Carcinogenesis [JOURNAL]
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200 papers
The importance of data from the atomic bomb survivors for international radiological protection.
Wakeford R, Laurier D
Carcinogenesis · 2025 Sep · PMID 41144268 · Full text
Epidemiological studies using data from the lifetime experience of the survivors of the atomic bombings of Japan have been fundamental in shaping the international system of radiological protection since a clear excess r...
Epidemiological studies using data from the lifetime experience of the survivors of the atomic bombings of Japan have been fundamental in shaping the international system of radiological protection since a clear excess risk of, first leukaemia and then other cancers, became apparent in the 1950s and 1960s. Cancer mortality and incidence data have been collected, collated and analysed by the Radiation Effects Research Foundation (RERF, and its predecessor, the Atomic Bomb Casualty Commission, ABCC) and the risk estimates so produced have been used subsequently by the International Commission on Radiological Protection (ICRP) to provide the main technical basis of its general recommendations, from its 1965 Recommendations to the latest 2007 Recommendations. As the database has grown with increasing follow-up of the survivors, together with continued refinement of the dosimetry system, ABCC/RERF analyses have become more sophisticated, permitting knowledge of the variation of risks for a growing number of specific types of cancer, as modified by sex, age-at-exposure and time-since-exposure/attained age. A growing database of non-cancer effects, such as diseases of the circulatory system and eye lens opacities, is also providing risk estimates. Even now, 80 years after the bombings, the survivors provide important information on risks decades after exposure at a young age. There is little doubt that recent RERF studies of cancer and non-cancer diseases in the survivors will continue to steer the ICRP in its progress towards the next Recommendations.
Risk of clonal hematopoiesis in families exposed to radiation following the Chornobyl accident.
Machiela MJ, Wong WSW, Mai JZ … +20 more , Karyadi DM, Drozdovitch V, Chan I, Vij V, Zhou W, Luo W, Wu D, Hutchinson A, Jones K, Hicks B, Bakhanova E, Chumak V, Gudzenko N, Kryuchkov V, Golovanov I, Bolton K, Cahoon EK, Morton LM, Bazyka D, Chanock SJ
Carcinogenesis · 2025 Sep · PMID 41144267 · Full text
Radiation exposure is a well-established risk factor for leukemia. Clonal hematopoiesis (CH), the expansion of mutated hematopoietic cells, is also associated with increased leukemia risk and its frequency is higher in c...
Radiation exposure is a well-established risk factor for leukemia. Clonal hematopoiesis (CH), the expansion of mutated hematopoietic cells, is also associated with increased leukemia risk and its frequency is higher in cancer patients following radiotherapy and chemotherapy. We investigated whether low to moderate environmental ionizing radiation determined by state-of-the-art dosimetric analysis was associated with CH in the Chornobyl Family Study (CFS). Our study conducted targeted high-depth sequencing and array genotyping to identify and characterize clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) in 882 participants from 292 CFS families. Fathers had mean bone marrow radiation doses of 0.24 Gy (range: 0-3.86) and mothers had mean doses of 0.009 Gy (range: 2 × 10-5-0.63). The expected relationship between increasing age and CHIP was observed. No detectable effect of red bone marrow radiation dose was observed for CHIP risk (Fathers: Excess OR (EOR)/Gy = 0.41; 95% confidence interval (CI) = -0.57,1.39; P-value = .42; Mothers (categorical model due to limited dose range): odds ratio (OR)0.01-0.09 versus <0.001 Gy = 0.73; 95% CI = 0.39,1.38; P-value = .33) and the distribution and types of CHIP and mCAs detected in CFS participants did not differ from that seen in previously published studies of unexposed populations. No transgenerational effect of parental gonadal radiation exposure was detected in the children (Fathers: P-value = .08; Mothers: P-value = .67). Our findings suggest the type and levels of radiation exposure investigated in CFS families are unlikely to be strong contributors to CH risk, which could have important implications for public health concerns following environmental exposure to low to moderate ionizing radiation.
Uranium mining and lung cancer: a legacy of the nuclear age.
