共查询到20条相似文献,搜索用时 15 毫秒
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Background
Diosgenin, a steroidal saponin obtained from fenugreek (Trigonella foenum graecum), was found to exert anti-carcinogenic properties, such as inhibiting proliferation and inducing apoptosis in a variety of tumor cells. However, the effect of diosgenin on cancer metastasis remains unclear. The aim of the study is to examine the effect of diosgenin on migration and invasion in human prostate cancer PC-3 cells.Methods and Principal Findings
Diosgenin inhibited proliferation of PC-3 cells in a dose-dependent manner. When treated with non-toxic doses of diosgenin, cell migration and invasion were markedly suppressed by in vitro wound healing assay and Boyden chamber invasion assay, respectively. Furthermore, diosgenin reduced the activities of matrix metalloproteinase-2 (MMP-2) and MMP-9 by gelatin zymography assay. The mRNA level of MMP-2, -9, -7 and extracellular inducer of matrix metalloproteinase (EMMPRIN) were also suppressed while tissue inhibitor of metalloproteinase-2 (TIMP-2) was increased by diosgenin. In addition, diosgenin abolished the expression of vascular endothelial growth factor (VEGF) in PC-3 cells and tube formation of endothelial cells. Our immunoblotting assays indicated that diosgenin potently suppressed the phosphorylation of phosphatidylinositide-3 kinase (PI3K), Akt, extracellular signal regulating kinase (ERK) and c-Jun N-terminal kinase (JNK). In addition, diosgenin significantly decreased the nuclear level of nuclear factor kappa B (NF-κB), suggesting that diosgenin inhibited NF-κB activity.Conclusion/Significance
The results suggested that diosgenin inhibited migration and invasion of PC-3 cells by reducing MMPs expression. It also inhibited ERK, JNK and PI3K/Akt signaling pathways as well as NF-κB activity. These findings reveal new therapeutic potential for diosgenin in anti-metastatic therapy. 相似文献4.
Objective
Metastasis is the most common cause of death of prostate cancer patients. Identification of specific metastasis biomarkers and novel therapeutic targets is considered essential for improved prognosis and management of the disease. MicroRNAs (miRNAs) form a class of non-coding small RNA molecules considered to be key regulators of gene expression. Their dysregulation has been shown to play a role in cancer onset, progression and metastasis, and miRNAs represent a promising new class of cancer biomarkers. The objective of this study was to identify down- and up-regulated miRNAs in prostate cancer that could provide potential biomarkers and/or therapeutic targets for prostate cancer metastasis.Methods
Next generation sequencing technology was applied to identify differentially expressed miRNAs in a transplantable metastatic versus a non-metastatic prostate cancer xenograft line, both derived from one patient''s primary cancer. The xenografts were developed via subrenal capsule grafting of cancer tissue into NOD/SCID mice, a methodology that tends to preserve properties of the original cancers (e.g., tumor heterogeneity, genetic profiles).Results
Differentially expressed known miRNAs, isomiRs and 36 novel miRNAs were identified. A number of these miRNAs (21/104) have previously been reported to show similar down- or up-regulation in prostate cancers relative to normal prostate tissue, and some of them (e.g., miR-16, miR-34a, miR-126*, miR-145, miR-205) have been linked to prostate cancer metastasis, supporting the validity of the analytical approach.Conclusions
The use of metastatic and non-metastatic prostate cancer subrenal capsule xenografts derived from one patient''s cancer makes it likely that the differentially expressed miRNAs identified in this study include potential biomarkers and/or therapeutic targets for human prostate cancer metastasis. 相似文献5.
