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1.
Front Neurol ; 15: 1334657, 2024.
Article in English | MEDLINE | ID: mdl-38638316

ABSTRACT

Purpose: In recent years, traditional Chinese medicine has received widespread attention in the field of cancer pain treatment. This meta-analysis is the first to evaluate the effectiveness and safety of acupuncture point stimulation in the treatment of stomach cancer pain. Methods: For this systematic review and meta-analysis, we searched PubMed, Web of Science, Cochrane Library, Embase, WANFANG, China National Knowledge Infrastructure (CNKI), and Chinese Journal of Science and Technology (VIP) databases as well as forward and backward citations to studies published between database creation to July 27, 2023. All randomized controlled trials (RCTs) on acupuncture point stimulation for the treatment of patients with stomach cancer pain were included without language restrictions. We assessed all outcome indicators of the included trials. The evidence from the randomized controlled trials was synthesized as the standardized mean difference (SMD) of symptom change. The quality of the evidence was assessed using the Cochrane Risk of Bias tool. This study is registered on PROSPERO under the number CRD42023457341. Results: Eleven RCTs were included. The study included 768 patients, split into 2 groups: acupuncture point stimulation treatment group (n = 406), medication control group (n = 372). The results showed that treatment was more effective in the acupuncture point stimulation treatment group than in the medication control group (efficacy rate, RR = 1.63, 95% CI 1.37 to 1.94, p < 0.00001), decreasing in NRS score was greater in acupuncture point stimulation treatment group than in the medication control group (SMD = -1.30, 95% CI -1.96 to -0.63, p < 0.001). Systematic Review Registration: https://clinicaltrials.gov/, identifier CRD42023457341.

2.
Front Immunol ; 15: 1362709, 2024.
Article in English | MEDLINE | ID: mdl-38415252

ABSTRACT

Colorectal cancer (CRC), known for its high metastatic potential, remains a leading cause of cancer-related death. This review emphasizes the critical role of immune responses in CRC metastasis, focusing on the interaction between immune cells and tumor microenvironment. We explore how immune cells, through cytokines, chemokines, and growth factors, contribute to the CRC metastasis cascade, underlining the tumor microenvironment's role in shaping immune responses. The review addresses CRC's immune evasion tactics, especially the upregulation of checkpoint inhibitors like PD-1 and CTLA-4, highlighting their potential as therapeutic targets. We also examine advanced immunotherapies, including checkpoint inhibitors and immune cell transplantation, to modify immune responses and enhance treatment outcomes in CRC metastasis. Overall, our analysis offers insights into the interplay between immune molecules and the tumor environment, crucial for developing new treatments to control CRC metastasis and improve patient prognosis, with a specific focus on overcoming immune evasion, a key aspect of this special issue.


Subject(s)
Colorectal Neoplasms , Humans , Colorectal Neoplasms/pathology , Prognosis , Treatment Outcome , Cytokines/therapeutic use , Tumor Microenvironment
3.
Eur J Hosp Pharm ; 30(1): 3-8, 2023 01.
Article in English | MEDLINE | ID: mdl-34497128

ABSTRACT

PURPOSE: To investigate the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) plus cytotoxic T lymphocyte antigen-4 (CTLA-4) antibodies ± other therapies in patients with advanced lung cancer. METHODS: In accordance with the retrieval strategy, we searched electronic databases for randomised controlled trials testing PD-1/PD-L1 plus CTLA-4 antibodies in patients with lung cancer; RR (for objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and immune-related adverse events (irAEs)) from individual studies were calculated and pooled by using random-effects models or fixed-effects models; heterogeneity and publication bias analyses were also performed, using Review Manager 5.3 and Stata 15.1 for statistical analysis. RESULTS: We included six studies. Four different immune checkpoint inhibitors (nivolumab, pembrolizumab, durvalumab, tremelimumab) were used. Dual checkpoint inhibitors ± other therapies for advanced lung cancer showed significant improvements in ORR (RR 1.49, 95% CI 1.11 to 1.98; p=0.007), OS (HR 0.72, 95% CI 0.63 to 0.83; p<0.00001), and PFS (HR 0.72, 95% CI 0.63 to 0.82; p<0.00001). The subgroup analyses were consistent with the pooled results. The PD-L1 ≥1% (HR 0.67, 95% CI 0.54 to 0.82; p<0.0001) subgroup differences indicated a statistically significant subgroup effect, but the PD-L1 <1% subgroup (HR 0.88, 95% CI 0.75 to 1.05; p=0.15) was not statistically significant. The incidence of adverse events (grade ≥3) was lower than that of the control group (RR 0.90, 95% CI 0.80 to 1.02; p=0.09), but was not significant. CONCLUSIONS: PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors ± other therapies can improve the ORR, OS and PFS of patients with advanced or metastatic lung cancer, but the incidence of adverse reactions is high although generally tolerable. PROSPERO REGISTRATION: CRD42020149216.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/therapy , Programmed Cell Death 1 Receptor , CTLA-4 Antigen , B7-H1 Antigen , Lung Neoplasms/pathology , Lung Neoplasms/therapy
4.
Front Immunol ; 14: 1329951, 2023.
Article in English | MEDLINE | ID: mdl-38235148

