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Postoperative asymptomatic patients with early cancer (lung cancer) have dormant disseminated tumor cells (DTCs) in their metastatic target organs, and the proliferation of these DTCs is the key link leading to clinical metastasis. The development of therapeutic agents to maintain DTCs dormant or eradicate dormant DTCs will prevent tumor metastasis and break through the bottleneck of improving the overall efficacy of treating malignant tumors. This paper reviews the methods of establishing in vitro and in vivo research models of DTCs with dormant characteristics to promote the understanding of dormant DTCs and improve the research and development efficiency of anti-tumor metastasis drugs.
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AiM: To observe the recruitment effect of lung cancer circulating tumor cells (CTCs) on neutrophils, and find out the effective components of jinfukang in inhibiting the recruitment of neutrophils by CTCs. METHODS: The ability of human lung adenocarcinoma circulating tumor cells CTC-TjH-01 cells to recruit neutrophils from whole blood leukocytes, and the effect of jinfukang and its six active ingredients on the recruitment of neutrophils by CTCs was detected by flow cytometry. CCK-8 assay was used to observe cell viability to determine the concentration of action; transwell chemotaxis assay was used to detect the effect of six active ingredients on the chemotaxis of CTC-TjH-01 cells to neutrophils. RESULTS: CTCTjH-01 cells could increase the recruitment of neutrophils compared to blank control (p < 0.01); after the effect of jinfukang, the neutrophils recruited by CTC-TjH-01 cells decreased (p < 0.01). Trigonelline and Ophiopogonin W reduced neutrophil recruitment to CTC-TjH-01 cells at concentrations that had no effect on cell viability (p < 0.01), trigonelline had the best effect; the chemotaxis of CTC-TjH-01 cells to neutrophils was weakened by trigonelline, astragaloside IVz and Ophiopogon pol-ysaccharide (p < 0.05), and trigonelline had the best effect. CONCLUSiON: jinfukang can inhibit the recruitment of neutrophils by circulating tumor cells, and trigonelline, an effective monomer with "Fuzheng" effect in jinfukang, can significantly inhibit the recruitment of neutrophils by circulating tumor cells in lung cancer, which proves that trigonelline may have the potential to inhibit lung cancer metastasis through targeting neutrophils.
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Increasing evidences suggest the important role of calcium homeostasis in hallmarks of cancer, but its function and regulatory network in metastasis remain unclear. A comprehensive investigation of key regulators in cancer metastasis is urgently needed. Transcriptome sequencing (RNA-seq) of primary esophageal squamous cell carcinoma (ESCC) and matched metastatic tissues and a series of gain/loss-of-function experiments identified potassium channel tetramerization domain containing 4 (KCTD4) as a driver of cancer metastasis. KCTD4 expression was found upregulated in metastatic ESCC. High KCTD4 expression is associated with poor prognosis in patients with ESCC and contributes to cancer metastasis in vitro and in vivo. Mechanistically, KCTD4 binds to CLIC1 and disrupts its dimerization, thus increasing intracellular Ca2+ level to enhance NFATc1-dependent fibronectin transcription. KCTD4-induced fibronectin secretion activates fibroblasts in a paracrine manner, which in turn promotes cancer cell invasion via MMP24 signaling as positive feedback. Furthermore, a lead compound K279-0738 significantly suppresses cancer metastasis by targeting the KCTD4‒CLIC1 interaction, providing a potential therapeutic strategy. Taken together, our study not only uncovers KCTD4 as a regulator of calcium homeostasis, but also reveals KCTD4/CLIC1-Ca2+-NFATc1-fibronectin signaling as a novel mechanism of cancer metastasis. These findings validate KCTD4 as a potential prognostic biomarker and therapeutic target for ESCC.
