Clinical & Experimental Metastasis最新文献

Brain metastasis is a common and devastating complication of cancer that affects over 50% of HER2-positive (HER2⁺) breast cancer patients. The lack of effective long-term treatment options for brain metastasis significantly increases morbidity and mortality among these patients. Therefore, understanding the underlying mechanisms that drive brain metastasis is critically important for developing new strategies to treat it effectively. Genetically engineered mouse models (GEMMs) of HER2⁺ breast cancer have been instrumental in understanding the development and progression of HER2⁺ breast cancer. However, the GEMM models for HER2⁺ breast cancer do not develop brain metastasis and are not suitable for the study of brain metastasis. We therefore developed a fully immunocompetent mouse model of experimental brain metastasis in HER2⁺ breast cancer by injecting a murine HER2/neu-expressing mammary-tumor-cell line into the arterial circulation of syngeneic FVB/N mice followed by isolation of brain-metastatic derivatives through in-vivo selection. By this in-vivo serial passaging process, we selected highly brain-metastatic (BrM) derivatives known as neu-BrM. Notably, after intracardiac injection, neu-BrM cells generated brain metastasis in 100% of the mice, allowing us to study the later stages of metastatic progression, including cancer-cell extravasation and outgrowth in the brain. Analogous to human brain metastasis, we observed reactive gliosis and significant immune infiltration in the brain tissue of mice injected with neu-BrM cells. We further confirmed that brain-metastatic lesions in the neu-BrM model express HER2. Consistently, we found that the brain-metastatic burden in these mice can be significantly reduced but not eliminated with tucatinib, an FDA-approved, blood-brain-barrier-penetrant HER2 inhibitor. Therefore, the neu-BrM HER2⁺ breast cancer model can be used to investigate the roles of innate and adaptive immune-system components during brain-metastatic progression and the mechanisms of HER2-therapy response and resistance.

Gallbladder cancer (GBC) is an aggressive malignancy with a poor prognosis, often diagnosed at advanced stages. TEA domain transcription factor 4 (TEAD4) has been implicated in mediating the progression of various cancers, but its function and underlying mechanism in gallbladder cancer remain unclear. This study assessed the expression levels of TEAD4 and TMPRSS4 using reverse transcription quantitative polymerase chain reaction and western blotting. The functional role of TEAD4 in the progression of gallbladder cancer was investigated through CCK-8, EdU assays, Transwell, wound-healing assays, western blotting, immunohistochemistry, and hematoxylin and eosin (H&E) staining in cellular and animal models. The potential regulatory mechanism was explored by chromatin immunoprecipitation and dual-luciferase reporter assays. Results revealed that TEAD4 expression was significantly elevated in GBC tissues and cell lines. TEAD4 knockdown suppressed cell viability, decreased the percentage of EdU-positive cells, reduced invasive capacity, and increased wound closure width in GBC-SD and NOZ cells. Conversely, overexpression of TEAD4 produced opposite effects. Mechanistically, TEAD4 was predicted and confirmed to bind with the promoter region of TMPRSS4, as validated by the Chip-PCR and dual luciferase results. The mitigatory role of sh-TEAD4 on cell growth, invasion, and mobility of GBC was reversed by overexpression TMPRSS4 overexpression. In vivo, silencing of TEAD4 declined the tumor size and weight, the expression of TEAD4 and TMPRSS4, the ki-67 level, and the numbers of liver metastasis foci. In conclusion, the knockdown of TEAD4 suppressed the growth and metastasis of GBC via TMPRSS4.

Tumor metastasis involves the spread of tumor cells from the primary site to distant organs via the lymphatic system, blood vessels, and other pathways. It stands as a major contributor to cancer incidence and mortality. Laminin α5 (LMα5) is a member of the laminin family, which is widely expressed in various tumor tissues and is significantly associated with poor cancer prognosis. Laminin α5 plays an important role in cancer metastasis, serving as a key regulator in this process. LMα5 facilitates tumor metastasis through its interactions with various receptors, including integrins and Lutheran/basal cell adhesion molecules (Lu/BCAM). Moreover, it modulates the epithelial-mesenchymal transition (EMT) by influencing the Notch signaling pathway, thus regulating the invasive capabilities of tumor cells. By mediating the interplay between tumors and their microenvironment, LMα5 disrupts the adhesion of tumor cells to vascular endothelial cells, consequently reducing metastatic tumor growth. In this review, we have discussed the core mechanisms of action underlying the role of LMα5 in tumor metastasis and its therapeutic potential. By shedding light on novel therapeutic targets and treatment strategies, the aim is to combat cancer metastasis and improve the efficacy of cancer treatments.

