfgs-null mice on the A/J genetic background were exposed to environmental tobacco smoke (ETS), a mixture of mainstream and sidestream smoke, for 6 hours/day, 5 days/week, for 5 months, at a target dose of 0 or 120 mg/m3 suspended total particulate matter. All mice were returned to filtered air (FA) for 4 months after cessation of ETS exposure. At approximately 11 months of age, mice were euthanized, and lungs were collected for tumor enumeration. ETS exposure increased tumor multiplicity (number of tumors per lung) in WT mice by 2.5-fold (p<0.0001), but only by 1.7-fold in Cyp2abfgs-null mice (p<0.001), compared to FA-exposed mice (n=∼180 per group, male and female). Multiplicity of ETS-induced tumors was significantly reduced (by 50%; p<0.01) in Cyp2abfgs-null relative to WT mice. These results demonstrate for the first time, in vivo, that bioactivation of ETS constituents by P450 enzymes, of the Cyp2abfgs gene subfamilies, play an important role in tobacco-smoke induced lung tumorigenesis in mice.
For decades, there has been a strong epidemiological association between solar ultraviolet (UV) radiation and skin cancer. UVB and UVA are the major UV bands that can penetrate the atmosphere, playing vital roles in skin...For decades, there has been a strong epidemiological association between solar ultraviolet (UV) radiation and skin cancer. UVB and UVA are the major UV bands that can penetrate the atmosphere, playing vital roles in skin carcinogenesis. Our research group previously discovered that a specific dose of UVA can inhibit the increase of activator protein 1 (AP-1) activity caused by UVB. It is unclear whether UVA plays a particular role in UVB-induced skin cancer. Here, we report that UVA was protective in UVB-induced cutaneous squamous cell carcinoma (cSCC) by attenuating UVB-induced DNA damage. DNA repair chip array results showed that the mRNA level of X-ray cross-complementing protein 4 (XRCC4) significantly increased in the UVA/B group compared with the UVB group, and knockdown of XRCC4 partly blocked the protective effect of UVA in UVB-induced DNA damage. AP-1, the predicted transcriptional regulatory factor of XRCC4, exhibited no sensitivity to UVB radiation upon pretreatment with UVA. More importantly, the luciferase reporter assay showed that c-Fos, which is the critical component of AP-1, inhibited the transcription of XRCC4, and mutation of c-Fos (cys154 > serine) partly enhanced this effect and promoted keratinocyte transformation. UVA was protective in UVB-induced cSCC by interacting with the c-Fos/XRCC4 axis.
Arciga BM, Katepalli A, Natesh NS
… +3 more, Teixeiro E, Kaifi JT, Rachagani S
Carcinogenesis
· 2025 Dec · PMID 41793158
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The aryl hydrocarbon receptor (AhR) is a ubiquitously expressed, ligand-activated transcription factor which has been extensively studied for its role in mediating the toxic effects of several common environmental pollut...The aryl hydrocarbon receptor (AhR) is a ubiquitously expressed, ligand-activated transcription factor which has been extensively studied for its role in mediating the toxic effects of several common environmental pollutants. However, more recent findings associating AhR with carcinogenesis and tumor progression have expanded the scope of AhR research and established the preclinical significance of AhR as a possible target for cancer therapy. In this review, the current knowledge of the role of AhR in cancer will be discussed, and evidence from an array of experimental cancer and immune models will be presented. It has been observed that AhR potentiates oncogenic mutations through induction of genetic damage and transactivates EGFR to promote proproliferative signaling along the classical Ras/Raf/MAPK and PI3K/Akt pathways. Furthermore, AhR downregulates E-cadherin via multiple axes to facilitate epithelial-to-mesenchymal transition and contributes to a shift of the tumor immune microenvironment to a predominantly regulatory milieu. The sheer versatility of AhR as a protumor factor should provide sufficient grounds for further investigation of the persisting question of whether targeting AhR can disrupt tumor progression in vivo.
