Carcinogenesis最新文献

Resistance is inevitable and a major challenge in treating lung adenocarcinoma (LUAD) patients with EGFR mutations. This study aimed to investigate the mechanism of EGFR-TKI resistance in LUAD using longitudinal single-cell RNA sequencing (scRNA-seq) data. We collected tumour samples of LUAD patients before and after EGFR inhibitor treatment and performed single-cell RNA sequencing. We used machine learning models for cell annotation and classified cells into subgroups. The inferCNV algorithm was used for CNV score calculation and tumour cell identification, and metabolic analysis was done using a gene-scoring approach. EGFR resistance score (ERscore), a gene signature derived from resistant tumour cells, was established to evaluate the predictiveness to EGFR-TKI inhibitors. The investigation classified subgroups of cells and identified three tumour cell types as critical cells mediating EGFR-TKI resistance. Our data also analysed the metabolic aspects of EGFR-TKI resistance using a single-cell approach. It showed that some tumour cell subtypes had a consistent metabolic profile, significantly up-regulating purine metabolism, oxidative phosphorylation, glycogen, and lipid metabolism. An assessment system called ERscore was established to evaluate the association between EGFR-TKI resistance and tumour ecosystem. The analysis showed a significant correlation between the ERscore and EGFR-TKI resistance, lung cancer phenotype, and prognosis. The findings suggest that the molecular mechanisms driving EGFR-TKI resistance in lung cancer may also contribute to poorer prognosis, particularly in lung adenocarcinomas with high EGFR mutation rates. Overall, the study provides important insights into the mechanisms of EGFR-TKI resistance in lung cancer at the single-cell level.

Chromosome 12q14.2 has been reported as a potential risk locus for epithelial ovarian cancer (EOC) in genome-wide association study (GWAS). We performed targeted sequencing around the rs11175194 at chromosome 12q14.2 and identified five potential risk variants. The association between these five variants and EOC risk was evaluated in 893 EOC cases and 1292 controls. We identified that rs11175195 (P = 1.94 × 10-6, OR = 1.36, 95% CI = 1.20-1.54) was significantly associated with EOC risk in validation study and after meta-analysis with previous GWAS data, rs11175195 reached genome-wide significant level (P < 5 × 10-8). Functional annotation and expression quantitative trait loci analysis prioritized rs11175194 as a causal variant at this locus. The presence of G-rs11175194 risk allele increased binding affinity of the transcription factor NR1H4 and upregulate SRGAP1 gene expression. Overexpression of SRGAP1 promotes the proliferation and invasion in ovarian cancer cell lines. In conclusion, we identified a novel susceptibility locus of ovarian cancer and revealed a potential molecular mechanism for ovarian cancer carcinogenesis. These results may provide a potential biomarker and therapeutic target for ovarian cancer.

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.

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.

Claudins, integral components of tight junctions, play a pivotal role in maintaining cellular adhesion and polarity. Aberrant expression of claudins has been implicated in the progression of various malignancies, including breast cancer (BC). This study aims to elucidate the clinical relevance of claudins by studying the expression of Claudins 3, 4, and 7 in BC cell lines (CLs) and cancer tissues and correlating it with cellular properties and clinicopathological parameters. The transcriptional expression of Claudins 3, 4, and 7 was assessed in four BCCLs (MDA-MB-231, MDA-MB-468, T47D, and SKBR-3) and tumor tissues by using quantitative PCR. Correlations between claudin expression profiles and clinicopathological parameters, including tumor grade, lymph node involvement, and proliferative index, were evaluated in patient samples. Compared to normal breast tissue, all BCCLs exhibited downregulated expression of Claudins 3, 4, and 7. Differential expression was observed among CLs, with MDA-MB-231 exhibiting the lowest and MDA-MB-468 the highest levels. Among BC patient samples (n = 65), 97% demonstrated significant (P < 0.05) dysregulation in the expression of one or more of these claudins. Prevalence of Claudins 3, 4, 7-low and -high tumors was found to be 29.23% and 21.53% respectively, in our patients. The former correlated significantly with adverse prognostic factors, including higher grade, nodal metastasis, and elevated proliferative indices. The pharmacological induction of Claudin 4 by celecoxib was found to attenuate cell viability, proliferation, and migration in aggressive claudin-low BC cells. These findings underscore the potential utility of modulating claudins as a therapeutic strategy for managing claudin-low BCs.

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.

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.

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.

Breast cancer (BC) is one of the leading causes of death among women, with obesity being a significant factor. Mammary adipose tissue (MAT) dysfunction in obesity creates a tumor-supportive environment, leading to increased risk. In obesity, MAT undergoes significant changes, including increased adiposity, chronic inflammation, aromatase overexpression, insulin resistance, and altered adipokine signaling, collectively fostering a protumorigenic microenvironment. The interaction between adipocytes and cancer cells further exacerbates BC progression through metabolic crosstalk and immune evasion. This review examines the role of MAT dysfunction in BC incidence and progression, in obesity. Interestingly, obesity appears to have a paradoxical effect on BC risk, offering a potentially protective role in premenopausal women, but increased risk in postmenopausal women, primarily due to differences in estrogen levels. Addressing the metabolic, inflammatory, and hormonal abnormalities in obese MAT can aid in enabling the development of precision therapies that reduce BC risk and improve treatment outcomes in obese patients.

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.