Breast cancer (BC), a highly heterogeneous disease, has demonstrated a gradual increase in both incidence and mortality rates. At present, it has become one of the most common malignant tumors and the main cause of cancer death worldwide. While early screening is recognized as an effective preventive and therapeutic measure for BC, the disease continues to exhibit a high rate of metastasis. Metastatic BC is still the main cause of poor prognosis and death of patients, necessitating urgent investigation and resolution. Among the various metastatic sites of BC, bone metastases warrant particular attention due to their prevalence. In numerous studies on BC bone metastasis mechanisms, cancer markers have been shown to significantly influence the pattern and extent of BC metastasis and dissemination. In the tumor microenvironment, Ras-proximate-1 (RAP1), a GTPase protein, is not only upregulated in various malignant tumors and bone-related diseases, including BC, but also regulates migration, invasion, distant metastasis, and other signaling pathways in numerous malignant tumor cells, including BC as well. Despite these findings, there remains a paucity of advanced research and discussion on the relationship between RAP1 and BC bone metastasis. Furthermore, no clinically approved RAP1-related inhibitors for BC bone metastasis are currently available. Nevertheless, RAP1 and its associated signaling molecules represent potential molecular targets for the prevention and treatment of BC bone metastasis, warranting further investigation. Therefore, this article provides a comprehensive review of RAP1's pathogenic role in BC bone metastasis, emphasizes RAP1 and its associated signaling pathways, and summarizes current research on natural compounds and extracts that modulate BC bone metastasis via RAP1 or RAP1-related signaling pathways. This review aims to offer novel perspectives for developing RAP1 as a potential molecular target in the prevention and treatment of BC bone metastasis, as well as for the development of related therapeutic agents.

Stereotactic radiosurgery poses a significant risk when treating brain metastases in close proximity to the brainstem. To address this issue, a novel approach known as "combined anti-vascular therapy" has been devised for these metastases. This treatment regimen involves a one-week course of two-staged stereotactic radiosurgery (2-SSRS), supplemented with the administration of the anti-vascular agent bevacizumab during the radiosurgery interval. We tried to find out the effectiveness and safety of 2-SSRS plus bevacizumab therapy for brain metastases that compress the brainstem, and prognostic factors that related to the tumor local control. A retrospective analysis was conducted on patients treated at five gamma knife treatment centers to assess changes in tumor size and peritumoral edema volume. Cox regression model was used to find out prognostic factors for tumor local control. Clinical symptom changes were evaluated using the Headache Scale (VAS), Dizziness Disorder Inventory (DHI), Vomiting Scale (VS), and Glasgow Coma Scale (GCS). The Karnofsky Task Scale (KPS) and Barthel Index (BI) were used to assess overall physical fitness and physical activity rehabilitation. Tumor local control (TLC) and overall survival (OS) rate were also calculated for the patients. Among the 36 patients with brain metastases with brainstem compression, 36 received combined anti-vascular therapy. Both edema volume and tumor volume significantly decreased during the treatment period and post-treatment 3 months (p < 0.01). Clinical symptoms, as indicated by median scores of VAS, DHI, VS, and GCS, showed significant improvement during treatment and at the 3-month follow-up (p < 0.01). Median changes in KPS and BI, reflecting overall physical fitness and physical activity rehabilitation, were also similar and statistically significant (p < 0.01). The patient cohort exhibited a median overall survival of 14.2 months, with corresponding 6-month and 12-month survival rates of 91.7% and 80.0%, respectively. Tumor local control rates at 6 and 12 months were 94.7% and 78.9%, Patient with KPS score > = 60 and single intracranial brain metastasis before treatment enjoy longer local tumor control. The combination of anti-vascular therapy with 2-SSRS demonstrates safety and efficacy in treating patients with brain metastases with brainstem compression. This approach rapidly alleviates patient symptoms, effectively manages tumor progression, extends overall survival, and exhibits manageable adverse effects.