Carcinogenesis
· 2025 Dec · PMID 41762686
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While the effect of hyperglycemia on cutaneous wound healing is well recognized, the impact of high-glucose (HG) environment on UVB-induced skin tumor formation remains inconclusive. Similar to impaired wound healing, sk...While the effect of hyperglycemia on cutaneous wound healing is well recognized, the impact of high-glucose (HG) environment on UVB-induced skin tumor formation remains inconclusive. Similar to impaired wound healing, skin tumor formation involves keratinocyte proliferation and migration. Intriguingly, SOX2 has been recognized to play an important role in both wound healing and UVB-induced skin tumor formation by modulating cell proliferation and migration. As hyperglycemia results in impaired cutaneous wound healing, we hypothesized that the HG environment also impacts UVB-induced tumor formation of the skin. This study aimed to explore the effects of HG environment on epidermal keratinocytes, focusing on the impact of UVB-induced cell proliferation and migration via SOX2 expression. In cultured keratinocytes, HG-cultivated keratinocytes showed reduced SOX2 levels compared to control with or without UVB treatment. SOX2 regulates keratinocyte migration and proliferation via modulation of AKT phosphorylation. Additionally, O-linked-N-acetylglucosamine glycosylation contributed to reduced SOX2 levels in HG-cultivated keratinocytes. Animal studies demonstrated that diabetic mice skin has significantly less UVB-induced tumor formation, epidermal thickening, SOX2, and pAKT expression than the control mice; mutant p53 expression was also lower in diabetic mice but did not reach statistical significance compared to control. In conclusion, HG environment reduces UVB-induced keratinocyte proliferation and migration, in association with decreased SOX2 expression and downstream AKT signaling. The current findings provide novel insights regarding UVB-induced skin tumor formation of skin in patients with diabetes.
Yuncu ME, Bilgin B, Avci D
… +3 more, Karadag A, Ozer F, Biray Avci C
Carcinogenesis
· 2025 Dec · PMID 41738561
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Glioblastoma is a highly aggressive primary brain tumour marked by extensive genomic and epigenomic alterations, cellular heterogeneity, and therapeutic resistance. Despite maximal surgical resection followed by chemorad...Glioblastoma is a highly aggressive primary brain tumour marked by extensive genomic and epigenomic alterations, cellular heterogeneity, and therapeutic resistance. Despite maximal surgical resection followed by chemoradiotherapy, median survival remains approximately 15 months, reflecting the tumour's invasive behaviour and adaptability. Advances in molecular oncology have revealed two promising therapeutic directions: epigenetic reprogramming and neurogenetic modulation. Glioblastoma exhibits widespread epigenetic dysregulation that disrupts transcriptional control, enhances cellular plasticity, and drives tumour progression. Concurrently, glioma cells aberrantly reactivate developmental programmes, acquiring neural stem cell-like states governed by transcription factors and signalling networks such as SOX2, OLIG2, Notch, and Wnt. These pathways collectively sustain stemness, lineage mimicry, and therapy resistance. This review proposes a focused conceptual framework centred on epigenetic and neurogenetic modulation as two core regulatory layers shaping glioblastoma plasticity and adaptive resistance. We highlight how DNA methylation, histone modifications, and chromatin remodelling contribute to transcriptional dysregulation, and how neurodevelopmental signalling reinforces malignant plasticity. Emerging preclinical and clinical studies combining epigenetic inhibitors with differentiation- or reprogramming-based therapies are discussed. By uniting mechanistic insights from chromatin biology, neurodevelopment, and cancer therapeutics, this integrative conceptual framework offers a structured lens for targeting key vulnerabilities underlying glioblastoma plasticity. The integration of these complementary strategies offers potential to enhance therapeutic responsiveness and improve disease management in this devastating malignancy.