Nicholas Erho Anamaria Crisan Ismael A. Vergara Anirban P. Mitra Mercedeh Ghadessi Christine Buerki Eric J. Bergstralh Thomas Kollmeyer Stephanie Fink Zaid Haddad Benedikt Zimmermann Thomas Sierocinski Karla V. Ballman Timothy J. Triche Peter C. Black R. Jeffrey Karnes George Klee Elai Davicioni Robert B. Jenkins 《PloS one》2013,8(6)
Purpose
Clinicopathologic features and biochemical recurrence are sensitive, but not specific, predictors of metastatic disease and lethal prostate cancer. We hypothesize that a genomic expression signature detected in the primary tumor represents true biological potential of aggressive disease and provides improved prediction of early prostate cancer metastasis.Methods
A nested case-control design was used to select 639 patients from the Mayo Clinic tumor registry who underwent radical prostatectomy between 1987 and 2001. A genomic classifier (GC) was developed by modeling differential RNA expression using 1.4 million feature high-density expression arrays of men enriched for rising PSA after prostatectomy, including 213 who experienced early clinical metastasis after biochemical recurrence. A training set was used to develop a random forest classifier of 22 markers to predict for cases - men with early clinical metastasis after rising PSA. Performance of GC was compared to prognostic factors such as Gleason score and previous gene expression signatures in a withheld validation set.Results
Expression profiles were generated from 545 unique patient samples, with median follow-up of 16.9 years. GC achieved an area under the receiver operating characteristic curve of 0.75 (0.67–0.83) in validation, outperforming clinical variables and gene signatures. GC was the only significant prognostic factor in multivariable analyses. Within Gleason score groups, cases with high GC scores experienced earlier death from prostate cancer and reduced overall survival. The markers in the classifier were found to be associated with a number of key biological processes in prostate cancer metastatic disease progression.Conclusion
A genomic classifier was developed and validated in a large patient cohort enriched with prostate cancer metastasis patients and a rising PSA that went on to experience metastatic disease. This early metastasis prediction model based on genomic expression in the primary tumor may be useful for identification of aggressive prostate cancer. 相似文献6.
Lincoln D Nadauld Sarah Garcia Georges Natsoulis John M Bell Laura Miotke Erik S Hopmans Hua Xu Reetesh K Pai Curt Palm John F Regan Hao Chen Patrick Flaherty Akifumi Ootani Nancy R Zhang James M Ford Calvin J Kuo Hanlee P Ji 《Genome biology》2014,15(8)
Background
Gastric cancer is the second-leading cause of global cancer deaths, with metastatic disease representing the primary cause of mortality. To identify candidate drivers involved in oncogenesis and tumor evolution, we conduct an extensive genome sequencing analysis of metastatic progression in a diffuse gastric cancer. This involves a comparison between a primary tumor from a hereditary diffuse gastric cancer syndrome proband and its recurrence as an ovarian metastasis.Results
Both the primary tumor and ovarian metastasis have common biallelic loss-of-function of both the CDH1 and TP53 tumor suppressors, indicating a common genetic origin. While the primary tumor exhibits amplification of the Fibroblast growth factor receptor 2 (FGFR2) gene, the metastasis notably lacks FGFR2 amplification but rather possesses unique biallelic alterations of Transforming growth factor-beta receptor 2 (TGFBR2), indicating the divergent in vivo evolution of a TGFBR2-mutant metastatic clonal population in this patient. As TGFBR2 mutations have not previously been functionally validated in gastric cancer, we modeled the metastatic potential of TGFBR2 loss in a murine three-dimensional primary gastric organoid culture. The Tgfbr2 shRNA knockdown within Cdh1-/-; Tp53-/- organoids generates invasion in vitro and robust metastatic tumorigenicity in vivo, confirming Tgfbr2 metastasis suppressor activity.Conclusions
We document the metastatic differentiation and genetic heterogeneity of diffuse gastric cancer and reveal the potential metastatic role of TGFBR2 loss-of-function. In support of this study, we apply a murine primary organoid culture method capable of recapitulating in vivo metastatic gastric cancer. Overall, we describe an integrated approach to identify and functionally validate putative cancer drivers involved in metastasis.Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0428-9) contains supplementary material, which is available to authorized users. 相似文献7.
Gregory KJ Zhao B Bielenberg DR Dridi S Wu J Jiang W Huang B Pirie-Shepherd S Fannon M 《PloS one》2010,5(10):e13428
Background
Vitamin D binding protein-macrophage activating factor (DBP-maf) is a potent inhibitor of tumor growth. Its activity, however, has been attributed to indirect mechanisms such as boosting the immune response by activating macrophages and inhibiting the blood vessel growth necessary for the growth of tumors.Methods and Findings
In this study we show for the first time that DBP-maf exhibits a direct and potent effect on prostate tumor cells in the absence of macrophages. DBP-maf demonstrated inhibitory activity in proliferation studies of both LNCaP and PC3 prostate cancer cell lines as well as metastatic clones of these cells. Flow cytometry studies with annexin V and propidium iodide showed that this inhibitory activity is not due to apoptosis or cell death. DBP-maf also had the ability to inhibit migration of prostate cancer cells in vitro. Finally, DBP-maf was shown to cause a reduction in urokinase plasminogen activator receptor (uPAR) expression in prostate tumor cells. There is evidence that activation of this receptor correlates with tumor metastasis.Conclusions
These studies show strong inhibitory activity of DBP-maf on prostate tumor cells independent of its macrophage activation. 相似文献8.