Samet JM, Richardson DB
Carcinogenesis · 2025 Sep · PMID 41144266 · Full text
The Nuclear Age spurred widespread mining of uranium for production of weapons and for nuclear power. The widespread mining of uranium, with historically limited control of radiation exposures, has resulted in high rates...
The Nuclear Age spurred widespread mining of uranium for production of weapons and for nuclear power. The widespread mining of uranium, with historically limited control of radiation exposures, has resulted in high rates of lung cancer among the former miners. This paper reviews the long and ongoing story of lung cancer among miners of uranium.
Summary of radiation effects on incidence of solid cancers in the Life Span Study of atomic bomb survivors: 1958-2009.
Brenner AV, Sugiyama H, Cologne J … +8 more , Sakata R, Utada M, Grant EJ, French B, Cahoon EK, Preston DL, Ozasa K, Mabuchi K
Carcinogenesis · 2025 Sep · PMID 41144265 · Full text
This paper concludes the third comprehensive report on radiation effects on solid cancer incidence within the Life Span Study (LSS) cohort of Japanese atomic bomb survivors, adding 11 years of follow-up. Over 1958-2009,...
This paper concludes the third comprehensive report on radiation effects on solid cancer incidence within the Life Span Study (LSS) cohort of Japanese atomic bomb survivors, adding 11 years of follow-up. Over 1958-2009, 22 538 solid cancer cases and 3.1 million person-years were identified among 105 444 individuals. The study utilized improved radiation doses (DS02R1), updated migration probabilities, and adjustments for smoking and lifestyle factors. Poisson regression was used to model excess relative risk (ERR) and excess absolute rate (EAR) per 1 Gy for all-solid cancers combined and specific sites. Among females, a linear dose-response model best described all-solid cancer risk [ERR = 0.64 Gy-1, 95% confidence interval (CI): 0.52-0.77], whereas among males, a linear-quadratic model with upward curvature provided the best fit (ERR = 0.20 at 1 Gy, 95% CI: 0.12-0.28). Radiation-associated ERR declined with attained age, more rapidly in males than in females, while EAR increased with age. Independently, radiation-associated ERR and EAR decreased with age at exposure. A significant dose-response was identified for prostate cancer for the first time; for brain and central nervous system tumors, female pancreatic, and uterine corpus cancers dose-response reached statistical significance. A new age-at-exposure pattern emerged for female breast and uterine corpus cancers, suggesting that radiation-associated risk increased as exposure age approached menarche (∼age 15), decreasing at older exposure ages. Most cancers exhibited linear dose-response, except non-melanoma skin, bone and joint, esophageal, and kidney parenchyma cancers in males. Sixty-four years post-exposure, solid cancer risks remain elevated, reinforcing the LSS's critical role in unraveling lifetime cancer effects of a-bomb radiation after exposure at various ages.
Eight decades of research on the long-term health effects of radiation in atomic bomb survivors and their offspring.
Kamiya K, Sakata R, Rajaraman P
Carcinogenesis · 2025 Sep · PMID 41144264 · Full text
This year marks the 80th anniversary of the atomic bombings of Hiroshima and Nagasaki. Over the past eight decades, large-scale cohort studies of atomic bomb survivors and their offspring conducted by the Radiation Effec...
This year marks the 80th anniversary of the atomic bombings of Hiroshima and Nagasaki. Over the past eight decades, large-scale cohort studies of atomic bomb survivors and their offspring conducted by the Radiation Effects Research Foundation and its predecessor, the Atomic Bomb Casualty Commission, have provided critical insights into the long-term health effects of radiation exposure. Key findings include early identification of radiation-associated leukemia, as well as excess risks of all solid cancers combined, and most individual cancer sites. Observed radiation dose-response relationships have generally followed a linear-quadratic model for leukemia and a linear model for all solid cancers. Recent findings indicating possible upward curvature in the dose-response for all solid cancers may reflect underlying heterogeneity in factors related to individual cancer sites and should be explored further. Generally, younger age at exposure, lower attained age, and female sex appear to show greater radiation sensitivity for all solid cancers combined but results differ by individual cancer site. Recent studies have also identified potential radiation-related excesses for non-cancer diseases such as cataracts, various circulatory diseases, and others. Studies of heritable effects on the offspring of exposed atomic bomb survivors, in contrast, have shown no elevated risk to date in offspring from parental radiation exposure, either at the molecular or disease level. With the cooperation of the atomic bomb survivors and their families, Radiation Effects Research Foundation's research will continue to play a crucial role in informing the health of survivors, their families, and global radiation protection in the decades to come.
