Clinical & Experimental Metastasis最新文献

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.

Although the intervention for triple-negative breast cancer (TNBC) patients has improved and survival time has increased, the combination of immune checkpoint inhibitors(ICIs) and PARP inhibitors (Poly ADP-Ribose Polymerase inhibitors, PARPis) is still controversial. Previous studies revealed that the combined use of ICIs and PARPis led to increased antitumor activity. However, most of these combined regimens are nonrandomized controlled trials with small sample sizes. The purpose of this meta-analysis was to evaluate the efficacy and safety of ICIs combined with PARPis in patients with advanced or metastatic TNBC. The PubMed, Embase, Cochrane Library and Web of Science databases were systematically searched. The results including the objective remission rate (ORR), disease control rate (DCR), progression-free survival (PFS) and adverse events (AEs), were subjected to further analysis. Four studies involving 110 subjects were included in this meta-analysis. The combined ORR and DCR were 23.6% and 53.6%, respectively; while the ORR and DCR of BRCAmut patients were 38.1% and 71.4%, respectively. The median PFS of the patients was 4.29 months. As for safety, the most common AEs were nausea (49.0%), anemia (44.3%) and fatigue (40.6%). Most of them were grade 1 or 2, and the incidence of adverse events ≥ III was obviously low. Except for anemia, the incidence of AEs ≥ III was < 10%. This meta-analysis revealed that the combination of ICIs and PARPis has good efficacy and safety for advanced or metastatic TNBC patients.

Metastatic breast cancer (MBC) is still an incurable disease, which eventually develops resistance mechanisms against systemic therapies. While most patients experience widespread disease progression during systemic treatment (ST), in some cases, progression may occur at a limited number of metastatic sites. Evidence from other malignancies suggests that local treatment with stereotactic ablative radiotherapy (SABR) of oligoprogressive disease (OPD) may allow effective disease control without the need to modify ST. Available evidence regarding local treatment of oligoprogressive breast cancer is limited, mostly consisting of retrospective studies. The only randomized data come from the randomized CURB trial, which enrolled patients with oligoprogressive disease, including both small cell lung cancer and breast cancer patients, and did not show a survival benefit from local treatment in the latter group. However, local treatment of oligoprogressive MBC is still considered in clinical practice, especially to delay the switch to more toxic STs. This review aims to identify patients who may benefit from this approach based on the current available knowledge, focusing also on the potential risks associated with the combination of radiotherapy (RT) and ST, as well as on possible future scenarios.

Circulating tumor cells (CTCs) are an established prognostic marker in metastatic prostate cancer (PrC) but have received little attention in localized high-risk disease. Peripheral blood was obtained from patients with early intermediate and high-risk PrC (n = 15) at baseline, after radiotherapy, and during follow-up, as well as from metastatic PrC patients (n = 23). CTCs were enriched using the microfluidic Parsortix^® technology. CTC-related marker were quantified with qPCR and RNA in-situ hybridization (ISH). Positivity and associations to clinical parameters were assessed using McNemar test, Fisher Exact test or log-rank test. The overall positivity was high in both cohorts (87.0% metastatic vs. 66.7% early at baseline). A high concordance of qPCR and RNA ISH was achieved. In metastatic PrC, PSA and PSMA were prognostic for shorter overall survival. In early PrC patients, an increase of positive transcripts per blood sample was observed from before to after radiation therapy, while a decrease of positive markers was observed during follow-up. CTC analysis using the investigated qPCR marker panel serves as tool for achieving high detection rates of PrC patient samples even in localized disease. RNA ISH offers the advantage of confirming these markers at the single cell level. Employing the clinically relevant marker PSMA, our CTC approach can be used for diagnostic purposes to screen patients profiting from PSMA-directed PET-CT or PSMA-targeted therapy.

The process of cervical lymph node metastasis is dependent on the phenotype of the tumor cells and their interaction with the host microenvironment and immune system; conventional research methods that focus exclusively on tumor cells are limited in their ability to elucidate the metastatic mechanism. In cancer tissues, a specialized environment called the tumor microenvironment (TME) is established around tumor cells, and inflammation in the TME has been reported to be closely associated with the development and progression of many types of cancer and with the response to anticancer therapy. In this study, to elucidate the mechanism of metastasis establishment, including the TME, in the cervical lymph node metastasis of oral cancer, we established a mouse-derived oral squamous cell carcinoma cervical lymph node highly metastatic cell line and generated a syngeneic orthotopic transplantation mouse model. In the established highly metastatic cells, epithelial-mesenchymal transition (EMT) induction was enhanced compared to that in parental cells. In the syngeneic mouse model, lymph node metastasis was observed more frequently in tumors of highly metastatic cells than in parental cells, and Cyclooxygenase-2 (COX-2) expression and lymphatic vessels in primary tumor tissues were increased, suggesting that this model is highly useful. Moreover, in the established highly metastatic cells, EMT induction was enhanced compared to that in the parent cell line, and CCL5 and IL-6 secreted during inflammation further enhanced EMT induction in cancer cells. This suggests the possibility of a synergistic effect between EMT induction and inflammation. This model, which allows for the use of two types of cells with different metastatic and tumor growth potentials, is very useful for oral cancer research involving the interaction between cancer cells and the TME in tumor tissues and for further searching for new therapeutic agents.