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Tumor metastasis depends on the dynamic balance of the actomyosin cytoskeleton. As a key component of actomyosin filaments, non-muscle myosin-IIA disassembly contributes to tumor cell spreading and migration. However, its regulatory mechanism in tumor migration and invasion is poorly understood. Here, we found that oncoprotein hepatitis B X-interacting protein (HBXIP) blocked the myosin-IIA assemble state promoting breast cancer cell migration. Mechanistically, mass spectrometry analysis, co-immunoprecipitation assay and GST-pull down assay proved that HBXIP directly interacted with the assembly-competent domain (ACD) of non-muscle heavy chain myosin-IIA (NMHC-IIA). The interaction was enhanced by NMHC-IIA S1916 phosphorylation via HBXIP-recruited protein kinase PKCβII. Moreover, HBXIP induced the transcription of PRKCB, encoding PKCβII, by coactivating Sp1, and triggered PKCβII kinase activity. Interestingly, RNA sequencing and mouse metastasis model indicated that the anti-hyperlipidemic drug bezafibrate (BZF) suppressed breast cancer metastasis via inhibiting PKCβII-mediated NMHC-IIA phosphorylation in vitro and in vivo. We reveal a novel mechanism by which HBXIP promotes myosin-IIA disassembly via interacting and phosphorylating NMHC-IIA, and BZF can serve as an effective anti-metastatic drug in breast cancer.
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Metastasis and resistance are main causes to affect the outcome of the current anticancer therapies. Heat shock protein 90 (Hsp90) as an ATP-dependent molecular chaperone takes important role in the tumor metastasis and resistance. Targeting Hsp90 and downregulating its expression show promising in inhibiting tumor metastasis and resistance. In this study, a redox-responsive dual-drug nanocarrier was constructed for the effective delivery of a commonly used chemotherapeutic drug PTX, and a COA-modified 4-arm PEG polymer (4PSC) was synthesized. COA, an active component in oleanolic acid that exerts strong antitumor activity by downregulating Hsp90 expression, was used as a structural and functional element to endow 4PSC with redox responsiveness and Hsp90 inhibitory activity. Our results showed that 4PSC/PTX nanomicelles efficiently delivered PTX and COA to tumor locations without inducing systemic toxicity. By blocking the Hsp90 signaling pathway, 4PSC significantly enhanced the antitumor effect of PTX, inhibiting tumor proliferation and invasiveness as well as chemotherapy-induced resistance in vitro. Remarkable results were further confirmed in vivo with two preclinical tumor models. These findings demonstrate that the COA-modified 4PSC drug delivery nanosystem provides a potential platform for enhancing the efficacy of chemotherapies.
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Metastasis is the leading cause of cancer-related death. Despite extensive treatment, the prognosis for patients with metastatic cancer remains poor. In addition to conventional surgical resection, radiotherapy, immunotherapy, chemotherapy, and targeted therapy, various nanobiomaterials have attracted attention for their enhanced antitumor performance and low off-target effects. However, nanomedicines exhibit certain limitations in clinical applications, such as rapid clearance from the body, low biological stability, and poor targeting ability. Biomimetic methods utilize the natural biomembrane to mimic or hybridize nanoparticles and circumvent some of these limitations. Considering the involvement of immune cells in the tumor microenvironment of the metastatic cascade, biomimetic methods using immune cell membranes have been proposed with unique tumor-homing ability and high biocompatibility. In this review, we explore the impact of immune cells on various processes of tumor metastasis. Furthermore, we summarize the synthesis and applications of immune cell membrane-based nanocarriers increasing therapeutic efficacy against cancer metastases via immune evasion, prolonged circulation, enhanced tumor accumulation, and immunosuppression of the tumor microenvironment. Moreover, we describe the prospects and existing challenges in clinical translation.