Radiation effects research foundation-a view to the future.
Gray JW, Feinberg AP
Carcinogenesis · 2025 Sep · PMID 41144263 · Full text
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Symposium report-ethical and social considerations regarding return of secondary findings in atomic bomb survivors.
Yoshida N, Stewart DR, Uchimura A … +20 more , Arita KI, Bombard Y, Frone M, Hinoi T, Kamiya K, Katamine S, Kayukawa J, Kodama K, Miller DT, Miura K, Muto K, Nagami F, Nakagawa H, Noda A, Ohishi W, Tanabe O, Terao C, Rajaraman P, Kato K, Biesecker LG
Carcinogenesis · 2025 Sep · PMID 41144262 · Full text
The Radiation Effects Research Foundation (RERF) conducts research on the health effects of atomic bomb (A-bomb) radiation, supported by the long-term cooperation of survivors and their children. In response to concerns...
The Radiation Effects Research Foundation (RERF) conducts research on the health effects of atomic bomb (A-bomb) radiation, supported by the long-term cooperation of survivors and their children. In response to concerns from A-bomb survivors, their offspring, and the global community, RERF has investigated transgenerational radiation effects for many years. Currently, RERF is planning the Trio Genome Study (TGS), which will utilize advanced genome sequencing to examine potential genetic effects on the offspring of survivors. This study could yield significant findings but also presents ethical challenges, particularly in ensuring that results are returned responsibly to the community. RERF first held an international workshop to address ethical, legal, and social issues related to genomic analysis in 2020, followed by formation of stakeholder committees to align the study with community perspectives. Most recently, in December 2024, an international symposium further explored frameworks important to the TGS, including risk communication, benefit-sharing, community involvement, and return of secondary findings. In genomic analysis, secondary findings comprise a deliberate search for pathogenic variants in an established list of genes in disorders associated with life-threatening manifestations. Returning these secondary findings to research participants is crucial from the perspective of benefit-sharing. Discussions emphasized the need for transparency in the return of secondary findings, especially those with actionable health implications, including sharing the rationale behind providing information about genetic variants to research participants. These frameworks will guide not only future RERF studies but also genomic research worldwide, ensuring that the findings benefit participants and communities.
Genomic landscape of radiation-induced somatic mutations in a normal cell.
Matsuda Y, Tanabe O
Carcinogenesis · 2025 Sep · PMID 41144261 · Full text
Atomic bomb survivors have been found to have an excess risk of late adverse effects, including leukemia, various solid cancers, and non-cancer diseases, depending on the dose of radiation exposure. Radiation-induced DNA...
Atomic bomb survivors have been found to have an excess risk of late adverse effects, including leukemia, various solid cancers, and non-cancer diseases, depending on the dose of radiation exposure. Radiation-induced DNA damage can lead to errors in DNA repair, resulting in the induction of somatic mutations in cells. Since these mutations are thought to contribute to an increased risk of radiation-induced carcinogenesis, various approaches, such as mutation analysis at specific genetic loci and chromosomal analysis, have been used to investigate their characteristics. However, previous methods were only capable of detecting a subset of radiation-induced mutations, making it difficult to quantitatively and comprehensively capture their specificity, including the mutation spectrum. Recently, whole-genome sequencing combined with of ex vivo single-cell culture has enabled a comprehensive analysis of radiation-induced mutations in individual cells. Such studies, including our own, have demonstrated that short, non-repeat deletions occurring outside of tandem repeats represent the most distinctive signature of radiation-induced mutagenesis, showing clear dose dependence and consistency across multiple tissues. Structural variants (excluding retroelement insertions) and multisite mutations also showed radiation specificity, albeit to a lesser extent and at a lower frequency than non-repeat deletions. These findings may offer insights into the molecular mechanisms underlying radiation-induced oncogenesis and non-cancer disease development.
History and current developments of RERF dosimetry.