The distribution of brain metastases (BMs) in patients with lung cancer may be associated with the primary tumor-related factors and cerebral small vascular diseases (CSVDs). The aim of this study was to investigate the potential effects of the above factors on the distribution of BMs. A total of 5,788 lesions in 823 patients with BMs from lung cancer were enrolled. The numbers of BMs and CSVDs in 15 brain regions were determined. CSVDs include recent small subcortical infarcts (RSSIs), perivascular spaces, and lacunes of presumed vascular origin (LPVOs). We collected the number of CSVDs, and primary tumor-related factors (including clinical and imaging features) in lung cancer patients with BMs. Univariate and multivariate linear regression were utilized to analyze the potential influence of the above factors on the number of BMs in 15 brain regions. In addition, we performed subgroup analyses of all patients with adenocarcinoma (AD), female patients with AD, male patients with AD, and patients with small cell lung cancer. Univariate linear regression analyses showed that bone metastasis, adrenal metastasis, RSSIs, and LPVOs were associated with the number of BMs in over half of the examined brain regions. Only the independent association of LVPOs persisted in the multivariate linear regression analyses, and similar phenomenon was found in the subgroup analyses. In conclusion, the distribution of BMs in lung cancer patients appears to be associated with the presence of LVPOs, while primary tumor-related factors have less influence.

Multiple myeloma (MM) is a clinical disorder characterized by aberrant plasma cell growth in the bone marrow microenvironment. Globally, the prevalence of MM has been steadily increasing at an alarming rate. In the United States, more than 30,000 cases will be diagnosed in 2024 and it accounts for about 2% of cancer diagnoses and more than 2% of cancer deaths, more than double the worldwide figure. Both symptomatic and active MM are distinguished by uncontrolled plasma cell growth, which results in severe renal impairment, anemia, hypercalcemia, and bone loss. Multiple drugs have been approved by the FDA and are now widely used in clinical practice for MM. Although triplet and quadruplet induction regimens, autologous stem cell transplantation (ASCT), and maintenance treatment are used, MM continues to be an incurable illness characterized by relapses that may occur at various phases of its progression. MM patients with frailty, extramedullary disease, plasma cell leukemia, central nervous system recurrence, functional high risk, and the elderly are among those with the greatest current unmet needs. The high cost of care is an additional challenge. MM cells are highly protein secretary cells and thus are dependent on the activation of certain translation pathways. MM also has a high chance of altering ribosomal protein-encoding genes like MYC mutation. In this article we discuss the importance of ribosome biogenesis in promoting MM and RNA polymerase I inhibition as an upcoming treatment with potential promise for MM patients.

Circular RNAs (circRNA) are a class of covalently-closed, single-stranded RNAs that have been implicated in cancer progression due to their regulation of metabolism. However, the roles of circRNA in prostate cancer remain largely unknown. In this study, fluorescence in situ hybridization and RT-qPCR were used to investigate hsa_circ_0006620 expressions in both prostate cancer cells and tissues, after high-throughput sequencing. The luciferase reporter assay was used to identify hsa_circ_0006620 downstream targets. Transwell migration assays, 5-ethynyl-20-deoxyuridine assays, and Cell Counting Kit-8assays were used to investigate both proliferation and migration. In vivo tumorigenesis and metastasis assays were performed to investigate the role of hsa_circ_0006620 in prostate cancer. The results showed that hsa_circ_0006620 expression increased in prostate cancer cells and tissues. Hsa_circ_0006620 downregulation inhibited prostate cancer cell proliferation as well as in vivo and in vitro migrations. The luciferase results validated that miR-502-3p and hexokinase 2 (HK2) were hsa_circ_0006620 downstream targets. HK2 overexpression or miR-502-3p inhibition reversed prostate cancer cell migration after hsa_circ_0006620 silencing. The study also found that overexpression of HK2 or inhibition of prostate cancer reversed aerobic glycolysis after hsa_circ_0006620 silencing. In summary, the results showed thathsa_circ_0006620 downregulation inhibited prostate cancerby regulation of the miR-502-3p/HK2 axis mediated by aerobic glycolysis.