British Journal of Cancer最新文献

Background: Prostate cancer (PC) is the commonest male visceral cancer, and second leading cause of cancer mortality in men in the Western world.

Methods: Using a forward-mutagenesis Sleeping Beauty (SB) transposon-based screen in a Probasin Cre-Recombinase (Pb-Cre) Pten-deficient mouse model of PC, we identified Arid1a loss as a driver in the development of metastatic disease.

Results: The insertion of transposon in the Arid1a gene resulted in a 60% reduction of Arid1a expression, and reduced tumour free survival (SB:Pten^fl/fl Arid1a^INT median 226 days vs SB:Pten^fl/fl Arid1a^WT 293 days, p = 0.02),with elevated rates of metastasis (SB:Pten^fl/fl Arid1a^INT 75% lung metastasis rate vs 17% SB:Pten^fl/fl Arid1a^WT, p < 0.001). We further generated a Pb-Cre Pten- and Arid1a-deficient mouse model, in which loss of Arid1a demonstrated a profound acceleration in tumorigenesis in Pten^fl/fl mice compared to Pten loss alone (Pb-Cre Pten^fl/flArid1a^+/+ median survival of 267 days vs Pb-Cre Pten^fl/fl Arid1a^fl/fl 103 days, p < 0.0001).

Conclusion: Our data revealed homozygous Arid1a loss is required to dramatically accelerate prostate tumourigenesis. Analysis of RNA and ChIP -Sequencing data suggests Arid1a loss enhanced the function of AP-1 subunit cFos. In clinical PC cohort, ARID1A and cFos levels stratified an aggressive subset of PC with a poor survival outcome with a median of only 30 months.

Background: Promising cancer treatments, such as DDR inhibitors, are often challenged by the heterogeneity of responses in clinical trials. The present work aimed to build a computational framework to address those challenges.

Methods: A semi-mechanistic pharmacokinetic-pharmacodynamic model of tumour growth inhibition was developed to investigate the efficacy of PARP and ATR inhibitors as monotherapies, and in combination. Key features of the DNA damage response were incorporated into the model to allow the emergence of synthetic lethality, including redundant DNA repair pathways that may be impaired due to genetic mutations, and due to PARP and ATR inhibition. Model parameters were calibrated using preclinical in vivo data for PARP inhibitors rucaparib and talazoparib and the ATR inhibitor gartisertib.

Results: The model successfully captured the monotherapy efficacies of rucaparib and talazoparib, as well as the combination efficacy with gartisertib. The model was evaluated against multiple tumour xenografts with diverse genetic backgrounds and was able to capture the observed heterogeneity of response profiles.

Conclusions: By enabling simulation of in vivo tumour growth inhibition with PARP and ATR inhibitors for specific tumour types, the model provides a rational approach to support the optimisation of dosing regimens to stratified populations.

Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits a high frequency of neural invasion (NI). Schwann cells (SCs) have been shown to be reprogrammed to facilitate cancer cell migration and invasion into nerves. Since extracellular vesicles (EVs) affect the tumour microenvironment and promote metastasis, the present study analysed the involvement of EVs from pancreatic cancer cells and their microenvironment in altering SC phenotype as part of the early events in the process of NI.

Methods: EVs were isolated from human/murine PDAC cells, pancreatic stellate cells (PSCs), human tissues and plasma to perform a novel 3D migration assay, qRT-PCR and western blot. Kaplan-Meier and Cox regression analyses were employed to evaluate the clinical potential of plasma EV-derived candidate from 165 PDAC patients.

Results: The EVs from PDAC cells, PSCs derived from human tumour tissues, other cell types in the tumour microenvironment from tumour tissues and circulating plasma act as drivers of a pro-migratory phenotype of SCs by inducing dedifferentiation in SCs. Notably, p75NTR expression was upregulated in the plasma-derived EVs from patients with NI (Pn1) relative to those without NI (Pn0). High expression of plasma-derived EV p75NTR correlated with reduced overall survival and was identified as an independent prognostic factor.

