Clinical & Experimental Metastasis最新文献

Brain metastases (BMs) represent the most prevalent intracranial malignancy within the adult. They are identified in up to 20% of patients with solid tumors and this percentage varies between tumor types and age. Due to the selective permeability of the blood-brain barrier, most anticancer drugs can't reach significant concentrations in the brain, representing a major obstacle to the patients' survival. Furthermore, intra- and inter-patient heterogeneity and the unique brain microenvironment add a layer of complexity to the clinical management of BMs. In the perspective of finding new therapeutic approaches and better understanding the molecular mechanisms involved in brain metastasis, the use of appropriate preclinical models is essential. Here, we review current in vivo, in vitro and ex vivo models for the study of brain metastasis while outlining their advantages and limitations.

Recent studies report excellent local control (LC) and favorable toxicities of stereotactic ablative radiotherapy (SABR) for pulmonary metastasis (PM) from sarcoma. This study compared the LC and survival of SABR and metastasectomy for sarcoma PM. We analyzed the LC rates of 54 PMs treated with SABR between 2008 and 2022. For survival analysis, we compared 14 patients who received SABR as first-line treatment with 61 patients who underwent metastatectomy. For SABR-treated PMs, a median total dose of 55 Gy (range, 48-60) was administered over 3-10 fractions. Median follow-up for LC in SABR-treated PMs was 19.2 months (range, 0.8-124.0), and the 2-year LC rate was 92.2%. No patients experienced toxicities of grade 3 or higher. The median age of the patients in the survival analysis was 73 years (range, 42-83) in the SABR group and 54 years (range, 19-78) in the metastasectomy group (p < 0.001). PMs in the "gray zone" were more common in the SABR group (35.7%) than in the metastasectomy group (8.2%) (p = 0.029). The median follow-up for survival analysis was 44.8 months (interquartile range, 21.5-66.4). The 3-year rates of LC and overall survival were 92.3% and 57.3% in the SABR group and 89.2% and 75.9% in the metastasectomy group (p = 0.807, 0.224), respectively. The out-of-field intrapulmonary failure-free survival and extrapulmonary systemic failure-free survival rates at 3 years were not significantly different (p = 0.673, 0.386). SABR for sarcoma PM demonstrated excellent LC with acceptable toxicity. Survival rates of SABR were comparable to those of metastasectomy.

Mediastinal and hilar lymphadenopathy (MHL) is a common pattern of cancer spread, particularly in lung disease. Recently, there has been interest in the use of SBRT for MHL, especially in the oligometastatic setting. The goal is to improve local control (LC) and to achieve shorter treatment durations to minimize systemic treatment interruptions. The primary endpoint of this study was local control (LC). The secondary endpoints were distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) and predictive factors of response. This is a retrospective study. It analyses a group of patients treated with SBRT for MHL with different primary tumours and histologies. From November 2007 to June 2023, we treated 159 MHL in 128 patients. The primary most represented was lung cancer. A single fraction was used in 16% of cases and multiple fractions in 84% of cases. The medium BED 10 was 75.06 Gy (range: 37-120 Gy). Actuarial LC rates at 1, 2 and 5 years were 80.0%, 78.8% and 75.2%. The actuarial DMFS rates at 1, 2 and 5 years were 43.9%, 34.1% and 14.1%, respectively. Actuarial PFS rates at 1, 2 and 5 years were 37.2%, 23.9% and 8.3%, respectively. Actuarial OS rates at 1, 2 and 5 years were 68.8%, 52.7% and 26.9%, respectively. SBRT may be an option for the treatment of MHL. In addition, achieving a complete response is one of the most important predictors of our endpoints, in addition to tumour burden and volume.

Studies conducted in the last few years have suggested a connection between clinical outcomes and the time of immune checkpoint inhibitors (ICIs) infusion. However, few data are available regarding the differences between early and late time-of-day (ToD) administration in metastatic renal cell carcinoma (mRCC) patients receiving immunotherapy and immune-based combinations. In this meta-analysis, we aimed to fully investigate the influence of timing of administration on the efficacy of mRCC immunotherapy, by comparing early ToD versus late ToD dosing in this setting. The present systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Overall Survival (OS) was measured as Hazard Ratios (HRs) and 95% confidence intervals (CIs). Our search resulted in the identification of 1429 potentially relevant reports, which were subsequently restricted to four following independent evaluation of three authors. The pooled HR for OS in RCC patients receiving early ToD versus late ToD dosing was 0.62 (95% Confidence Interval, 0.50-0.72; p < 0.001). According to our findings, a statistically significant improvement in terms of OS for mRCC patients receiving early ToD administration compared with late ToD dosing was observed, with a reduction of death by 38%. Well-designed, randomized clinical and translational trials are required to clarify this issue and to establish recommendations for personalized treatments according to ToD.