Cullings HM, Funamoto S, Egbert SD … +9 more , Griffin KT, Paulbeck CJ, Domal SJ, Correa-Alfonso CM, Shimizu S, Sato T, Lee C, Endo A, Bolch WE
Carcinogenesis · 2025 Sep · PMID 41144260 · Full text
Studies of the health effects among Japanese atomic bomb survivors, including radiation-induced carcinogenesis, necessitate accurate radiation dose estimates for individual survivors from the Hiroshima and Nagasaki bombi...
Studies of the health effects among Japanese atomic bomb survivors, including radiation-induced carcinogenesis, necessitate accurate radiation dose estimates for individual survivors from the Hiroshima and Nagasaki bombings. Efforts toward this goal commenced shortly after the bombings in 1945, resulting in a series of dosimetry systems developed over the years to calculate survivor doses for a roster currently numbering 135 852 survivors. These systems estimate a survivor's dose based on data such as the survivor's location and shielding by structures such as houses. This paper focuses on a series of systems created over the years, first by US groups and later by binational US-Japan groups, with particular emphasis on the most recent dosimetry systems: Dosimetry System 2002 and DS02 Revision 1. Furthermore, we discuss the latest advancement, the J45 phantoms, which introduces a new system of anthropomorphic phantoms for calculations of dose to specific organs of the human body with consideration of body self-shielding and has been in development over the last few years.
Recent evolution of risk analyses in atomic bomb survivor studies: new methods and applications.
Cologne J, Misumi M, Lindner H … +2 more , Liu Z, Sposto R
Carcinogenesis · 2025 Sep · PMID 41144259 · Full text
Several decades ago a dramatic leap forward occurred in the development and application of statistical methods for modeling radiation risk at the Radiation Effects Research Foundation (RERF). Poisson regression analysis...
Several decades ago a dramatic leap forward occurred in the development and application of statistical methods for modeling radiation risk at the Radiation Effects Research Foundation (RERF). Poisson regression analysis for grouped person-year cohort data and the linear excess relative risk model were introduced, and subsequently a devoted software system, Epicure® (https://www.hirosoft.com), was developed by researchers at RERF and at the U.S. National Cancer Institute. Numerous advancements in understanding radiation effects on humans were made possible with these methods, which are still the state-of-the-art for risk assessment at RERF and have remained part of the standard toolbox for radiation-and other environmental-epidemiological studies worldwide. Nevertheless, as our understanding of radiation risk has increased, so have the breadth and depth of questions that require answers based on emerging data that are not amenable to these conventional methods. This overview briefly recounts the conventional methods and then describes our recent diversification into the use or development of new statistical approaches to meet the challenges of burgeoning biological data and emerging mechanistic information. We briefly discuss the development and application of new methods, current and planned, that are part of the RERF Statistics Department's role in supporting institution-wide research, especially in our collaborations involving the Life Span Study, Adult Health Study, and First-generation Offspring Clinical Study. Some approaches to modeling and assessing radiation risk with newer methods mentioned herein have already been published, while some are still in development or are only beginning at the proposal stage.
MAPK3 modulates enhancer-promoter interactions of SKAP2 in acute myeloid leukemia.
Hu Y, Chen F, Wang T … +7 more , Wang B, Wang Z, Zheng J, Shen Y, Shen Y, Ma J, Guo Y
Carcinogenesis · 2025 Nov · PMID 41139207 · Publisher ↗
The regulation of gene expression through chromatin architecture plays a critical role in acute myeloid leukemia (AML). In this study, the influence of MAPK3 on CTCF-mediated chromatin interactions in AML was examined, f...
