British Journal of Cancer最新文献

Background: Tongue squamous cell carcinoma (TSCC) is a malignant oral cancer with unclear pathogenesis that shows a tendency for early-stage lymphatic metastasis. This results in a poor prognosis, with a low 5-year survival rate. Dietary sodium nitrite (NaNO₂) has proposed associations with disease, including cancer. However, a direct relationship between NaNO₂ and TSCC has not been established.

Methods: In vitro and in vivo assays were used to investigate the role of NaNO₂ in TSCC. Protein expression in TSCC specimens was detected by immunohistochemistry and immunofluorescence. The molecular mechanism was determined using RT-qPCR, western blot, RNA-seq, luciferase reporter assays, migration assays, and FACS analysis. More detail of methods can be found in the Materials and methods section.

Results: The data in this study showed that NaNO₂ did not initiate carcinogenesis in the tongue but improved the lymphatic metastatic potential of TSCC cells in the specified experimental period. During metastasis to lymph nodes, monocyte-macrophage markers were upregulated in TSCC cells, whereas keratin markers were downregulated. Specifically, expression of the CD68 gene was high in TSCC cells following NaNO₂-induced TSCC phenotypic switching. These phenotypic changes were associated with activation of transcription factor cyclic-AMP response binding protein (CREB1), which directly targets CD68 transcription. Furthermore, blocking CREB1 activity either through gene knockout or specific inhibitor treatment decreased the migration ability of TSCC cells and suppressed CD68 expression.

Conclusions: Our findings highlight the role of NaNO2 in enabling macrophage mimicry in TSCC cells through the CREB1-CD68 signaling pathway, which promotes lymphatic metastasis. Shedding light on drivers of lymphatic metastasis in TSCC and providing a new perspective on dietary strategies to improve outcomes of patients with TSCC.

Background: Alkaline phosphatase (ALP) declines and pain responses can occur during radium-223 (²²³Ra) treatment, but their association with treatment outcomes is unclear.

Methods: For patients with metastatic castration-resistant prostate cancer treated with ²²³Ra in the REASSURE study, we investigated whether ALP decline (Week 12) and/or pain response (during treatment) are associated with improved overall survival (OS). The Brief Pain Inventory-Short Form (BPI-SF) was used to assess pain at baseline and pain response (in patients with baseline BPI-SF score ≥2).

Results: Of 785 patients with baseline and Week 12 ALP measurements, 779 were eligible for the OS analyses. Overall, 80% of patients had an ALP decline. Median OS was longer in patients with than without an ALP decline (18.1 versus 14.2 months; HR 0.74; 95% CI 0.60-0.92). In patients with an ALP decline, there was no clear OS difference between those with versus without a pain response. For patients without ALP decline, median OS was longer in those with versus without a pain response (16.2 versus 10.9 months; HR 0.50; 95% CI 0.32-0.77).

Conclusions: Decreases in ALP and/or pain during ²²³Ra treatment are associated with improved OS. This may help support clinical decisions.

Clinical trial registration: ClinicalTrials.gov identifier NCT02141438. Analyses from the radium-223 REASSURE global study suggest that declines in alkaline phosphatase and pain during treatment may predict longer survival in patients with advanced prostate cancer and may help doctors make decisions with their patients.

Background: This study aimed to investigate the prognostic impact of lymph node metastasis (LNM) on patients with colorectal cancer liver metastasis (CRLM) and elucidate the underlying immune mechanisms using multiomics profiling.

Methods: We enrolled patients with CRLM from the US Surveillance, Epidemiology, and End Results (SEER) cohort and a multicenter Chinese cohort, integrating bulk RNA sequencing, single-cell RNA sequencing and proteomics data. The cancer-specific survival (CSS) and immune profiles of the tumor-draining lymph nodes (TDLNs), primary tumors and liver metastasis were compared between patients with and without LNM. Pathological evaluations were used to assess immune cell infiltration and histological features.

Results: The CRLM patients with LNM had significantly shorter CSS than patients without LNM in two large cohorts. Our results showed that nonmetastatic TDLNs exhibited a greater abundance of immune cells, including CD4+ T cells, CD8+ T cells, and CD19+ B cells, whereas metastatic TDLNs were enriched with fibroblasts, endothelial cells, and macrophages. Immunohistochemical analysis confirmed elevated levels of CD3+ T cells, CD8+ T cells, and CD19+ B cells in nonmetastatic TDLNs. The presence of nonmetastatic TDLNs was associated with enhanced antitumor immune responses in primary tumors, characterized by a higher Klintrup-Makinen (KM) grade and the presence of tertiary lymphoid structures. Furthermore, liver metastasis in patients with nonmetastatic TDLNs were predominantly of the desmoplastic growth pattern (dHGP), while those with metastatic TDLNs were predominantly of the replacement growth pattern (rHGP).

Conclusions: This research highlights the adverse prognostic impact of LNM on patients with CRLM and reveals potential related mechanisms through multiomics analysis. Our research paves the way for further refinement of the AJCC TNM staging system for CRLM in clinical practice.

Background: Pyroptosis is closely associated with chemotherapeutic drugs and immune response. Here, we investigated whether oxaliplatin, a key drug in FOLFOX-hepatic artery infusion chemotherapy (FOLFOX-HAIC), induces pyroptosis in hepatoma cells and enhances antitumor immunity after tumor cell death.