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Neurons migrate from their birthplaces to the destinations, and extending axons navigate to their synaptic targets by sensing various extracellular cues in spatiotemporally controlled manners. These evolutionally conserved guidance cues and their receptors regulate multiple aspects of neural development to establish the highly complex nervous system by mediating both short- and long-range cell-cell communications. Neuronal guidance genes (encoding cues, receptors, or downstream signal transducers) are critical not only for development of the nervous system but also for synaptic maintenance, remodeling, and function in the adult brain. One emerging theme is the combinatorial and complementary functions of relatively limited classes of neuronal guidance genes in multiple processes, including neuronal migration, axonal guidance, synaptogenesis, and circuit formation. Importantly, neuronal guidance genes also regulate cell migration and cell-cell communications outside the nervous system. We are just beginning to understand how cells integrate multiple guidance and adhesion signaling inputs to determine overall cellular/subcellular behavior and how aberrant guidance signaling in various cell types contributes to diverse human diseases, ranging from developmental, neuropsychiatric, and neurodegenerative disorders to cancer metastasis. We review classic studies and recent advances in understanding signaling mechanisms of the guidance genes as well as their roles in human diseases. Furthermore, we discuss the remaining challenges and therapeutic potentials of modulating neuronal guidance pathways in neural repair.
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Humans , Axon Guidance/genetics , Neurons , Axons/metabolism , Signal Transduction/genetics , Cell CommunicationABSTRACT
【Objective】 To investigate the value of prostate cancer prevention trial risk calculator （PCPT-RC） combined with biopsy Gleason score for predicting the risk of metastasis in newly diagnosed prostate cancer patients. 【Methods】 We retrospectively collected the data of 74 patients with newly diagnosed prostate cancer confirmed by biopsy from April 2019 to August 2021， concurrent with 18F-PSMA-1007 PET/CT whole body imaging in the same period. Based on this， a binary logistic regression model was established to obtain the high risk probability of PCPT. We calculated the receiver operating characteristic curve （ROC） was drawn and the area under the curve， Yuden index， sensitivity， specificity， positive predictive value and negative predictive value. We compared the predictive value of the prostate cancer prevention trial risk calculator and Gleason score alone or in combination in predicting the risk of prostate cancer metastasis. 【Results】 Based on the PSMA PET/CT results， 74 patients were divided into non-metastatic group （46/74） and metastatic group （28/74）. PCPT high risk probability ［41.14% （16%-67%）］ vs. ［30.89% （5%-65%）］， Gleason score ［8.5（6-10） score］ vs. ［7.7（6-9） score］， tPSA ［26.24（5.70-42.32） ng/mL］ vs. ［19.58（2.47-49.35） ng/mL］， and fPSA ［3.94（0.82-12.00） ng/mL］ vs. ［2.33（0.35-10.20） ng/mL］ were significantly higher in metastatic group than in non-metastatic group. Binary Logistic regression analysis showed that Gleason score and PCPT low risk probability may be independent predictors of prostate cancer metastasis. PCPT low risk probability alone did not predict the risk of prostate cancer metastasis （P=0.172）. The predictive accuracy of Gleason score and high probability of PCPT in predicting prostate cancer metastasis were 0.715 and 0.679， respectively， and the accuracy of the combined prediction was 0.809. 【Conclusion】 PCPT-RC combined with Gleason score is valuable for predicting the metastasis risk of newly diagnosed prostate cancer patients， which has certain guiding significance for clinical individualized treatment.