The regulation of gene expression through chromatin architecture plays a critical role in acute myeloid leukemia (AML). In this study, the influence of MAPK3 on CTCF-mediated chromatin interactions in AML was examined, focusing on gene regulation and chromatin architecture. Immunoprecipitation coupled with mass spectrometry (IP-MS) was conducted to identify CTCF-binding proteins in AML cell lines. Chromatin immunoprecipitation sequencing (ChIP-seq) was used to assess the impact of MAPK3 modulation on CTCF DNA binding, following treatment with an MAPK3 activator or inhibitor. Additionally, chromatin interactions were evaluated using 3C-qPCR, and specific enhancer sites at the SKAP2 locus were deleted using CRISPR-Cas9. Results demonstrated that IP-MS identified MAPK3 as a key CTCF-binding protein, indicating its potential role in AML chromatin regulation. MAPK3 significantly influences CTCF binding at distal intergenic regions upstream of SKAP2, as confirmed by ChIP-seq. Chromatin interaction analyses revealed that CTCF-regulated enhancer-promoter interactions at SKAP2 are modulated by MAPK3 activity. Furthermore, deletion of enhancer regions E4 and E6 led to decreased SKAP2 expression. These findings highlight the critical role of MAPK3 in regulating CTCF-mediated chromatin interactions and suggest that targeting MAPK3-regulated chromatin remodeling could be a novel therapeutic strategy for AML.
CarD-T: an automated pipeline for the nomination and analysis of potential human carcinogens.
O'Neill J, Reddy GA, Dhillon N … +3 more , Tripathi O, Alexandrov L, Katira P
Carcinogenesis · 2025 Dec · PMID 41139201 · Full text
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 Trans...
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.
A2AR-phospho-STAT1 (Y701)-HLA-E axis as a potential immune modulatory pathway in radiotherapy-resistant triple negative breast cancer.
Ko YS, Jin H, Lee SE … +8 more , Won JY, Lee JH, Lee JS, Kim DC, Yun SP, Park SW, Lee GW, Kim HJ
Carcinogenesis · 2025 Nov · PMID 41122851 · Publisher ↗
Triple-negative breast cancer (TNBC) patients have lower survival rates and higher recurrence risks than non-TNBC patients. Moreover, radiotherapy-resistant TNBC (RT-R-TNBC) exhibits enhanced chemotherapy resistance and...
Triple-negative breast cancer (TNBC) patients have lower survival rates and higher recurrence risks than non-TNBC patients. Moreover, radiotherapy-resistant TNBC (RT-R-TNBC) exhibits enhanced chemotherapy resistance and invasiveness. Therefore, there is a critical need for innovative treatments for RT-R-TNBC and TNBC patients. Our previous study indicated that NK cells exhibit reduced cytotoxicity against RT-R-TNBCs due to human leukocyte antigen class I histocompatibility antigen, alpha chain E (HLA-E) upregulation. Thus, this study aimed to identify the mechanism responsible for the upregulation of HLA-E and suggest potential therapeutic targets for overcoming the RT-resistance of TNBC. We found that HLA-E expression was significantly higher in TNBC tumor tissues than in normal epithelial tissues and non-TNBC tissues, correlating with A2AR levels. In addition, MDA-MB-231 (TNBC) and RT-R-MDA-MB-231 (RT-R-TNBC) showed an A2AR-dependent HLA-E overexpression. NK cell-mediated cytotoxicity against MDA-MB-231 and RT-R-MDA-MB-231 was reduced and restored by A2AR or STAT1 knockdown. Interestingly, STAT1 phosphorylation (Y701) by adenosine (ADO) aligned with the HLA-E expression pattern by ADO, and fludarabine, a STAT1 inhibitor, effectively reduced phospho-STAT1 (Y701) levels but not phospho-STAT1 (S727) levels. Fludarabine also inhibited ADO-induced HLA-E expression in MDA-MB-231 and RT-R-MDA-MB-231, including basal HLA-E expression in RT-R-MDA-MB-231. Additionally, fludarabine reduced tumor progression, lung metastasis, HLA-E expression, and phospho-STAT1 (Y701) in RT-R-MDA-MB-231-injected mice. Moreover, monalizumab, an NKG2A monoclonal antibody, significantly reduced tumor progression and lung metastasis with increased population of cytotoxic NK cells (CD25 + NK1.1+ and CD69 + NK1.1+) in the inguinal lymph nodes of RT-R-MDA-MB-231-injected mice. This study suggests that the A2AR-phospho-STAT1 (Y701)-HLA-E axis may serve as an alternative target for overcoming RT-resistance in TNBC.
HS-10296 (almonertinib) enhances radiosensitivity in EGFR-mutant nonsmall cell lung cancer (including T790M) through inhibition of EGFR downstream signaling and DNA damage repair.