Carcinogenesis
· 2025 Dec · PMID 41718030
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Rhabdomyosarcoma (RMS) is a predominantly paediatric cancer that is classified by the presence or absence of a PAX-FOXO1 fusion gene, which is associated with a worse prognosis. Previous classification was based on histo...Rhabdomyosarcoma (RMS) is a predominantly paediatric cancer that is classified by the presence or absence of a PAX-FOXO1 fusion gene, which is associated with a worse prognosis. Previous classification was based on histology, alveolar RMS (ARMS) or embryonal RMS (ERMS). In other paediatric cancers, fusion gene status has been shown to associate with differences in the tumour microenvironment (TME). However, comprehensive understanding of the TME in RMS and how it may differ between subtypes is lacking. This systematic review aimed to identify differences in the TME between fusion-positive RMS and fusion-negative RMS, to better understand how the fusion gene drives malignancy. The Web of Science, MEDLINE (Ovid), and EMBASE (Ovid) were searched to identify relevant studies investigating the TME in RMS. A total of 17 studies met the inclusion criteria and were included in the review, but only three studies specified fusion status in their sample data. Nine studies investigated the extracellular matrix and stroma, and another nine investigated the immune microenvironment. Significant differences in CD163+ macrophages, matrix metalloproteinases and stromal platelet-derived growth factor receptors-α/β were observed between ARMS and ERMS. Regarding fusion status, there were differences in the prevalence of T cell dysfunction, NECTIN-3 expression, and genes related to PD-1 signalling and interferon (IFN) response. This review highlights a need for further research of the TME in each fusion subtype. This will improve our understanding of how the fusion gene drives malignancy and ultimately aids in the development of novel treatment strategies.
Hecht SS, Carmella SG, Basu S
… +14 more, Chen M, Wittman M, Tang MK, Zhao Y, Lu J, Ng D, Heath E, Fujioka N, Egbert A, Strayer L, Usman A, Thomson NM, Murphy SE, Hatsukami DK
Carcinogenesis
· 2025 Dec · PMID 41699775
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Human exposure to toxicants and carcinogens occurs via polluted air, the diet, occupational settings, endogenous processes, and tobacco products. The glutathione-S-transferase detoxification pathway resulting in the excr...Human exposure to toxicants and carcinogens occurs via polluted air, the diet, occupational settings, endogenous processes, and tobacco products. The glutathione-S-transferase detoxification pathway resulting in the excretion of mercapturic acids is one of the most important human systems for processing and excreting toxicants and carcinogens. Maximizing effectiveness of this pathway through dietary modifications can potentially decrease the impact of such exposures. We conducted a two-site clinical trial with a crossover, single blind (to participants) design, randomized to order of product receipt comparing levels of selected urinary mercapturic acids when participants consumed a drink made from freeze-dried watercress (3× daily, 2 weeks) naturally containing 2-phenethyl isothiocyanate (PEITC) vs. a placebo drink containing maltodextrin (3× daily, 2 weeks) with a 4-week washout between the treatment periods. Two hundred forty participants (157 F) were recruited and 188 (125 F, 152 non-smokers) were compliant and completed the study. Among compliant subjects, urinary mercapturic acid detoxification products of acrolein, acrylonitrile, benzene, crotonaldehyde, methacrolein, and methyl vinyl ketone increased significantly (P ≤ 0.002), with the largest increases being observed for the mercapturic acids of acrolein (65.6%) and benzene (37.3%), both P < 0.001. Consumption of a drink, three times daily, prepared from freeze-dried watercress containing PEITC (total of approximately 40 mg/day) significantly increased the detoxification of 6 of 7 environmental toxicants and carcinogens monitored. The results indicate that watercress consumption can ameliorate exposure to environmental toxicants and carcinogens. These results are particularly timely and relevant to exposures to atmospheric pyrolysis products resulting from wildfires. Clinical trial registration number: NCT03978117.