Yeona Cho Jee Suk Chang Koon Ho Rha Sung Joon Hong Young Deuk Choi Won Sik Ham Jun Won Kim Jaeho Cho 《PloS one》2016,11(1)
Purpose/Objectives
Treatment of the primary tumor reportedly improves survival in several types of metastatic cancer. We herein evaluated the efficacy and toxicity of radiotherapy for the primary tumor in prostate cancer with metastasis.Materials/Methods
The study cohort included 140 men with metastatic prostate cancer at initial diagnosis. Metastatic sites were divided into 4 groups as follows: solitary bone, 2–4 bones, ≥5 bones, and visceral organs. Patient, tumor, and treatment characteristics, and clinical outcomes were compared between patients treated with (prostate radiotherapy [PRT] group) or without radiotherapy to the primary tumor.Results
Patients in PRT group presented with a statistically significantly younger age (p = .02), whereas other characteristics showed no significant difference. Overall survival (OS) and biochemical failure-free survival (BCFFS) were improved in PRT patients (3-year OS: 69% vs. 43%, p = 0.004; 3-year BCFFS: 52% vs. 16%, p = 0.002). Multivariate analysis identified PRT as a significant predictor of both OS (hazard ratio [HR] = 0.43, p = 0.015). None of the 38 PRT patients experienced severe (grade ≥3) genitourinary or gastrointestinal toxicity.Conclusions
Our data suggest that radiotherapy to the primary tumor was associated with improved OS and BCFFS in metastatic prostate cancer. The results of this study warrant prospective controlled clinical trials of this approach in stage IV prostate cancer patients with limited extent of bone metastasis and good performance status. 相似文献9.
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Sajni Josson Yasuhiro Matsuoka Murali Gururajan Takeo Nomura Wen-Chin Huang Xiaojian Yang Jin-tai Lin Roger Bridgman Chia-Yi Chu Peter A. Johnstone Majd Zayzafoon Peizhen Hu Haiyen Zhau Dror Berel Andre Rogatko Leland W. K. Chung 《PloS one》2013,8(7)
Background
Bone metastasis is the most lethal form of several cancers. The β2-microglobulin (β2-M)/hemochromatosis (HFE) complex plays an important role in cancer development and bone metastasis. We demonstrated previously that overexpression of β2-M in prostate, breast, lung and renal cancer leads to increased bone metastasis in mouse models. Therefore, we hypothesized that β2-M is a rational target to treat prostate cancer bone metastasis.Results
In this study, we demonstrate the role of β2-M and its binding partner, HFE, in modulating radiation sensitivity and chemo-sensitivity of prostate cancer. By genetic deletion of β2-M or HFE or using an anti-β2-M antibody (Ab), we demonstrate that prostate cancer cells are sensitive to radiation in vitro and in vivo. Inhibition of β2-M or HFE sensitized prostate cancer cells to radiation by increasing iron and reactive oxygen species and decreasing DNA repair and stress response proteins. Using xenograft mouse model, we demonstrate that anti-β2-M Ab sensitizes prostate cancer cells to radiation treatment. Additionally, anti-β2-M Ab was able to prevent tumor growth in an immunocompetent spontaneous prostate cancer mouse model. Since bone metastasis is lethal, we used a bone xenograft model to test the ability of anti-β2-M Ab and radiation to block tumor growth in the bone. Combination treatment significantly prevented tumor growth in the bone xenograft model by inhibiting β2-M and inducing iron overload. In addition to radiation sensitive effects, inhibition of β2-M sensitized prostate cancer cells to chemotherapeutic agents.Conclusion
Since prostate cancer bone metastatic patients have high β2-M in the tumor tissue and in the secreted form, targeting β2-M with anti-β2-M Ab is a promising therapeutic agent. Additionally, inhibition of β2-M sensitizes cancer cells to clinically used therapies such as radiation by inducing iron overload and decreasing DNA repair enzymes. 相似文献11.