Liu W, Liu Y, Xie Y … +5 more , Huang H, Wan M, Zhou L, Xu F, Zhong M
Carcinogenesis · 2025 Nov · PMID 41092159 · Publisher ↗
Nonsmall cell lung cancer (NSCLC) harboring EGFR mutations, including the resistant T790M variant, continues to require improved therapeutic strategies despite the development of EGFR tyrosine kinase inhibitors (TKIs). T...
Nonsmall cell lung cancer (NSCLC) harboring EGFR mutations, including the resistant T790M variant, continues to require improved therapeutic strategies despite the development of EGFR tyrosine kinase inhibitors (TKIs). This study evaluates the radiosensitizing potential of HS-10296 (almonertinib), a third-generation EGFR-TKI, in EGFR-mutant NSCLC models. In vitro studies demonstrated selective growth inhibition in mutant cells (PC-9: half-maximal inhibitory concentration (IC50) = 2.62 μM; H1975: IC50 = 5.22μM at 48 h) compared to wild-type A549 cells (IC50 = 11.42 μM). Clonogenic assays revealed significant radiosensitization in mutant cells (SER: PC-9 = 1.22; H1975 = 1.55) through multiple mechanisms including enhanced DNA damage (1.5-2.0-fold increase in comet tail moments with 4-10× persistent γH2A.X foci), marked suppression of RAD51-mediated DNA repair, and increased apoptosis (combination therapy: 19.53%-20.71% versus monotherapies: 12.08%-14.05%). Mechanistic investigation showed HS-10296 attenuated phosphorylation of EGFR and downstream effectors AKT and ERK, potentially disrupting DNA damage response pathways. In vivo validation using H1975 xenografts demonstrated superior tumor growth inhibition with the combination of HS-10296 and radiotherapy, which correlated with reduced expression of p-EGFR, p-AKT, and RAD51, along with increased γH2A.X levels. These findings establish HS-10296 as a promising radiosensitizer for EGFR-mutant NSCLC through simultaneous targeting of oncogenic signaling via PI3K/AKT and MAPK/ERK pathways and critical DNA repair mechanisms. The study provides compelling preclinical evidence supporting clinical evaluation of HS-10296 combined with radiotherapy for EGFR-driven NSCLC, including tumors with T790M-mediated resistance.
Polo-like kinase 4 (PLK4) as a therapeutic target in breast cancer.
Parsyan A, Athwal H, Bhat V … +1 more , Allan AL
Carcinogenesis · 2025 Nov · PMID 41092110 · Full text
Polo-like kinase 4 (PLK4) is a key kinase regulating centriole duplication, centrosome maturation, cytokinesis and other cellular processes. Growing evidence suggests a critical role of PLK4 in the development and progre...
Polo-like kinase 4 (PLK4) is a key kinase regulating centriole duplication, centrosome maturation, cytokinesis and other cellular processes. Growing evidence suggests a critical role of PLK4 in the development and progression of various cancers. In many cancer types, its upregulation leads to pro-oncogenic phenotypes, while its pharmacologic inhibition leads to anticancer effects. Functionally, PLK4 affects cancer cell proliferation, growth, motility, invasion, migration, epithelial-mesenchymal transition, apoptosis and other critical oncogenic processes. In breast cancer, PLK4 is associated with centrosome amplification, aneuploidy and chromosomal instability, promoting invasive phenotypes and resistance to cancer cell death. PLK4 shows great promise as a prognostic and predictive biomarker in breast cancer. It is commonly found to be overexpressed in primary human breast cancers and is associated with poor oncologic outcomes, clinicopathologic parameters, and high-risk subtypes. Various compounds, such as CFI-400945, centrinone B, and others have been developed to inhibit PLK4 activity. Preclinical studies have shown that PLK4 inhibitors lead to decreased proliferation, growth and migration and increased breast cancer cell death. Moreover, PLK4 inhibition can serve to enhance the effects of other treatments, including radiotherapy. Clinical studies have been initiated with some of these compounds in cancer patients, including those with breast cancer. This manuscript discusses the role of PLK4 as a promising therapeutic target in breast cancer, one of the most common causes of morbidity and mortality in women.