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Aim To explore the effect of THPA1 in the metasta- sis of gastric cancer and the underlying mechanism. Methods The correlation between TRPA1 and the survival time of gastric cancer patients was analyzed using Kaplan-Meier plotter data base. The expressions of TRPA1 in different cells were detected by Western blot. Docking was used to explore the binding poten tial between cardamonin and TRPA1. Long-term dynamic cell imaging, CCK-8 and Transwell were used to evaluate the effects of HC-030031 and cardamonin on the proliferation and migration of MKN-45 cells. The differential metabolites between normal gastric epithelial cells and gastric cancer cells were studied by GC-MS. Results The expression of TRPA1 in gastric cancer patients was significantly negatively correlated with their surviv al. TRPA1 was overexpressed in gastric cancer cells. And the migration of gastric cancer cells was positively correlated with the expression and activation of TRPA1. Cardamonin had similar pharmacological effects with HC-030031, both of which could reduce the migration of gastric cancer cells. The metabolic path ways of asparagine and myo-inositol were found to be different between gastric cancer cells and normal gastric epithelial cells by cell metabolomics analysis. Conclusions TRPAI may be an indicator for detecting gastric cancer metastasis. Cardamonin in hibits metastasis by binding to TRPAI, meanwhile restrains the activation of TRPAI. Cardamonin may inhibit the function of TRPAI by binding to TRPAI, playing a role in inhibiting gastric cancer metastasis.
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BACKGROUND@#Lung cancer is one of the most dangerous diseases to human health, with high morbidity and mortality. It can be cured by surgery at early stage, therefore, the early detection and early treatment of lung cancer are especially important. Serum tumor markers play an important role in the detection and diagnosis of lung cancer. Galectin-3 is known to be expressed in a variety of malignant tumors. This study was to explore the serum levels of Galectin-3 and its clinical significance in non-small cell lung cancer (NSCLC) patients.@*METHODS@#The serum levels of Galectin-3 in peripheral blood were detected by enzyme linked immunosorbent assay (ELISA) in 69 NSCLC patients and 77 cases of healthy control subjects, and compared between the two groups. Then we analyze the correlations between the serum levels of Galectin-3 and the clinical features of lung cancer.@*RESULTS@#The serum levels of Galectin-3 in NSCLC patients were significantly higher than those of healthy control subjects (P<0.01). The serum levels of Galectin-3 with lymph node metastasis were significantly higher than those of patients without lymph node metastasis (P<0.01), and N2 lymph node metastasis had higher levels of serum Galectin-3 than those of N1 lymph node metastasis (P<0.01). Clinical stage III and stage IV patients had higher levels of serum Galectin-3 than those of clinical stage I and clinical stage II (P<0.05).@*CONCLUSIONS@#Our study showed the serum levels of Galectin-3 are highly expressed in NSCLC patients and are significantly related to lymph node metastasis. It may be a potential tumor marker for lung cancer.
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@#The three-dimensional cell model cultures different types of cells in vitro. By means of special materials or carriers, the cells can grow, migrate and differentiate in a three-dimensional environment. The three-dimensional cell model provides the cells with an in vitro environment that is close to in vivo, making the gene expression and signal exchange of the cells more physiologically relevant. This paper starts with the concept and classification of three-dimensional cell model, then summarizes the applications and progresses of three-dimensional cell model in tumor micro-environment, cancer metastasis and anti-tumor drug development in recent years. Based on the current shortcomings of the three-dimensional cell model, this paper presents the assumptions and prospects for the application of three-dimensional cell model in tumor therapy.
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Lung cancer is one kind of malignant tumors with the highest morbidity and mortality, and lung cancer metastasis is the leading cause of death in patients. Lung cancer metastasis is a complex process. A large number of studies have confirmed that lung tumors can secrete soluble molecules, mobilize and recruit related bone marrow cells or immune cells, regulate the matrix remodeling in distant organs which leads to the formation of pre-metastatic niche, therefore, promote tumor cells metastasis and implantation in distant organs. Detection of key target factor molecules and cellular components involving in pre-metastatic niche is of great clinical significance for diagnosis and prognostic evaluation. This article will summarize the progression of lung cancer metastasis modulated by the pre-metastatic niches and its clinical application status.
