Clinical & Experimental Metastasis最新文献

Liver metastases, a hallmark of systemic disease, carry a poor prognosis despite advancements in systemic therapies. Stereotactic body radiation therapy (SBRT) has emerged as a promising local treatment, offering durable tumor control with minimal toxicity. However, the optimal dosimetric strategies to maximize outcomes remain an area of active investigation. This retrospective study evaluated 76 patients with 101 liver metastases treated with SBRT between November 2012 and June 2024. Dosimetric parameters were analyzed, including prescribed dose (PD) and dose metrics for planning target volume (PTV) and gross tumor volume (GTV), with doses converted to equivalent doses in 2 Gy fractions (EQD2, α/β = 10). Tumor control probability (TCP) models and survival outcomes were assessed, with a focus on the prognostic impact of dosimetric and clinical factors. Median overall survival (OS) was 33 months, with 1-year and 3-year OS rates of 74.1% and 39.4%, respectively. Freedom from local progression (FFLP) was 82.5% at 12 months. PD emerged as the strongest independent predictor of local control, with an optimal threshold of 77.44 Gy EQD2 significantly improving 1-year FFLP rates (96.8% vs. 67.2%; p = 0.007). Advanced motion management techniques, including internal breath-hold (iBH) with image-guided radiotherapy (IGRT), demonstrated superior local control outcomes. Predictive modeling confirmed PD as the most robust dosimetric metric, correlating with a high TCP and outperforming other dose metrics. Toxicity was minimal, with only 3.9% experiencing grade ≥ 3 adverse events. SBRT represents a highly effective and safe approach for liver metastases, with PD and advanced imaging emerging as pivotal determinants of tumor control. These findings underscore the importance of precise dosimetric planning and motion management in optimizing SBRT outcomes. This study provides a robust framework for personalized treatment strategies, contributing to the integration of SBRT as a cornerstone in the multidisciplinary management of liver metastases.

This study investigated hypofractionated stereotactic radiotherapy (HSRT) for resected brain metastases and how the dose-fractionation affects local control (LC) and radionecrosis (RN). We retrospectively evaluated patients with brain metastases who were treated between 2010 and 2023. Post-operative HSRT was delivered in three or five fractions. The primary objective was to determine the effect of dose escalation and fractionation on LC. Secondary objectives included identifying factors associated with RN. Statistical analyses were conducted using Chi-square or Fisher's exact tests for categorical data and Mann-Whitney U tests for continuous variables (significance level: p < 0.05). After a median follow-up of 19 months, 34 patients out of 212 (16%) had local recurrence. A biologically effective dose (BED₁₀) > 28.8 Gy was associated with better LC (p = 0.002), but no benefit was found for a BED₁₀ > 48 Gy. RN developed in 34 patients (16%). A prescription BED₁₀ > 48 Gy was associated with an increased incidence of symptomatic RN (p = 0.002). For HSRT in three fractions, a CTV D99% ≥ 29 Gy significantly improved the LC (p = 0.04), and V30Gy, V23.1 Gy, and V18Gy were significantly associated with an increased risk of RN. The fractionation was not found to affect the LC or RN. This large, retrospective cohort study on post-operative HSRT indicates that a BED₁₀ of 40.9-48 Gy (3 × 7,7 Gy or 5 × 6 Gy) to the planning target volume results in excellent LC while limiting the risk of RN. No difference in LC or RN was found for different fractionations.

This study investigates crucial genes involved in lung cancer metastasis and their interactions within a Competitive endogenous RNA (ceRNA) regulatory network using comprehensive transcriptomic data from the TCGA and GEO databases. Differential expression analysis identified ten genes associated with lung cancer metastasis, with Glypican-3 (GPC3) emerging as a key mRNA through survival analysis. A ceRNA network involving GPC3, hsa-miR-135b-3p, and FTLP3 was constructed and validated in both cellular and animal models, elucidating their roles in cell migration, invasion, and tumorigenic potential. The analysis confirmed the significance of key genes like GPC3, with the FTLP3/hsa-miR-135b-3p/GPC3 axis playing a fundamental role in lung cancer progression. Additionally, the study identified correlations between GPC3 expression, immune cell infiltration and immune checkpoints, underscoring its impact on the immune landscape of lung cancer. Overexpression of FTLP3 effectively suppressed the migratory, invasive, and metastatic abilities of lung cancer cells, demonstrating the pivotal role of the FTLP3/hsa-miR-135b-3p/GPC3 ceRNA network in modulating tumor progression and immune responses. These results underscore its potential as a therapeutic target for managing lung cancer metastasis.

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.