Conclusions: These findings suggest that EV-mediated SC migration underlies the interactions contributing to PDAC-associated NI with implications for improved outcome and therapeutic strategy.

Background: Emerging evidence suggests that non-coding somatic single nucleotide variants (SNVs) in cis-regulatory elements (CREs) contribute to cancer by disrupting gene expression networks. However, the role of non-coding SNVs in cancer, particularly neuroblastoma, remains largely unclear.

Methods: SNVs effect on CREs activity was evaluated by luciferase assays. Motif analysis and ChIP-qPCR experiments were employed to reveal the transcription factors (TFs) involved in these processes. We exploited CRISPR-Cas9 experiments to elucidate the role of these SNVs on the CREs target genes expression. Cell proliferation and invasion assays were performed to assess their role in neuroblastoma tumorigenesis.

Results: Our findings demonstrate that non-coding SNVs modify the transcriptional activity of two CREs altering the binding of STAT3 and SIN3A. Therefore, these SNVs reduce the expression of CTTNBP2 and MCF2L. We demonstrate that these two genes act as tumor suppressor in neuroblastoma. These pathogenetic SNVs may serve as oncogenic drivers by impairing the transcriptional programs essential for neuronal development and differentiation in which both the investigated TFs and target genes are involved.

Conclusion: Overall, the understanding of the functional role of non-coding variants elucidates their impact on tumorigenesis and can uncover new potential targets of cancer therapeutic strategies.

Background: Burkitt lymphoma (BL) may be HIV-associated but data on BL trends in South Africa (SA), where HIV is highly prevalent, are scarce. We compared BL incidence trends over 36 years among Black African and White individuals.

Methods: We included histologically diagnosed BL from the National Cancer Registry in SA between 1986-2021. We computed yearly age-standardised incidence rates (ASIR) by race, and annual percentage changes in ASIR using Joinpoint regression.

Results: Between 1986-2021, 2205 Black African (ASIR: 1.68/1,000,000; 95% confidence interval [CI] 1.63-1.73) and 366 White individuals (ASIR: 2.34/1,000,000; 95% CI 2.15-2.53) had incident BL. Median age at diagnosis increased over time, while the male proportion among those diagnosed declined. The ASIR among Black Africans increased from 1986-2012 and declined thereafter with BL incidence peaks shifting from children and elderly to middle-aged adults. Among White individuals, BL rates rose among all age groups over time.

Conclusions: The BL epidemiology among Black Africans, with decreasing rates since 2012, may reflect SA's evolving HIV epidemic. In contrast, BL rates among White individuals in SA and many high-income countries continue to increase over time. Further studies are needed to better understand the differences in BL epidemiology across geographic regions and population groups.

Background: Abnormal results in commonly used primary care blood tests could be early markers of cancer in patients presenting with non-specific abdominal symptoms.

Methods: Using linked data from the UK Clinical Practice Research Datalink (CPRD) and national cancer registry we compared blood test use and abnormal results from the 24-months pre-diagnosis in 10,575 cancer patients (any site), and 52,875 matched-controls aged ≥30 presenting, with abdominal pain or bloating to primary care.

Results: Cancer patients had two-fold increased odds of having a blood test (odds ratio(OR):1.51-2.29) and 2-3-fold increased odds of having an abnormal blood test result (OR:2.42-3.30) in the year pre-diagnosis compared to controls. Raised inflammatory markers were the most common abnormality (74-79% of tested cases). Rates of blood test use and abnormal results progressively increased from 7 months pre-diagnosis in cancer patients, with relatively small corresponding increases in symptomatic controls. In cancer patients, the largest increases from baseline were raised platelets in males with abdominal pain (increased 33-fold), raised white blood cell count in males with abdominal bloating (increased 37-fold) and low albumin in females with either symptom (increased 22-41 fold).

Conclusions: Common blood test abnormalities are early signals of cancer in some individuals with non-specific abdominal symptoms and could support expedited cancer diagnosis.

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.