Methods: Hepatoma cells were treated with oxaliplatin. Pyroptosis and immunoreactivity were evaluated in vitro and in vivo.

Results: Oxaliplatin activated caspase-3-mediated gasdermin E (GSDME) cleavage and induced pyroptosis in Hep G2 and SK-Hep-1 cells in vitro. Liver cancer cells with high levels of GSDME expression are prone to pyroptosis. Bioinformatic analysis revealed that pyrolysis-related genes are closely related to immunity. In vivo experiments revealed that oxaliplatin exhibited superior antitumor efficacy in mice with normal immune function and more pronounced inhibitory effect on hepatocellular carcinoma with high GSDME levels. Higher levels of cytokines and greater CD8⁺ T cell infiltration were observed in tumor tissues with better efficacy. Furthermore, an in vitro coculture assay confirmed that oxaliplatin-induced pyroptosis in Hep G2 cells overexpressing GSDME and activated the p38/MAPK signaling pathway to improve the cytotoxicity of CD8⁺ T cells. Analysis of clinical samples of HCC suggested that the efficacy of FOLFOX-HAIC in patients with high GSDME expression was better than that in patients with low GSDME expression.

Conclusions: Oxaliplatin induced pyroptosis in hepatoma cells by activating caspase-3-mediated cleavage of GSDME, which enhanced the cytotoxicity of CD8⁺ T cells by regulating the p38/MAPK signaling pathway. These results suggest that GSDME level may be used as a marker to predict the efficacy of FOLFOX-HAIC.

Background: Peripheral T cell lymphoma (PTCL) is characterized by high heterogeneity, strong aggressiveness, and extremely poor prognosis. Ferroptosis, a novel form of programmed cell death, has been involved in tumor development and targeting ferroptosis holds great potential for tumor therapy.

Methods: Lentiviral transfection was performed to regulate gene expression, followed by Tandem mass tag (TMT)-mass spectrometry and RNA-sequencing. Tumor xenograft models were established for in vivo experiments.

Results: High expression of prostaglandin D2 synthase (PTGDS) was closely associated with poor prognosis of PTCL patients. PTGDS knockdown and AT56 treatment significantly inhibited the progression of PTCL through regulating cell viability, proliferation, apoptosis, cell cycle and invasion in vitro and in vivo. We further revealed that targeting PTGDS promoted ferroptosis process and enhanced the sensitivity of PTCL cells to ferroptosis inducers Sorafenib in vitro and in vivo. Mechanically, PTGDS interacted with heme-degrading enzymes HMOX1, and targeting PTGDS increased the level of iron and induced ferroptosis in PTCL through promoting HMOX1-mediated heme catabolism and ferritin autophagy process. Through the construction of H25A mutation, the specific gene site of HMOX1 corresponding to its role was identified.

Conclusions: Taken together, our findings firstly identified that targeting PTGDS promotes the ferroptosis in PTCL through regulating HMOX1-mediated iron metabolism, and highlighted novel therapeutic strategies to improve the efficacy of ferroptosis-targeted therapy in PTCL patients.

Background: Quiescence is reversible proliferative arrest. Multiple mechanisms regulate quiescence that are not fully understood. High expression of the CDK inhibitor p21^Cip1/Waf1 correlates with a poor prognosis in non-small cell lung cancer (NSCLC) and, in non-transformed cells, p21 promotes quiescence after replication stress. We tested whether NSCLC cells enter p21-dependent quiescence and if this is advantageous to NSCLC cells.

Methods: Through analysis of patient data and quantitative, single-cell, timelapse imaging of genetically-engineered NSCLC reporter cell lines we investigated the role of p21 in NSCLC during normal proliferation and after chemotherapy.

Results: High p21 expression correlates with a poor prognosis in TP53 wild-type, but not TP53 mutant, NSCLC patients and TP53 wild-type NSCLC cells can enter p21-dependent quiescence, downstream of replication stress. Without p21, unrepaired DNA damage propagates into S-phase and cells display increased genomic instability. p21 expression confers survival advantages to TP53 wild-type NSCLC cells, during proliferation and after chemotherapy. p21 can promote tumour relapse by allowing recovery from both G1 and G2 arrests after chemotherapy.

Conclusions: p21-dependent quiescence exists in TP53 wild-type NSCLC cells and provides survival advantages to these cells. Targeting p21 function in TP53 wild-type tumours could lead to better outcomes for chemotherapy treatment in NSCLC patients.

Background: There are scarce data on risk factors for epithelial ovarian cancer (EOC) in Asian populations. Our goal was to advance knowledge on reproductive -related risk factors for EOC in a large population of Asian women.

Methods: This study used pooled individual data from baseline questionnaires in 11 prospective cohorts (baseline years, 1958-2015) in the Asia Cohort Consortium. A Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for age, parity and cohort.

Results: After a mean = 17.0 years (SD = 6.3) of follow-up, 674 incident invasive EOC cases were identified among 325,626 women. In multivariable adjusted models we observed an inverse association with parity (5+ children vs. 0, HR = 0.44, 95% CI = 0.28-0.68, Ptrend < 0.001), and a positive association with increasing menopausal age (55+ years vs. <45, HR = 1.77, 95% CI = 1.05-3.01, Ptrend = 0.02) for risk of all EOC.

Conclusions: In this large study of Asian women we identified an inverse association with parity and a positive association with higher menopausal age in relation to EOC risk. Further work is needed to understand EOC risk factors for rare histologic subtypes that occur more frequently in Asian populations.