BRG1 deficiency in patients with lung adenocarcinoma that has metastasized to the brain, termed BRG1-deficient brain metastasis lung adenocarcinoma, is an uncommon event. Prior to this study, these patients had not undergone extensive molecular and (epi)genetic analysis. We report a comprehensive clinical, histopathologic, and molecular assessment of 9 BRG1-deficient brain metastasis lung adenocarcinoma cohort (BRG1-deficient BM cohort) in comparison with a 16 BRG1-retained brain metastasis lung adenocarcinoma cohort (BRG1-retained BM cohort). Patients with BRG1-deficient BM exhibited a significantly increased risk of mortality. Molecular analysis revealed a high prevalence of mutations in SMARCA4 and TP53 genes within this group. DNA methylation molecular diagnostics showed a high rate of genomic instability and a markedly lower DNA methylation age in these patients. Functional enrichment analysis of differentially methylated genes suggested that hypomethylation genes were primarily associated with the negative regulation of neuron differentiation, G protein-coupled receptor signaling pathways, and cell differentiation. Conversely, hypermethylation was linked to the regulation of small GTPase mediated signal transduction, Rho protein signal transduction, DNA damage response, and apoptotic processes. This study investigated a rare subgroup of lung adenocarcinoma patients with brain metastasis characterized by BRG1 deficiency and a poor prognosis. Our study not only provides a comprehensive multi-omic data resource but also provides valuable biological insights into patients. The findings may serve as a valuable reference for the future pathological diagnosis of BRG1-deficient brain metastasis in lung adenocarcinoma patients.

Brain metastasis is thought to be related to the high mortality and poor prognosis of lung cancer. Despite significant advances in the treatment of primary lung cancer, the unique microenvironment of the brain renders current therapeutic strategies largely ineffective against brain metastasis. The lack of effective drugs for brain metastasis treatment is primarily due to the incomplete understanding of the mechanisms underlying its initiation and progression. Currently, our understanding of brain metastasis remains limited, primarily due to the absence of appropriate models that can realistically simulate the entire process of tumor cell detachment from the primary site, circulation through the bloodstream, and eventual colonization of the brain. Therefore, there is a pressing need to develop more suitable lung cancer brain metastasis models that can effectively replicate these critical stages of metastasis. Here, based on the traditional carotid artery injection model, we established a novel orthotopic mouse model by using a light-controlled hydrogel to repair the puncture site on the carotid artery, with sustained cerebral blood circulation and the capability of multiple delivery cancer cell to mimic lung cancer brain metastasis. The optimized orthotopic mouse model significantly reduced cerebral ischemia and improved cerebral oxygenation by 60% compared to the traditional orthotopic mouse model, enhancing post-operative survival rates. It also showed a reduction in pro-inflammatory cytokines and featured less inflammatory and more resting states of microglial and astrocyte cells. Furthermore, the optimized orthotopic mouse model markedly increased the success rate and absolute number of the metastatic clones in the brain. Additionally, the multiple delivery model based on the optimized orthotopic mouse model substantially augmented the tumor clone number and formation rates compared to single injection in the optimized orthotopic mouse model. This model overcomes previous limitations by maintaining cerebral circulation, providing a more accurate simulation of the continuous entry of tumor cells into cerebral circulation. It offers a robust platform for studying the interactions of cancer cells with the brain microenvironment and testing new therapeutic approaches.