ABSTRACT

Background: Treatment for platinum-resistant ovarian cancer is challenging. Currently, platinum-resistant ovarian cancer is typically treated with non-platinum single-agent chemotherapy ± bevacizumab, but the prognosis is often extremely poor. In the treatment of platinum-resistant ovarian cancer patients, reports of triple therapy with interstitial implantation radiotherapy combined with immunotherapy and granulocyte-macrophage colony-stimulating factor (GM-CSF) (PRaG for short) are relatively rare. Case description: Here, we report a patient with oligometastatic platinum-resistant ovarian cancer. The patient achieved partial response (PR) of the lesion and sustained benefit for more than six months after receiving interstitial implantation radiotherapy combined with immunotherapy along with GM-CSF. Conclusion: This triple therapy may provide additional options for these patients.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor , Ovarian Neoplasms , Humans , Female , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Bevacizumab/therapeutic use , Prognosis , Immunotherapy , Ovarian Neoplasms/therapy , Ovarian Neoplasms/pathology
5.
Front Oncol ; 11: 657024, 2021.
Article in English | MEDLINE | ID: mdl-33968760

ABSTRACT

BACKGROUND: More clinical practice need to be performed to verify the toxicity of the hypofractionated radiotherapy (HFRT) combined with PD-1 blockade in lung cancer. This phase I study aimed to investigate the safety and efficacy of nivolumab combined with HFRT in patients with progressive advanced lung cancer following multiline treatment. METHODS: We enrolled 31 patients with advanced lung cancer pathologically confirmed to have progressive disease and treated with first-line or a higher therapy. Selected lesions were treated using HFRT, and nivolumab was administered within 7 days subsequently. Nivolumab was administered once a month following partial remission. Peripheral blood was collected before and after 1 month of treatment to evaluate relevant cytokines between nivolumab responders and non-responders. RESULTS: Overall, 23 patients who completed the treatment were evaluated. Of them, 9 and 14 patients underwent hypofractionated brachytherapy with 30 Gy in a single fraction via percutaneous interstitial implantation of (192)Ir and 40-50 Gy in 5 fractions via stereotactic body radiation therapy, respectively. The median follow-up period was 11 months. At the 1-year follow-up, no patient developed grade ≥ 3 pneumonitis. The overall objective response and complete remission rates were 39.13% and 13.04%, respectively. The 1-year overall survival and median progression-free survival were 60.9% and 6 months, respectively. The plasma levels of interleukin IL-6, IL-10, and IL-17A were significantly reduced after treatment in nivolumab responders. CONCLUSIONS: HFRT could increase the responsivity to nivolumab and reduce its administration frequency. This combination treatment is well tolerated with acceptable toxicity and thus merits further trials to validate benefits. CLINICAL TRIAL REGISTRATION: http://www.chictr.org.cn/index.aspx, identifier ChiCTR-1900027768.

6.
Mol Med Rep ; 23(1)2021 01.
Article in English | MEDLINE | ID: mdl-33179106

ABSTRACT

Triple­negative breast cancer (TNBC) is characterized by strong invasiveness, frequent local recurrence and distant metastasis, with poor prognosis. According to tumor angiogenesis theory, tumor cells can obtain blood supply not only by fusing with host blood vessels, but also by constructing a new vascular system through angiogenesis, so as to continuously obtain nutrients and oxygen supply; this is called vasculogenic mimicry (VM). In our previous study, differential expression profiles of miRNAs were examined with gene chip in TNBC and corresponding paracancer tissues, which demonstrated significant up­regulation of microRNA (miR)­93. Bioinformatics found that the target genes of miR­93 were associated with cell proliferation, invasion and migration. The present study investigated the association between miR­93, epithelial­to­mesenchymal transition (EMT) and VM formation in TNBC cell lines. The results indicated that miR­93 depletion suppressed MDA­MB­231 cell viability, invasion and migration (P<0.001). In addition, knockdown of miR­93 significantly upregulated the expression levels of EMT­associated genes such as E­cadherin and occludin, but downregulated the expression levels of vimentin and N­cadherin in MDA­MB­231 cells. VM formation assay showed a significant decrease in microtubule­forming ability of cells following miR­93 knockdown, which was associated with the occurrence of EMT, suggesting that miR­93 may promote the formation of VM via EMT and may be a therapeutic target for the treatment of TNBC.