Awad O Yustein JT Shah P Gul N Katuri V O'Neill A Kong Y Brown ML Toretsky JA Loeb DM 《PloS one》2010,5(11):e13943
Background
Cancer stem cells are a chemotherapy-resistant population capable of self-renewal and of regenerating the bulk tumor, thereby causing relapse and patient death. Ewing''s sarcoma, the second most common form of bone tumor in adolescents and young adults, follows a clinical pattern consistent with the Cancer Stem Cell model – remission is easily achieved, even for patients with metastatic disease, but relapse remains frequent and is usually fatal.Methodology/Principal Findings
We have isolated a subpopulation of Ewing''s sarcoma cells, from both human cell lines and human xenografts grown in immune deficient mice, which express high aldehyde dehydrogenase (ALDHhigh) activity and are enriched for clonogenicity, sphere-formation, and tumor initiation. The ALDHhigh cells are resistant to chemotherapy in vitro, but this can be overcome by the ATP binding cassette transport protein inhibitor, verapamil. Importantly, these cells are not resistant to YK-4-279, a small molecule inhibitor of EWS-FLI1 that is selectively toxic to Ewing''s sarcoma cells both in vitro and in vivo.Conclusions/Significance
Ewing''s sarcoma contains an ALDHhigh stem-like population of chemotherapy-resistant cells that retain sensitivity to EWS-FLI1 inhibition. Inhibiting the EWS-FLI1 oncoprotein may prove to be an effective means of improving patient outcomes by targeting Ewing''s sarcoma stem cells that survive standard chemotherapy. 相似文献12.
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Background
Metastasis is the major cause of cancer related death and targeting the process of metastasis has been proposed as a strategy to combat cancer. Therefore, to develop candidate drugs that target the process of metastasis is very important. In the preliminary studies, we found that schisandrin B (Sch B), a naturally-occurring dibenzocyclooctadiene lignan with very low toxicity, could suppress cancer metastasis.Methodology
BALB/c mice were inoculated subcutaneously or injected via tail vein with murine breast cancer 4T1 cells. Mice were divided into Sch B-treated and control groups. The primary tumor growth, local invasion, lung and bone metastasis, and survival time were monitored. Tumor biopsies were examined immuno- and histo-pathologically. The inhibitory activity of Sch B on TGF-β induced epithelial-mesenchymal transition (EMT) of 4T1 and primary human breast cancer cells was assayed.Principal Findings
Sch B significantly suppressed the spontaneous lung and bone metastasis of 4T1 cells inoculated s.c. without significant effect on primary tumor growth and significantly extended the survival time of these mice. Sch B did not inhibit lung metastasis of 4T1 cells that were injected via tail vein. Delayed start of treatment with Sch B in mice with pre-existing tumors did not reduce lung metastasis. These results suggested that Sch B acted at the step of local invasion. Histopathological evidences demonstrated that the primary tumors in Sch B group were significantly less locally invasive than control tumors. In vitro assays demonstrated that Sch B could inhibit TGF-β induced EMT of 4T1 cells and of primary human breast cancer cells.Conclusions
Sch B significantly suppresses the lung and bone metastasis of 4T1 cells via inhibiting EMT, suggesting its potential application in targeting the process of cancer metastasis. 相似文献14.
Background
The -160C/A polymorphism (rs16260) of E-cadherin, a tumor repressor gene, has been shown to be a tumor susceptibility allele for various types of cancers. Because the significance of this polymorphism to cancer risk has been recognized, there are increasing studies investigating -160C/A in different types of cancers and ethnic populations. However, there is still uncertainty about the level of risk for a variety of cancers.Methods
To resolve the controversial question raised by these studies as of March 2012 and provide more statistical power for detecting the significance of -160C/A, we performed a meta-analysis of 47 case-control studies in 16 types of cancers (18,194 cases and 20,207 controls). A meta-regression model and subgroup analysis were employed to identify the source of heterogeneity. Publication bias was evaluated, and sensitivity analysis and cumulative evidence assessment were also performed.Results
Using fixed- and random-effects models, the -160AA homozygote was more susceptible to urothelial cancer compared with the -160CA heterozygote. Additionally, the -160A allele is an ethnicity-dependent risk factor for prostate and colorectal cancers. Carriers of the -160A allele in Asians and Europeans were more susceptible to prostate cancer, whereas their North American counterparts seemed tolerant. The -160AA homozygote plays a protective role for Europeans who develop colorectal cancer. The stability of these observations was confirmed by a one-way sensitivity analysis. However, the cumulative evidence for all cancer types was considered ‘weak’ using the Venice guidelines.Conclusions
A meta-analysis indicated that the -160A allele of E-cadherin provides a higher risk for the development of prostate and urothelial cancers and a protective role for colorectal cancer in an ethnicity-dependent manner. 相似文献15.