Thrombospondin-4 from cancer-associated fibroblasts downregulates ERBB2 expression in gastric cancer cells.
Tsujio G, Yashiro M, Sakuma T … +11 more , Yamamoto Y, Imanishi D, Fan C, Wang Q, Kawabata K, Nishikubo H, Kanei S, Aoyama R, Maruo K, Ohira M, Maeda K
Carcinogenesis · 2025 Sep · PMID 41055077 · Publisher ↗
The intra-tumoral heterogeneity of HER2 expression is associated with resistance to anti-HER2 therapy in HER2-positive gastric cancers (GCs). We previously reported that thrombospondin-4 (THBS4) is overexpressed in cance...
The intra-tumoral heterogeneity of HER2 expression is associated with resistance to anti-HER2 therapy in HER2-positive gastric cancers (GCs). We previously reported that thrombospondin-4 (THBS4) is overexpressed in cancer-associated fibroblasts (CAFs) in the GC microenvironment and is associated with GC remodeling. To clarify the relationship between CAFs and the intra-tumoral heterogeneity of HER2 in GC, the effect of CAFs on HER2 expression was investigated in GC cells. Two HER2-positive GC cell lines (NCI-N87 and OE19) and two pairs of gastric CAFs were used. The effect of fibroblasts on HER2 expression in cancer cells was analyzed by immunohistochemical staining and reverse transcription-polymerase chain reaction. THBS4 siRNA was used for knockdown assays. The effects of Herceptin or gabapentin, a THBS4 receptor inhibitor, on subcutaneous tumors were examined in nude mice. CAFs and THBS4 recombinant significantly downregulated HER2 (ERBB2) expression in GC cells. THBS4 siRNA and gabapentin significantly inhibited the HER2-decreasing activity in CAFs. In vivo, CAFs suppress HER2 expression of subcutaneous GC tumors and induce Herceptin resistance. Gabapentin overcomes CAF-induced Herceptin resistance. THBS4 from CAFs downregulated HER2 (ERBB2) expression in GC cells. Thus, THBS4 receptor inhibitors may be useful in preventing the acquisition of resistance to anti-HER2 therapy.
An update on the World Trade Center cancer tissue biobank: a scientific resource for molecular and mechanistic studies on WTC-related cancer.
Turner WM, Zegarelli A, Ivic-Pavlicic T … +3 more , Brody R, Tuminello S, Taioli E
Carcinogenesis · 2025 Nov · PMID 41042997 · Publisher ↗
World Trade Center (WTC) responders were exposed to a complex mixture of toxins and carcinogens through dust, fumes, and smoke at ground zero. Since then, studies have indicated that WTC responders have elevated cancer r...
World Trade Center (WTC) responders were exposed to a complex mixture of toxins and carcinogens through dust, fumes, and smoke at ground zero. Since then, studies have indicated that WTC responders have elevated cancer rates compared with the general population. While studies have detailed the overarching connection between WTC exposure and cancer, a tissue biobank is needed to enable molecular and mechanistic studies on WTC-related cancers. The cohort includes responders involved in rescue, recovery, or cleanup enrolled in the World Trade Center Health Program (WTCHP) who consented to participate in research. Responders with cancer were identified through WTCHP certification. WTCHP provided data with patients' demographic information, contact details, and cancer diagnoses. Potential participants were contacted by mail, email, or phone for consent and procedure location. If consented, samples were requested from pathology departments. A biobank of cancer tissues from WTC responders has been established with 551 distinct primary cancers from 521 patients. Of these, prostate makes up 39.0%, thyroid 9.8%, melanoma 8.9%, kidney 6.5%, bladder 6.0%, colorectal 5.8%, breast 5.6%, lung 4.7%, head and neck 4.7%, and other cancers 9%. An additional 343 patients have consented for biobank projects and their samples are being requested. To date, we have created a valuable tissue biobank available to the scientific community for high-impact oncology studies in the unique population of WTC responders. By studying links between carcinogenic exposure and cancer sites, exposure signatures, and markers of cancer aggressiveness, this biobank offers an unprecedented opportunity to advance cancer research in an exposed population.