Subject(s)
MicroRNAs/genetics , Neovascularization, Pathologic/genetics , Triple Negative Breast Neoplasms/genetics , Up-Regulation , Cell Line, Tumor , Cell Movement , Cell Survival , Epithelial-Mesenchymal Transition , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Oligonucleotide Array Sequence Analysis
7.
PLoS One ; 15(5): e0232174, 2020.
Article in English | MEDLINE | ID: mdl-32380517

ABSTRACT

BACKGROUND: Previous studies have reported on several genetic variants related to breast cancer, but a substantial proportion of mutation loci have not yet been identified. In the current study, we aimed to evaluate the association between single nucleotide polymorphisms (SNPs) of interleukin-10 (IL-10) and susceptibility to breast cancer in Shaanxi Han women in China. METHODS: Six SNPs were genotyped in 530 breast cancer patients and 628 healthy women from the First Affiliated Hospital of Xi'an Jiaotong University Hospital. Odds ratios and 95% confidence intervals were calculated by unconditional logistic regression analysis to assess the association between breast cancer risk and polymorphisms of six loci. RESULTS: Two SNPs, rs3024490 and rs1800871, were found to be significantly different between breast cancer patients and healthy women. These SNPs also increased the risk of breast cancer in co-dominant and dominant models. Moreover, another SNP, rs1554286, was significantly associated with an increased risk of breast cancer in the co-dominant model. Functional assessments indicated that these three variants may influence the expression and transcription factor binding of IL-10. CONCLUSIONS: Our findings suggest that variants of IL-10 may be likelihood risk factors for the development and progression of breast cancer. Future studies should replicate this study and evaluate functional assessments in Chinese Han women and women from other regions.


Subject(s)
Breast Neoplasms/genetics , Interleukin-10/genetics , Adult , Aged , Alleles , Asian People/genetics , Case-Control Studies , China , Ethnicity/genetics , Female , Gene Frequency/genetics , Genetic Predisposition to Disease/genetics , Genotype , Humans , Interleukin-10/metabolism , Middle Aged , Odds Ratio , Polymorphism, Single Nucleotide/genetics , Risk Factors
8.
Oncol Rep ; 42(6): 2499-2511, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31578575

ABSTRACT

The recurrence and metastasis of breast cancer limit the effectiveness of clinical treatments, making them important issues for clinicians to address. Tumor­associated macrophages (TAMs) contribute to regulating the immune system. C­C motif chemokine ligand 5 (CCL5) is an inflammatory chemokine that promotes chemotaxis on cells involved in the immune/inflammatory response. Breast cancer cells that secrete CCL5 act on THP­1 cells, influencing the invasion and metastasis of tumors. However, knowledge remains limited regarding the mechanism underlying the effects of CCL5 on breast cancer cells and TAMs, as well as the mechanisms promoting the migration and invasion of breast cancer. The present study demonstrated that the positive expression of CCL5 was associated with lymph node status and tumor­node­metastasis stage. Treatment with ≥20 ng/ml CCL5 significantly promoted the migration and invasion of MCF­7 and MDA­MB­231 cells. CCL5­small interfering RNA intervention significantly decreased the migration and invasion of the two cell types. In vitro, THP­1 cells were successfully induced to become TAMs, which were then recruited via the chemotactic effects of CCL5. This process was achieved through the co­stimulation of phorbol­12­myristate­13­â€‹acetate, interleukin­4 (IL­4) and IL­13. The nuclear factor­κB (NF­κB) signaling pathway was activated to regulate EMT, as well as the migration and invasion process of MCF­7 cells, when co­cultured with TAMs. We also reported that blocking the expression of CCL5 in vivo may significantly inhibit the growth of human breast cancer xenografts. Therefore, targeting CCL5 may be considered as a novel therapeutic strategy for suppressing the invasion and metastasis of breast cancer.


Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Breast Neoplasms/immunology , Chemokine CCL5/immunology , Lymphatic Metastasis/immunology , Macrophages/immunology , Adult , Aged , Antibodies, Neutralizing/pharmacology , Antibodies, Neutralizing/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Breast/pathology , Breast/surgery , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Chemokine CCL5/antagonists & inhibitors , Chemokine CCL5/metabolism , Chemotaxis/drug effects , Chemotaxis/immunology , Coculture Techniques , Female , Follow-Up Studies , Humans , Lymph Nodes/pathology , Lymphatic Metastasis/pathology , Lymphatic Metastasis/prevention & control , MCF-7 Cells , Mastectomy , Middle Aged , Neoplasm Invasiveness/immunology , Neoplasm Invasiveness/prevention & control , Survival Analysis , Treatment Outcome , Xenograft Model Antitumor Assays
9.
Int J Oncol ; 55(5): 1003-1018, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31545416

ABSTRACT

Human epidermal growth factor receptor (HER)­2­positive breast cancer accounts for ~25% of all breast cancer cases, has a high propensity for relapse, metastasis and drug resistance, and is associated with a poor prognosis. Therefore, it is necessary to develop more effective therapeutic targets for the treatment of HER­2­positive breast cancer. CD44+/CD24­/low is currently the most commonly used marker for breast cancer stem cells (CSCs), which are considered the main cause of drug resistance, relapse and metastasis. In the present study, the ratio of CD44+/CD24­/low cells was almost zero in SK­BR­3 cells; however, it was >90% in MDA­MB­231 cells, as determined by flow cytometry. Since SK­BR­3 and MDA­MB­231 cells both exhibit a strong propensity for invasion and migration, it was hypothesized that there may be other markers of CSCs in SK­BR­3 cells. Therefore, transcriptome sequencing was performed for SK­BR­3 and MDA­MB­231 cells. It was observed that several leukocyte differentiation antigens and other CSC markers were significantly more highly expressed in SK­BR­3 cells. Furthermore, the expression of aldehyde dehydrogenase (ALDH)1A3, CD164 and epithelial cell adhesion molecule (EpCAM) was higher in SK­BR­3 cells compared with in other subtypes of breast cell lines, as determined by reverse transcription­polymerase chain reaction and western blot analysis. In addition, the expression levels of ALDH1A3, ALDH3B2 and EpCAM were higher in HER­2­positive breast cancer compared with in paracancerous tissues and other subtypes of breast cancer, as determined by immunohistochemistry. The expression of ß­catenin in the Wnt signaling pathway was lower in SK­BR­3 cells compared with in MDA­MB­231 cells, which may be used as a prognostic indicator for breast cancer. These findings may help identify novel CSC markers and therapeutic targets for HER­2­positive breast cancer.


Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Lobular/metabolism , Gene Expression Regulation, Neoplastic , Neoplastic Stem Cells/metabolism , Receptor, ErbB-2/metabolism , Adult , Aged , Apoptosis , Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/pathology , Carcinoma, Lobular/genetics , Carcinoma, Lobular/pathology , Cell Proliferation , Female , Follow-Up Studies , Humans , Middle Aged , Neoplastic Stem Cells/pathology , Prognosis , Transcriptome , Tumor Cells, Cultured , Exome Sequencing , Xenograft Model Antitumor Assays
10.
Mol Carcinog ; 58(10): 1822-1831, 2019 10.
Article in English | MEDLINE | ID: mdl-31197899

ABSTRACT

Single nucleotide polymorphisms (SNPs) in interleukin-23 receptor (IL23R) are involved in the pathogenesis of many cancers and autoimmune diseases. IL23R gene is still controversial in the study of esophageal cancer. The aim of this research is to investigate the influence of IL23R SNPs on the risk of esophageal cancer. Five hundred six esophageal cancer and 507 controls frequency matched by age and gender were conducted, and the genotypes were determined by the Agena MassARRAY. Logistic regression analysis was used to evaluate the odd ratios (ORs) and 95% confidence intervals (CIs) of rs1884444 and rs6682925 with susceptibility of esophageal cancer. A total of 30 articles are eligible. Pooled ORs and the 95% CI were calculated using the random-effect model. Database predicts the expression of IL23R gene in esophageal cancer. IL23R rs1884444 allele G decreased the risk of esophageal cancer under allele, genotype, and additive models (allele model: OR = 0.82, 95% CI: 0.68-0.98, P = .032; genotype model: OR = 0.65, 95% CI: 0.44-0.97, P = .035; additive model: OR = 0.82, 95% CI: 0.68-0.98, P = .031). Meta-analysis shown that IL23R rs1884444 increased the risk of overall disease in allele model (OR = 1.16, 95% CI: 1.08-1.25, P < .001), and also increased the risk of gastrointestinal tumor (OR = 1.18, 95% CI: 1.05-1.31, P = .005). The database analysis showed that the expression of IL23R gene was upregulated in esophageal cancer tissues. IL23R rs1884444 may play an important role in the susceptibility of esophageal cancer.