The behaviour of metastases in patients with liver-metastatic colorectal cancer (CRC) is still not adequately considered during treatment planning. However, studies in large cohorts have shown that the disease course in these patients depends on the histopathological growth pattern (HGP) of the liver metastases, with the desmoplastic (or encapsulated) pattern responsible for a favourable outcome and the replacement pattern for an unfavourable course. To increase our knowledge of cancer biology in general as well as to design clinical trials that take into account the diverse behaviour of liver metastases, it is necessary to know the cellular and molecular determinants of these growth patterns. For that purpose, we compared the transcriptome of tumour tissue (prospective cohort; n = 57) sampled very precisely at the transition of metastasis and adjacent liver, between the desmoplastic and replacement HGP. In addition, the mutational profiles for 46 genes related to CRC were extracted from the RNA sequencing reads. First, we show that the genetic constitution of a liver metastasis from colorectal cancer does not determine its HGP. Second, we show clear differences between HGPs regarding the expression of genes belonging to the Molecular Signatures Database hallmark gene sets. Biological themes of the replacement HGP reflect cancer cell proliferation and glucose metabolism, while the desmoplastic HGP is characterized by inflammation and immune response, and angiogenesis. This study supports the view that HGPs are a reflection of the biology of CRC liver metastases and suggests the HGPs are driven epigenetically rather than by specific gene mutations.

Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy, with metastasis being the leading cause of death in patients. Unfortunately, therapeutic options for metastatic OSCC remain limited. Peptidylarginine deiminases (PADI) are implicated in various tumorigenesis and metastasis processes across multiple cancers. However, the role of PADI2, a type of PADI, in OSCC is not well understood. This study aimed to explore the impact of PADI2 on epithelial-mesenchymal transition (EMT), angiogenesis, and OSCC metastasis. The effect of PADI2 on EMT was evaluated using cell lines by Western blot analysis with shRNA targeting PADI2. In addition, the selective PADI2 inhibitor AFM32a was used to assess the effect of PADI2 on cancer metastasis and angiogenesis in animal models. Our findings indicated that PADI2 expression correlated with EMT changes, and PADI2 knockdown reversed these changes, reducing cell proliferation, cell migration, and invasion. PADI2 inhibition also diminished tube formation in HUVECs and decreased secretion of angiogenesis-related chemokines CCL3, CCL5 and CCL20. In a mouse model, AFM32a markedly reduced lung metastasis and production of CCL3 and CCL5. Our in vitro and in vivo studies suggested inhibiting PADI2 could prevent OSCC metastasis by impeding EMT and angiogenesis via AKT/mTOR signaling pathway. These results highlight PADI2 as a potential therapeutic target for combating OSCC metastasis.

Immunotherapy improves survival outcomes in cancer patients, but there is still an unmet clinical need in the treatment of brain metastases. Here, we used a mouse model to investigate the antitumor effect of programmed death-ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) dual blockade on metastatic brain tumors and evaluated immune responses during treatment. After establishing hematogenous brain metastasis by transplanting murine bladder carcinoma MBT2 cells stably expressing secNLuc reporter via the internal carotid artery of C3H/HeNCrl mice, we observed the formation of metastases not only in the brain parenchyma but also in the ventricles. The observed pathological areas showed that metastases in the ventricle were histologically larger than that in the brain parenchyma. Regarding the total tumor burden in the whole brain as revealed by Nluc activities, the combination of anti-PD-L1 antibody and anti-VEGF antibody showed a stronger anti-tumor effect than each single agent. Anti-PD-L1 antibody alone enhanced CD8⁺ T cell priming in regional lymph nodes, increased the proportion of activated CD8⁺ T cells in whole brain, and increased the density of CD8⁺ cells in the brain parenchyma. Furthermore, anti-VEGF antibody alone decreased microvessel density (MVD) in ventricular metastases, and the combination treatment increased intratumoral CD8⁺ cell density in the brain parenchyma and ventricular metastases. These results suggest that PD-L1 blockade enhanced cancer immunity not only in brain metastases lesions but also in the regional lymph nodes of the metastases, and that the addition of VEGF blockade increased the antitumor effect by increasing the infiltration of activated CD8⁺ T cell and decreasing MVD.