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Dongmei Diao Zhe Wang Yao Cheng Hao Zhang Qi Guo Yongchun Song Kun Zhu Kang Li Di Liu Chengxue Dang 《PloS one》2014,9(7)
Background
Plasma D-dimer levels have been shown to be high in advanced tumor stage patients and can be used to predict clinical outcome in cancer patients. As most advanced tumor stage patients exhibit asymptomatic metastasis, which contributes to early tumor recurrence after surgery, we hypothesized that plasma D-dimer levels can be used to predict patients with potential metastasis.Methods
We enrolled 1042 primary gastric cancer patients in three multiple cancer centers in Northwest China and examined plasma D-dimer levels using the latex-enhanced immunoturbidimetric assay (LEIA) method. Plasma D-dimer levels were compared with the clinicopathological characteristics in this large-scale case-control study with follow up. We also performed regular follow-up studies for 395 patients to analyze the 2-year survival rate and early tumor recurrence.Results
In this large-scale clinical study, we found that plasma D-dimer levels were increased in patients with distant metastasis and especially hematogenous metastasis patients. The cut-off value of the D-dimer levels was determined to be 1.5 mg/ml based on the ROC curve, and the sensitivity and specificity for metastasis prediction were 61.9% and 86.6%, respectively. Additionally, patients with high D-dimer levels displayed early tumor recurrence and poor outcome during the follow-up study.Conclusion
Plasma D-dimer may represent an easy to measure and lower cost marker for the testing of gastric cancer patients to predict asymptomatic hematogenous metastasis. 相似文献17.
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Salma Khan Jessica M. S. Jutzy Malyn May A. Valenzuela David Turay Jonathan R. Aspe Arjun Ashok Saied Mirshahidi Dan Mercola Michael B. Lilly Nathan R. Wall 《PloS one》2012,7(10)
Background
Survivin is expressed in prostate cancer (PCa), and its downregulation sensitizes PCa cells to chemotherapeutic agents in vitro and in vivo. Small membrane-bound vesicles called exosomes, secreted from the endosomal membrane compartment, contain RNA and protein that they readily transport via exosome internalization into recipient cells. Recent progress has shown that tumor-derived exosomes play multiple roles in tumor growth and metastasis and may produce these functions via immune escape, tumor invasion and angiogenesis. Furthermore, exosome analysis may provide novel biomarkers to diagnose or monitor PCa treatment.Methods
Exosomes were purified from the plasma and serum from 39 PCa patients, 20 BPH patients, 8 prostate cancer recurrent and 16 healthy controls using ultracentrifugation and their quantities and qualities were quantified and visualized from both the plasma and the purified exosomes using ELISA and Western blotting, respectively.Results
Survivin was significantly increased in the tumor-derived samples, compared to those from BPH and controls with virtually no difference in the quantity of Survivin detected in exosomes collected from newly diagnosed patients exhibiting low (six) or high (nine) Gleason scores. Exosome Survivin levels were also higher in patients that had relapsed on chemotherapy compared to controls.Conclusions
These studies demonstrate that Survivin exists in plasma exosomes from both normal, BPH and PCa subjects. The relative amounts of exosomal Survivin in PCa plasma was significantly higher than in those with pre-inflammatory BPH and control plasma. This differential expression of exosomal Survivin was seen with both newly diagnosed and advanced PCa subjects with high or low-grade cancers. Analysis of plasma exosomal Survivin levels may offer a convenient tool for diagnosing or monitoring PCa and may, as it is elevated in low as well as high Gleason scored samples, be used for early detection. 相似文献20.