Subject(s)
Esophageal Neoplasms/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Receptors, Interleukin/genetics , Alleles , China , Esophageal Neoplasms/pathology , Female , Genotype , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Risk Factors
11.
BMC Cancer ; 19(1): 446, 2019 May 14.
Article in English | MEDLINE | ID: mdl-31088428

ABSTRACT

BACKGROUND: TIMP-2 gene plays an important role in the development of breast cancer. The present study was conducted to evaluate whether TIMP-2 gene polymorphisms are associated with breast cancer risk in a Han Chinese cohort. METHODS: Six single nucleotide polymorphisms (SNPs) within the TIMP-2 gene in 571 breast cancer and 578 healthy control subjects were genotyped through the Agena MassARRAY. Logistic regression analysis was used to assess the influence of TIMP-2 polymorphisms on breast cancer. Functional annotation of TIMP-2 variants and TIMP-2 expression were analyzed by bioinformatics. RESULTS: Bioinformatics analysis found that rs4789936 was likely to affect transcription factor binding, motifs, DNase footprint, and DNase peaks; and TIMP-2 was under-expressed in breast cancer, the risk allele of rs4789936 was associated with increased expression of TIMP-2 in peripheral blood samples. Importantly, individuals carrying TIMP-2 rs2277698 T allele have a 19% lower risk of breast cancer than individuals with allele C, providing protection (OR = 0.81, 95%CI = 0.67-0.99, p = 0.041). In the breast cancer patients with c-erb positive and PR positive, when the CC genotype was used as a reference, individuals carrying the TT genotype increased the risk of breast cancer. Haplotype analysis showed "TCC" was associated with a reduced risk of breast cancer (OR = 0.79, 95%CI = 0.63-0.97, p = 0.028). CONCLUSION: Our study indicated that TIMP-2 rs2277698 was associated with breast cancer susceptibility.


Subject(s)
Breast Neoplasms/genetics , Down-Regulation , Polymorphism, Single Nucleotide , Tissue Inhibitor of Metalloproteinase-2/genetics , Adult , Breast Neoplasms/ethnology , Case-Control Studies , China/ethnology , Female , Gene Expression Regulation, Neoplastic , Genetic Association Studies , Genetic Predisposition to Disease , Haplotypes , Humans , Logistic Models , Middle Aged
12.
J Cancer Res Clin Oncol ; 145(2): 411-427, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30483898

ABSTRACT

The pre-metastatic niche has been shown to play a critical role in tumor metastasis, and its formation is closely related to the tumor microenvironment. However, the underlying molecular mechanisms remain unclear. In the present study, we successfully established a mouse model of lung metastasis using luciferase-expressing MDA-MB-435s cells. In this model, recruitment of vascular endothelial growth factor receptor-1 (VEGFR1)+CD133+ hematopoietic progenitor cells (HPCs) was gradually increased in lung but gradually decreased after the formation of tumor colonies in lung. We also established a highly metastatic MDA-MB-435s (MDA-MB-435s-HM) cell line from the mouse model. Changes in protein profiles in different culture conditions were investigated by protein microarray analysis. The levels of CXC chemokine ligand 16, interleukin (IL)-2Rα, IL-2Rγ, matrix metalloproteinase (MMP)-1, MMP-9, platelet-derived growth factor receptor (PDGFR)-α, stromal cell-derived factor (SDF)-1α, transforming growth factor (TGF)-ß, platelet endothelial cell adhesion molecule (PECAM)-1 and vascular endothelial (VE)-cadherin were significantly greater (> fivefold) in the culture medium from MDA-MB-435s-HM cells than in that from MDA-MB-435s cells. Moreover, the levels of MMP-9, PDGFR-α, and PECAM-1 were significantly greater in the co-culture medium of MDA-MB-435s-HM cells and CD133+ HPCs than in that from MDA-MB-435s-HM cells. Differentially expressed proteins were validated by enzyme-linked immunosorbent assay, and expression of their transcripts was confirmed by quantitative real-time polymerase chain reaction. Moreover, inhibition of MMP-9, PDGFR-α, and PECAM-1 by their specific inhibitors or antibodies significantly decreased cell migration, delayed lung metastasis, and decreased recruitment of VEGFR1+CD133+ HPCs into lung. Intra-hepatic growth of HPCs enhanced the invasive growth of MDA-MB-435s-HM cells in the liver. Our data indicate that VEGFR1+CD133+ HPCs contribute to lung metastasis.


Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/pathology , Hematopoietic Stem Cells , Lung Neoplasms/secondary , Vascular Endothelial Growth Factor Receptor-1/metabolism , Animals , Apoptosis , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Cell Movement , Cell Proliferation , Female , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Invasiveness , Protein Array Analysis , Small Molecule Libraries/pharmacology , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
13.
Oncol Rep ; 40(6): 3297-3312, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30542711

ABSTRACT

Networks of nanotubes and microtubules are highly valued in cellular communication, and collective cancer movement has been revealed to be associated with cell information exchange. In the present study, cellular communication was demonstrated to participate in mammosphere growth, differentiation and collective invasion. By promoting differentiation, networks of cells and microtubule­like structures were verified. Analyses of cell cycle progression, stemness markers and gene expression indicated that mammospheres had collective characteristics of stemness and differentiation. Invasion assays revealed that networks of microtubule­like structures promoted collective invasion. Conversely, using anti­angiogenic intervention, the growth of stem­like mammospheres and cellular communication links were effectively inhibited. In vivo experiments revealed that cellular communication promoted tumor growth and metastasis through the formation of nodular fusion, cluttered microtubule­like structures and cancer stem cells, as well as vascular niches. In conclusion, the present results demonstrated that a network of cells and structures were largely present in mammosphere cellular communication in vitro and in vivo. Therefore, blocking cellular communication may prove beneficial in halting the progression of mammary tumors.


Subject(s)
Breast Neoplasms/pathology , Cell Communication/physiology , Microtubules/pathology , Neovascularization, Pathologic/pathology , Spheroids, Cellular/pathology , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Animals , Bevacizumab/pharmacology , Bevacizumab/therapeutic use , Breast Neoplasms/blood supply , Breast Neoplasms/drug therapy , Cell Culture Techniques , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/physiology , Female , Humans , Mice , Mice, Nude , Microtubules/drug effects , Neoplasm Invasiveness/pathology , Neoplasm Invasiveness/prevention & control , Neoplastic Stem Cells/pathology , Neovascularization, Pathologic/drug therapy , Spheroids, Cellular/cytology , Spheroids, Cellular/drug effects , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/metabolism , Xenograft Model Antitumor Assays
14.
Cancer Sci ; 109(12): 3865-3873, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30259603

ABSTRACT

Thymoquinone (TQ, 2-methyl-5-isopropyl-1,4-benzoquinone), a bioactive constituent extracted from the seeds of Nigella sativa, has been proved to exert anti-tumor efficiency in various cancers. Autophagy is a self-digestion phenomenon, and its role in tumor formation and progression remains controversial. In the present study, we investigated the effects of TQ on renal cell cancer (RCC) cell lines (786-O and ACHN) using wound healing assay, transwell assay and western blot analysis. We found that TQ effectively inhibited the metastatic capacity of RCC cells in vitro, which was also verified in a xenograft model. Meanwhile, we observed LC3 puncta and detected the expression of LC3 in TQ-treated RCC cells, and then found that autophagy was induced by TQ in 786-O and ACHN cell lines. In addition, TQ inhibited the migration and invasion as well as the EMT in RCC cells in an autophagy-dependent manner. To further explore the underlying mechanism, we detected the AMPK/mTOR signaling pathway. The results indicated that TQ inhibited the metastasis of RCC cells by inducing autophagy via AMPK/mTOR signaling pathway. In conclusion, our findings provide a novel therapeutic strategy that aims at TQ-induced autophagy in RCC treatment.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Benzoquinones/administration & dosage , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , TOR Serine-Threonine Kinases/metabolism , Animals , Autophagy , Benzoquinones/pharmacology , Carcinoma, Renal Cell/metabolism , Cell Line, Tumor , Cell Movement , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Kidney Neoplasms/metabolism , Mice , Neoplasm Metastasis , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
15.
Cancer Sci ; 109(5): 1503-1512, 2018 May.
Article in English | MEDLINE | ID: mdl-29575477

ABSTRACT

Distinguishing the surface markers of cancer stem cells (CSCs) is a useful method for early diagnosis and treatment of tumors, as CSCs may participate in tumorigenesis and metastasis by migrating into the circulatory system. However, the potential targets of CSCs are expressed at low levels in the natural state and are always changing. Thus, dynamic screening has been reported to be an effective measure for exploring CSC markers. In recent years, diverse single-chain variable fragments (scFvs) have been widely used in immunotherapy. In this study, we determined that the scFvs, screened using RD, had a high affinity to microspheres and could inhibit their progression. We also observed that the selected scFvs underwent evolution in vitro, and antitumor-associated proteins were successfully expressed. Combined with chemotherapy, the scFvs had a synergistic effect on the inhibition of the microspheres' progression in vitro and in vivo, which could be ascribed to their high affinity for stem-like cells and the inhibition of the microspheres' collective behaviors. In addition, proteins inhibiting CD44+ /CD24+ and MAPK were involved. Our data indicated that dynamic screening of the scFvs in a natural state was of great significance in the inhibition of the microspheres in vitro and in vivo.