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Hypoxia is a serious impediment to current treatments of many malignant tumors. Catalase, an antioxidant enzyme, is capable of decomposing endogenous hydrogen peroxide (H
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@# Objective: To explore the molecular mechanism of miR-17-5p regulating the proliferation and invasion of nasopharyngeal carcinoma cells by regulating the expression of breast cancer metastasis suppressor 1 like (BRMS1-like or BRMS1L) gene. Methods:A total of 40 cases of nasopharyngeal carcinoma tissues and corresponding paracancerous tissues resected from nasopharyngeal carcinoma patients, who were admitted to the General Hospital of Pingdingshan Shenma Medical Group during January 2014 to December 2017, were included in this study; in addition, nasopharyngeal carcinoma cell lines CNE 2, HONE 1, C666-1 and nasopharyngeal immortalized epithelial cell line NP69 were also collected for this study. The expression of miR-17-5p in nasopharyngeal carcinoma tissues and cell lines was detected by qPCR. The targeted relationship between BRMS1L and miR-17-5p was predicted by the StarBase and verified by the Dual luciferase reporter gene assay. Effects of transfection of miR-17-5p mimics and inhibitors on the expression of BRMS1Lin CNE2 cells were detected by WB assay. CCK-8, Transwell and Flow cytometry were used to detect the effects of miR-17-5p/BRMS1L axis on the proliferation, migration, invasion and apoptosis of CNE 2 cells. Results: miR-17-5p was highly expressed in nasopharyngeal carcinoma tissues and cell lines (P<0.05 or P<0.01). Knockdown of miR-17-5p significantly inhibited proliferation, invasion and migration of CNE2 cells but promoted apoptosis (P<0.05 or P<0.01); miR-17-5p targeted BRMS1Land down-regulated its expression. Over-expression of BRMS1Lsignificantly inhibited the proliferation, invasion and migration of CNE2 cells but promoted apoptosis (all P<0.01); while simultaneous over-expression of miR-17-5p and BRMS1L reversed the above effects (all P<0.01). Conclusion: miR-17-5p promoted proliferation, invasion, migration and inhibited apoptosis of CNE 2 cells by down-regulating the expression of BRMS1L.
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Foreign body injections into breasts may produce foreign body reactions, fibrosis, and local swelling of involved lymph nodes, which can be misdiagnosed as metastasis or malignancy. Here, the authors report MR imaging, PET-CT imaging, and pathologic findings of contralateral internal mammary lymphadenopathy suspicious of breast cancer metastasis in a 58-year-old woman with history of left breast cancer, and previous interstitial mammoplasty by paraffin injection in both breasts.
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Female , Humans , Middle Aged , Breast Neoplasms , Breast , Fibrosis , Foreign Bodies , Lymph Nodes , Lymphatic Diseases , Magnetic Resonance Imaging , Mammaplasty , Neoplasm Metastasis , ParaffinABSTRACT
The aim of this study was to investigate the effect and mechanisms of miR-29a in migration and inva-sion of human breast cancer MCF-7 cells in vitro. MCF-7 cells were treated with miR-29a mimic or miR-29a inhibitor to up-regulate/down-regulate the expression level of miR-29a. Wound-healing assay and transwell chamber were employed to determine cell migration and invasion in vitro. The target gene of miR-29a was predic-ted with the Targetscan7. 1 database and verified through luciferase reporter method. The effects of miR-29a on the expression of the potential target were detected by Western blot and real-time PCR. Results showed that in vitro migration and invasion ability of MCF-7 cells was increased significantly by miR-29a,which could target HBP1 in the 3′-UTR region. The protein expression of HBP1 was decreased by miR-29a overexpression. However, the alteration of miR-29a had no significant effect on the expression of HBP1 mRNA. The results validated that miR-29a,highly expressed in breast cancer,could down-regulate HBP1 ,which in turn promotes migration and invasion ability of breast cancer cells,thus promoting breast cancer metastasis.