Patients with metastatic urothelial carcinoma (mUC) are typically elderly and often have other comorbidities that require the use of concomitant medications. In our study we evaluated the association of concomitant use of antibiotics (ATBs), proton pump inhibitors (PPIs), corticosteroids, statins, metformin and insulin with patient outcomes and we validated the prognostic role of a concomitant drug score in mUC patients treated with enfortumab vedotin (EV) monotherapy. Data from 436 patients enrolled in the ARON-2^EV retrospective study were analyzed according to the concomitant medications used at baseline. Finally, the patients were stratified into three risk groups according to the concomitant drug score based on ATBs, corticosteroids and PPIs. Statistical analysis involved Fisher exact test, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. Inferior survival outcomes were observed in ATB users compared to non-users (OS: 7.3 months, 95%CI 5.0 - 12.3 vs 13.7 months, 95%CI 12.2 - 47.3, p = 0.001; PFS: 5.1 months 95%CI 3.3 - 17.7 vs 8.3 months, 95%CI 7.1 - 47.3, p = 0.001) and also in corticosteroid users compared to non-users (OS: 8.4 months, 95%CI 6.6 - 10.0 vs 14.2 months, 95%CI 12.7 - 47.3, p < 0.001; PFS: 6.0 months 95%CI 4.6 - 7.9 vs 8.9 months, 95%CI 7.2 - 47.3, p = 0.004). In the Cox multivariate analysis, the concomitant drug score was a significant factor predicting both OS (HR = 1.32 [95% CI 1.03 - 1.68], p = 0.026) and PFS (HR = 1.23 [95% CI 1.01 - 1.51], p = 0.044). Our findings suggest detrimental impact of concomitant use of ATBs and corticosteroids on survival outcomes and the prognostic utility of the concomitant drug score in previously treated mUC patients receiving EV.

Postoperative radiotherapy improves local control (LC) after resection of brain metastases. In comparison to whole brain radiotherapy (WBRT) stereotactic radiosurgery (SRS) to resection cavity significantly reduces cognitive side effects. However, two phase-III trials have reported suboptimal LC with SRS, leading to increased interest in hypofractionated stereotactic radiotherapy (SRT) as an alternative to improve outcomes. This single-centre study, based on a prospective quality assurance protocol, included 161 patients with 185 resected brain metastases treated with either SRS or SRT between February 2018 and June 2023. Patients were assigned to treatment based on cavity size, with SRS typically used for cavities < 10 cc and SRT for larger volumes. Primary and secondary endpoints were LC and radiation necrosis (RN), respectively. Data analysis was conducted retrospectively. Median cavity size was 13.3 cc, with 20% of cavities receiving SRS and 80% SRT. 12-month LC was 92.6% (95-CI: 88.2 - 97.3%), 12-month RN incidence was 9% (95-CI: 3-14%), with RN limited to CTCAE v5 ≤ 2. In cavities < 10 cc, no significant difference in LC was found between SRS and SRT. For cavities > 10 cc, PTV volume was the only significant predictor of LC, while fractionation and dose did not significantly impact outcomes. SRS and SRT both offer excellent LC for resection cavities < 10 cc with low rates of RN, suggesting SRS as the preferred treatment in this collective, in consideration of patient comfort and resource allocation. In larger cavities, PTV volume significantly influences LC. Dose escalation might be beneficial in improving outcomes in these cases.

Combining radiotherapy (RT) with Ipilimumab, a CTLA-4 inhibitor, holds promise in treating metastatic brain melanoma (MBM). Despite promising preclinical evidence, clinical studies evaluating their combined efficacy are limited and varied, necessitating a systematic review and meta-analysis to consolidate evidence and identify predictors of response or resistance in this challenging patient population. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The electronic databases of PubMed, Embase, Scopus, and Web of science were searched on July 9th, 2024, using the relevant key terms without filters. All statistical analysis was performed by STATA v.17. A total of 26 studies with 1059 participants were included. The 1, 2, and 3-year overall survival rates were 0.44 [95% CI: 0.32-0.55], 0.28 [95% CI: 0.17, 0.39], and 0.19 [95% CI: 0.06-0.32], respectively. The pooled 12-month local control and 1-year progression-free survival rate were 0.53 [95% CI: 0.34-0.71] and 0.20 [95%CI: 0.10-0.30]. The pooled overall response rate, partial response rates, and stable disease rate were 0.26 [95% CI: 0.10-0.41], 0.10 [95% CI:0.05-0.15], 0.17 [95%CI:0.10-0.23], and 0.58 [95%CI: 0.45-0.70]. This study demonstrated promising results regarding adding RT to ipilimumab which was associated with significantly higher 1-year OS, 18-month OS, 2-year OS, 3-year OS, overall radiological response rate, and stable disease rate and significantly lower rate of progressive disease rate compared to ipilimumab without RT. However, no significant difference was observed between two groups in 6-month OS, 12-month LC, 1-year PFS, and partial response rate.