Subject(s)
Breast Neoplasms/drug therapy , Neoplastic Stem Cells/drug effects , Ribosomes/genetics , Single-Chain Antibodies/pharmacology , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Surface Display Techniques , Drug Synergism , Drug Therapy , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Microspheres , Neoplastic Stem Cells/metabolism , Ribosomes/immunology , Xenograft Model Antitumor Assays
16.
J Cancer Res Ther ; 13(5): 778-784, 2017.
Article in English | MEDLINE | ID: mdl-29237903

ABSTRACT

BACKGROUND: Bone metastases (BMs) are common for breast cancer patients. However, triple-negative breast cancer (TNBC) with BM is relatively rare and few data on it are available. In this study, we aim to investigate the incidence and clinicopathological features and to evaluate the prognosis of TNBC patients with BM. MATERIALS AND METHODS: A total of 616 patients with TNBC (120 out of them had BM) between 2007 and 2011 were involved in the study. Clinicopathological characteristics were statistically analyzed. RESULTS: A total of 120 (19.5%) patients developed BM with a median age of 53.1 years. The median overall survival (OS) was 40 months, and the 5-year OS rate was 37.3% in TNBC patients with BM. Patients without BM had longer survival time than those with BM (P < 0.001). In the univariate analysis, lymph nodes metastasis, tumor Stage III-IV, multiple BMs, and coexistence of visceral metastasis were correlated to a poor prognosis (P = 0.020; P < 0.001; P < 0.001; P < 0.001). Moreover, multivariate analysis demonstrated that tumor stage, number of BM, and visceral metastasis were significantly independent factors for OS (P < 0.001; P < 0.001; P < 0.001). CONCLUSIONS: Tumor Stage III-IV, multiple BMs, or coexistence of visceral metastasis were associated with poor prognosis for OS in TNBC patients with BM. These associations may contribute to prevention, early detection, and goal-directed treatment of bone metastatic TNBC.


Subject(s)
Bone Neoplasms/pathology , Carcinoma/pathology , Neoplasm Recurrence, Local/epidemiology , Triple Negative Breast Neoplasms/pathology , Adult , Aged , Bone Neoplasms/epidemiology , Bone Neoplasms/secondary , Bone Neoplasms/therapy , Carcinoma/epidemiology , Carcinoma/secondary , Carcinoma/therapy , Disease-Free Survival , Female , Follow-Up Studies , Humans , Incidence , Lymphatic Metastasis , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Prognosis , Receptor, ErbB-2 , Retrospective Studies , Survival Rate , Time Factors , Triple Negative Breast Neoplasms/epidemiology , Triple Negative Breast Neoplasms/therapy
17.
Biochem Biophys Res Commun ; 490(3): 969-976, 2017 08 26.
Article in English | MEDLINE | ID: mdl-28666869

ABSTRACT

Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the effect of Celecoxib, a COX-2 inhibitor on two molecular breast cancer subtypes-MDA-MB-231 and SK-BR-3. Firstly, MDA-MB-231 and SK-BR-3 cells were treated with various concentration of Celecoxib for 24 and 48 h. Celecoxib-inhibition of NF-κB (p52 and p65) transcriptional activity and effect of Caspase 3 pathway were examined by western blotting. COX-2 mRNA was assessed by RT-PCR. Cell viability was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazoliumbromide (MTT) assay. Both cell cycle profiles and apoptosis were analyzed using flow cytometry. We found that Celecoxib inhibited the proliferation of the MDA-MB-231 cell line in a dose-time dependent manner versus SK-BR-3 in a dose dependent manner only (p < 0.05). Celecoxib induced apoptosis of the MDA-MB-231 and SK-BR-3 cell lines in a dose-time dependent manner (p < 0.05) with more mean apoptotic cells in MDA-MB-231 than SK-BR-3. Significant cell-cycle arrest at the G1 phase in the MDA-MB-231 versus G2 phase in SK-BR-3 cell lines. NF-κB (p52 and p65) and COX-2 expressions were downregulated in a dose dependent manner, while Caspase 3 expression was upregulated in both cell lines. In this present study, our data indicated Celecoxib might affect each breast cancer subtype independently. Therefore, when using Celecoxib in treatment of breast cancer, it is imperative to consider the subtype of breast cancer on a molecular level.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Celecoxib/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , NF-kappa B/metabolism , Signal Transduction/drug effects , Breast/drug effects , Breast/metabolism , Breast/pathology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Caspase 3/metabolism , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Down-Regulation/drug effects , Female , Humans
18.
Tumour Biol ; 39(5): 1010428317701649, 2017 May.
Article in English | MEDLINE | ID: mdl-28475015