The Oncogenic Role of AURKA in Gastric Cancer: Mechanisms, Pathways, and Clinical Relevance.
Lv C, Liu Y, Zhang H
Carcinogenesis · 2025 Sep · PMID 40924158 · Publisher ↗
Aurora kinase A (AURKA) is a serine/threonine kinase that plays a critical role in cell cycle regulation, particularly during mitosis. Recent studies have identified AURKA as an oncogene overexpressed in various cancers,...
Aurora kinase A (AURKA) is a serine/threonine kinase that plays a critical role in cell cycle regulation, particularly during mitosis. Recent studies have identified AURKA as an oncogene overexpressed in various cancers, including gastric cancer (GC). This review summarizes the molecular mechanisms by which AURKA contributes to GC pathogenesis, including its roles in cell proliferation, apoptosis inhibition, epithelial-mesenchymal transition (EMT), and cancer stemness. AURKA regulates key signaling pathways such as PI3K/Akt, Wnt/β-catenin, NF-κB, and JAK2/STAT3, promoting tumor growth, metastasis, and therapy resistance. Additionally, AURKA interacts with critical tumor suppressors like p53 and PTEN, further enhancing its oncogenic potential. Clinical studies have demonstrated that AURKA overexpression correlates with poor prognosis in GC patients, highlighting its potential as a diagnostic and therapeutic target. This review also discusses the efficacy of AURKA inhibitors in preclinical settings, offering insights into their therapeutic potential. By elucidating the multifaceted roles of AURKA in GC, this review aims to provide a comprehensive understanding of its mechanisms and implications for future research and treatment strategies.
Epithelial Ikkβ deletion modulates immune responses and the IFNγ/CXCL9 axis during early esophageal carcinogenesis.
Hodge N, Tétreault MP
Carcinogenesis · 2025 Sep · PMID 40916746 · Full text
Esophageal cancer is a major cause of cancer-related death, often preceded with chronic inflammation and injuries. The NFκB/IKKβ pathway plays a central role in inflammation, yet its role in early esophageal carcinogenes...
Esophageal cancer is a major cause of cancer-related death, often preceded with chronic inflammation and injuries. The NFκB/IKKβ pathway plays a central role in inflammation, yet its role in early esophageal carcinogenesis remains unclear. This study investigated the role of epithelial IKKβ in early esophageal carcinogenesis. Mice were treated with the carcinogen 4-nitroquinoline-1-oxide (4-NQO) or a vehicle for one month to induce precancerous lesions. Esophagi were harvested and examined through histological, protein, flow cytometry, and RNA analyses. Histological analysis revealed that 4-NQO treatment led to increased inflammation, intraepithelial CD45+ immune cells, and elevated IKKβ phosphorylation levels. Mice with esophageal epithelial-specific Ikkβ deletion (4-NQO/IkkβEEC-KO) showed delayed progression to a precancerous state, with reduced immune cell recruitment compared to 4-NQO/controls. Immunophenotyping showed decreased recruitment of T cells, including CD4+, CD8+ and regulatory (Tregs) T cells, and increased recruitment of macrophages in 4-NQO/IkkβEEC-KO mice compared with 4-NQO/controls. RNA sequencing data identified 262 differentially expressed genes in 4-NQO/IkkβEEC-KO mice, implicating pathways related to inflammation and wound healing. Notably, the chemokine CXCL9, a T cell chemoattractant, was significantly upregulated in 4-NQO control mice, but not in 4-NQO/IkkβEEC-KO mice. Further analysis identified IFNγ as an upstream regulator of Cxcl9 expression, and neutralization of IFNγ reduced Cxcl9 expression levels in 4-NQO treated mice. Additionally, in vitro studies demonstrated that IFNγ upregulates Cxcl9 in an NFκB dependent manner in esophageal keratinocytes. These findings suggest that epithelial IKKβ regulates the immune microenvironment in early esophageal carcinogenesis through the IFNγ/CXCL9 axis and influencing T cell recruitment and inflammatory responses.
Correction to: p62/SQSTM1 interacts with vimentin to enhance breast cancer metastasis.
Carcinogenesis · 2025 Sep · PMID 40906552 · Full text
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