Cells constantly reshape there plasma membrane and cytoskeleton during physiological and pathological processes (Hagmann et al. in J Cell Biochem 73:488-499, 1999). Cell blebbing, the formation of bulges or protrusions on the cell membrane, is related to mechanical stress, changes in intracellular pressure, chemical signals, or genetic anomalies. These membrane bulges interfere with the force balance of actin filaments, microtubules, and intermediate filaments, the basic components of the cytoskeleton (Charras in J Microsc 231:466-478, 2008). In the past, these blebs with circular structures were considered apoptotic markers (Blaser et al. in Dev Cell 11:613-627, 2006). Cell blebbing activates phagocytes and promotes the rapid removal of intrinsic compartments. However, recent studies have revealed that blebbing is associated with dynamic cell reorganization and alters the movement of cells in-vivo and in-vitro (Charras and Paluch in Nat Rev Mol Cell Biol 9:730-736, 2008). During tumor progression, blebbing promotes invasion of cancer cells into blood, and lymphatic vessels, facilitating tumor progression and metastasis (Weems et al. in Nature 615:517-525, 2023). Blebbing is a dominant feature of tumor cells generally absent in normal cells. Restricting tumor blebbing reduces anoikis resistance (survival in suspension) (Weems et al. in Nature 615:517-525, 2023). Hence, therapeutic intervention with targeting blebbing could be highly selective for proliferating pro-metastatic tumor cells, providing a novel therapeutic pathway for tumor metastasis with minimal side effects. Here, we review the association between cell blebbing and tumor cells, to uncover new research directions and strategies for metastatic cancer therapy. Finaly, we aim to identify the druggable targets of metastatic cancer in relation to cell blebbing.

Oral squamous cell carcinoma (OSCC) often exhibits a propensity for metastasis to lymph nodes (LNs), significantly influencing prognosis. Neck dissection (ND) is an important part in the treatment of OSCC. Variations in the preference for and pathways of lymph node metastasis (LNM) in different regions of the oral cavity have been observed. Currently, there is a lack of sufficient emphasis on the anatomical perspectives of LNM and ND. This review elucidates the lymphatic system of the maxillofacial regions from an anatomical standpoint, details the distribution of the sentinel LNs across different subsites, and summarizes the various classifications of the cervical LNs. Additionally, we elaborate on the methods used to study the lymphatic system, particularly imaging techniques. Furthermore, we investigate the pathways of cervical LNM and evaluate the efficacy of ND from an anatomical viewpoint. The overall objective of this review is to provide essential anatomical knowledge for managing LNs in OSCC, in the hope of providing patients with effective treatment modalities to enhance their quality of life.

Colorectal cancer (CRC) is a prevalent malignancy with a high mortality rate, primarily due to liver metastasis. This study explores the role of centromere protein N (CENP-N) in mediating the methylation of septin 9 (SEPT9) and its subsequent effects on aerobic glycolysis and liver metastasis in CRC. We employed in vitro and in vivo experiments, including single-cell RNA sequencing, methylation-specific PCR (MSP), ChIP assays, and various functional assays to assess the impact of CENP-N and SEPT9 on CRC cell proliferation, migration, invasion, and metabolic reprogramming. Our data reveal that CENP-N directly interacts with SEPT9, enhancing its methylation at specific lysine residues. This modification significantly upregulates key glycolytic enzymes, thereby promoting aerobic glycolysis, CRC cell proliferation, and migration. In vivo studies further demonstrate that the CENP-N/SEPT9 axis facilitates liver metastasis of CRC, as confirmed by fluorescence imaging and histological analysis. This study identifies a novel pathway where CENP-N-mediated methylation of SEPT9 drives metabolic reprogramming and metastasis in CRC. These findings suggest potential therapeutic targets for inhibiting CRC progression and liver metastasis, offering new insights into CRC pathogenesis.