ABSTRACT

Fibrinogen Asn-Gly-Arg motif can specifically recognize and bind to Aminopeptidase N (CD13) on vascular endothelial cells in newly formed tumor vessels. Adipose-derived stem cells can serve as ideal vectors for gene therapy because of their ability of migrating to tumor tissues. First, this study was aimed to design a new peptide (CNGRCLLII(KLAKLAK)2) named CNAK which contains cyclic Asn-Gly-Arg motif and test its biological activity against human umbilical vein endothelial cells. Second, we aimed to construct stably transfected adipose-derived stem cells which express the CNAK peptide and investigate their anti-angiogenic activity in vivo. Adipose-derived stem cells were employed to localize CNAK on vascular endothelial cells in tumors based on their homing property. First of all, the new peptide was synthesized, which effectively entered into CD13+ human umbilical vein endothelial cells and showed cytotoxicity against human umbilical vein endothelial cells. The peptide induced apoptosis of human umbilical vein endothelial cells in a time- and dose-dependent manner, inhibited the expression of Bcl-2, and promoted the expression of Caspase-3 in human umbilical vein endothelial cells. Furthermore, the migration and tube formation of human umbilical vein endothelial cells were inhibited by CNAK. Primary adipose-derived stem cells were then isolated and identified. Stably transfected adipose-derived stem cells which express CNAK peptide (CNAK-ASCs) were successfully established, and the migration of CNAK-ASCs was assessed. In vivo, CNAK-ASCs were found to inhibit the growth and angiogenesis of breast cancer xenografts. This effect may be through inhibiting the secretion of matrix metalloproteinase-2 and membrane type 1-matrix metalloproteinase in vivo. It was also found that CNAK-ASCs reduced the quantity of breast cancer stem cells in tumor tissues. Our data suggested that the new peptide CNAK containing Asn-Gly-Arg motif had anti-angiogenic activity in vitro and in vivo.


Subject(s)
Apoptosis/drug effects , Breast Neoplasms/therapy , Genetic Therapy , Oligopeptides/administration & dosage , Peptides/administration & dosage , Adipose Tissue/cytology , Animals , Apoptosis/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , CD13 Antigens/genetics , Cell Line, Tumor , Female , Fibrinogen/chemistry , Fibrinogen/genetics , Fibrinogen/therapeutic use , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Mice , Oligopeptides/chemistry , Oligopeptides/genetics , Peptides/chemistry , Peptides/genetics , Stem Cells/chemistry , Stem Cells/cytology , Transfection , Xenograft Model Antitumor Assays
19.
Oncol Lett ; 13(3): 1745-1752, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28454319

ABSTRACT

Vascular endothelial growth factor (VEGF)165 is one of the most abundant and potent angiogenic factors in both physiological and pathological conditions. However, the function and mechanism of VEGF165 in tumors and their environment remain to be elucidated. In the present study, a lentivirus vector (LV) that contained the VEGF165-enhanced green fluorescent protein (EGFP) fusion gene was constructed and transfected into the human breast cancer cell line MCF-7. Following transfection, the expression of VEGF165 in MCF-7 cells was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Further cellular localization of VEGF165 was observed through fluorescence microscopy. The titer of the recombinant lentivirus was 5.44×107 TU/ml in the LV-VEGF165-EGFP group and 5.00×108 TU/ml in the LV-EGFP negative control group. RT-qPCR and western blotting demonstrated that the expression of VEGF165 was significantly increased in the LV-VEGF165-EGFP group compared with the control group. The present study lays the foundation for in vitro and in vivo studies on tumor cell derived-VEGF165. Furthermore, the present fusion gene expression vector may provide a potential approach for gene therapy treatment of cancer and other diseases that require regulation of angiogenesis.

20.
Oncol Lett ; 13(2): 579-586, 2017 Feb.
Article in English | MEDLINE | ID: mdl-28356932

ABSTRACT

Gene therapy is one of the most promising potential therapeutic strategies for many types of cancer. Cell apoptosis is an active, programmed physiological process of the body, and its disruption has been closely associated with the occurrence of tumor development. Apoptin is known to induce tumor cell apoptosis. In the present study, the MCF-7 breast cancer cell line was transfected with a human serum albumin (HSA) and apoptin expressing plasmid [HSA-polyethylenimine (PEI)-pcDNA-Apoptin]. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to detect the expression of apoptin in the transfected MCF-7 cells, while MTT assays and flow cytometry were conducted to detect cell viability and apoptosis. Furthermore, hematoxylin and eosin staining was used to observe the morphology of xenografts from mice injected with MCF-7 cells. It was demonstrated that the HSA-PEI-pcDNA-Apoptin expression plasmid resulted in the upregulation of apoptin in MCF-7 cells, and efficiently suppressed breast tumor growth in vivo. These findings indicated that the use of HSA as an apoptin expression vector has potential therapeutic benefits for cancer and confirms the requirement for the further evaluation of apoptin in clinical trials.

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