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Objective To investigate the mechanism of miR-758 in hepatocellular carcinoma cell HepG2,and to investigate the regulatory role of miR-758 on astrocyte elevated gene-1 (AEG-1).Methods Transient transfection of miR-758 into HepG2 cells was performed to study the effect of miR-758 on tumor cell metastasis by transwell migration and invasion experiments.CCK8 assay was used to detect the cell proliferation activity.The cell cycle was analyzed by flow cytometry.The effect of miR-758 on epidermal mesenchymal transition (EMT) was determined by the expression of EMT markers.Transient transfection of miR-758 into human umbilical vein endothelial cells (HUVECs) was performed to explore the effect of miR-758 on luminal formation.AEG-1 3'UTR containing the binding site of miR-758 was constructed into luciferase expression vector.The miR-758 and the vector was co-transfected into HepG2 cells.And then the change in expression level of AEG-1 protein was detected through Western Blot.Results The overexpression of miR-758 inhibited HepG2 cell migration and invasion,as well as the cell proliferation and the cell cycle.The miR-758 was also found to inhibit EMT of HepG2 cells and the lumen formation of HUVEC cells.After the co-transfection of miR-758 with the plasmid containing AEG-1 gene 3'UTR into HepG2 cells,the luciferase expression was decreased.The luciferase expression was restored when the binding site of miR-758 in the 3'UTR was mutated.Further evidence by Western Blot showed the protein level of AEG-1 in HepG2 cells was significantly decreased after transfection of miR-758.Conclusions The miR-758 negatively regulates multiple steps during cancer metastasis,including cell migration,invasion,cell proliferation,EMT,as well as angiogenesis.And AEG-1 has been identified as a downstream target of miR-758.
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Objective To evaluate the association between the expression of breast cancer metastasis suppressor gene 1 (BRMS1) and the progression of cancer,and provide the basis for predicting the occurrence and metastasis of cancer.Methods Articles about BRMS1 with the clinical research literatures of cancer from PubMed,EMBase,China National Knowledge Infrastructure,Wanfang and VIP database were retrieved.The association between the expression of BRMS1 and tumorigenesis was evaluated by odds ratio (OR).The RevMan 5.3 software was used to complete the meta-analysis.Results A total of 27 articles were included,involving 2 282 cases in cancer group and 1 236 cases in the control group.The meta-analysis results showed that BRMS1 expression was significantly upregulated in cancer lesions compared with paired non-cancer (OR =0.10,95％ CI:O.08-0.14,Z =15.37,P ＜0.000 O1).In the subgroup about the type of cancers,there was statistically significant difference in the pooled OR between breast cancer and the control group (OR =0.10,95％ CI:0.05-0.20,Z =6.18,P ＜ 0.000 01).Conclusion The level of BRMS1 is negatively correlated with tumorigenesis including breast cancer.Low or absent BRMS1 expression in the tumor tissue may be an adverse predictive factor of tumorigenesis and metastasis.
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Breast cancer metastasis suppressor gene 1 (BRMS1) significantly reduces the invasion and metastasis of cancer cells.BRMS1 gene expression is decreased or deleted in the cells of various malignant tumors.BRMS1 gene can inhibit tumor cells invasion and metastasis by means of regulating gene transcription and protein translation by phosphoinositide signaling and nuclear factor-κB (NF-κB) signaling pathways,repairing intercellular communication and interacting with the mSin3-histone deacetylase (HDAC) complex,estrogen receptor and other proteins.BRMS1 gene may be a new target for the gene treatment of tumor metastasis.
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Objective To provide the reference for early diagnosis and treatment of breast cancer by detecting its metastasis-related genes.Methods Breast cancer metastasis-related genes were searched from PubMed-covered papers with their conception matched according to the MetaMap.A gene-gene matrix was generated using data a-nalysis software.An interaction network of breast cancer metastasis-related genes was established using Ucinet 6 and its related indexes were analyzed.Results tp53, thra, erbb2, esr1, cdh1, egfr, nr4al and cd69 were the core genes for breast cancer metastasis.Conclusion Co-word analysis can show breast cancer metastasis-related genes. However, the role of cd69 in breast cancer metastasis remains unclear and is thus necessary to be further confirmed.