Carcinogenesis
· 2025 Dec · PMID 41670044
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When, ∼20 years ago, investigators first determined that components of the genome considered nonfunctional had, in fact, gene regulatory capacity, they probably had no idea of their potential in controlling cell fate and...When, ∼20 years ago, investigators first determined that components of the genome considered nonfunctional had, in fact, gene regulatory capacity, they probably had no idea of their potential in controlling cell fate and were forced to revise and somehow reorganize their view of the molecular biology. Indeed, it is currently well documented how a class of small non-coding RNAs, microRNAs, are conserved among the species, expressed in different tissues and cell types and involved in almost every biological process, including cell cycle, growth, apoptosis, differentiation and stress response, exerting a finely tuned regulation of gene expression by targeting multiple molecules. As a consequence of the widespread range of processes they are able to influence, it is not surprising that miRNA deregulation is a hallmark of several pathological conditions, including cancer. Indeed, the aberrant expression of these tiny molecules in human tumors is not just a casual association, but they can exert a causal role, as oncogenes or tumor suppressors, in every step of tumor development, from occurrence to progression. An increasing body of evidence has indeed proved the importance of miRNAs in cancer, suggesting their possible use as diagnostic, prognostic and predictive biomarkers and leading to exploit miRNA-based anticancer therapies, either alone or in combination with current targeted therapies, with the goal to improve disease response and increase cure rates. Here, we review our current knowledge about miRNA involvement in cancer.
Adali Y, Loughrey MB, Craig S
… +5 more, Gray RT, James JA, Salto-Tellez M, Dunne PD, Coleman HG
Carcinogenesis
· 2025 Dec · PMID 41631717
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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 s...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.
Nakano S, Takai A, Iguchi E
… +13 more, Fujii Y, Amino H, Ueno M, Ito T, Teramura M, Mishima M, Kumagai K, Inuzuka T, Takeda H, Eso Y, Shimizu T, Maruno T, Seno H
Carcinogenesis
· 2025 Dec · PMID 41610140
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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 h...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.
Wadhonkar K, Das D, Kant Chittela R
… +2 more, Obukhov AG, Baig MS
Carcinogenesis
· 2025 Dec · PMID 41554687
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Colorectal cancer (CRC) is one of the deadliest malignancies and is characterized by a complex tumor microenvironment (TME) comprising cancer and immune cells engaged in extensive signaling crosstalk. The composition of...Colorectal cancer (CRC) is one of the deadliest malignancies and is characterized by a complex tumor microenvironment (TME) comprising cancer and immune cells engaged in extensive signaling crosstalk. The composition of the TME changes with disease stage and contributes to tumor aggressiveness and resistance to therapy. Although tumor associated immune cells are known to promote cancer progression, the mechanisms underlying these effects are not fully understood. In this study, we show that communication between CRC cells and immune cells, particularly tumor associated macrophages (TAMs), is mediated by soluble factors and extracellular vesicles, including exosomes. We find that the phenotypic transition of CRC associated TAMs is initially driven by activation of the nuclear factor kappa B transcription factor. With time, exosomal cargo promotes anti-inflammatory signaling, leading to the development of a tumor supportive microenvironment that favors tumor growth. Together, these findings highlight exosome mediated modulation of TAM function as an important mechanism in CRC progression and suggest that targeting this pathway to delay the shift of TAMs from pro-inflammatory to tumor supportive states may attenuate CRC aggressiveness.
Amano K, Tachibana H, Tsuruoka C
… +7 more, Daino K, Morioka T, Shang Y, Ishikawa A, Imaoka T, Matsuura A, Kakinuma S
Carcinogenesis
· 2025 Dec · PMID 41542965
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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 pot...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.
Xie X, Zhou J, Wu Q
… +11 more, Sun J, Shu C, Huang J, Li C, Wang X, Shen X, Li X, Luo Z, Xu C, Wang Z, He Y
Carcinogenesis
· 2025 Dec · PMID 41537569
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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-...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 penalized Cox regression identified five overall survival (OS)-and eleven disease-free survival-associated proteins, and the multiprotein signature for OS prediction was then validated in the UK Biobank (UKB) cohort (N = 1133). To overcome possible effects from confounders, we then employed Mendelian randomization analysis leveraging protein quantitative trait loci to investigate associations between genetically determined protein concentration and OS and cancer-specific survival of CRC in the UKB. We found that multiprotein 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 multiprotein signatures for CRC prognosis and identified plasma PD-L1 as a possible biomarker and therapeutic target.
Carcinogenesis
· 2026 Jan · PMID 41521690
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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. Alth...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.