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Sample records for cell migration metastasis

  1. STRIPAK components determine mode of cancer cell migration and metastasis

    DEFF Research Database (Denmark)

    Madsen, Chris D; Hooper, Steven; Tozluoglu, Melda;

    2015-01-01

    and MST4 kinases, which promote the co-localization of the contractile actomyosin machinery with the Ezrin/Radixin/Moesin family proteins by phosphorylating the inhibitors of PPP1CB, PPP1R14A-D. Using computational modelling, in vitro cell migration assays and in vivo breast cancer metastasis assays we...

  2. Angiotensin II facilitates breast cancer cell migration and metastasis.

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    Sylvie Rodrigues-Ferreira

    Full Text Available Breast cancer metastasis is a leading cause of death by malignancy in women worldwide. Efforts are being made to further characterize the rate-limiting steps of cancer metastasis, i.e. extravasation of circulating tumor cells and colonization of secondary organs. In this study, we investigated whether angiotensin II, a major vasoactive peptide both produced locally and released in the bloodstream, may trigger activating signals that contribute to cancer cell extravasation and metastasis. We used an experimental in vivo model of cancer metastasis in which bioluminescent breast tumor cells (D3H2LN were injected intra-cardiacally into nude mice in order to recapitulate the late and essential steps of metastatic dissemination. Real-time intravital imaging studies revealed that angiotensin II accelerates the formation of metastatic foci at secondary sites. Pre-treatment of cancer cells with the peptide increases the number of mice with metastases, as well as the number and size of metastases per mouse. In vitro, angiotensin II contributes to each sequential step of cancer metastasis by promoting cancer cell adhesion to endothelial cells, trans-endothelial migration and tumor cell migration across extracellular matrix. At the molecular level, a total of 102 genes differentially expressed following angiotensin II pre-treatment were identified by comparative DNA microarray. Angiotensin II regulates two groups of connected genes related to its precursor angiotensinogen. Among those, up-regulated MMP2/MMP9 and ICAM1 stand at the crossroad of a network of genes involved in cell adhesion, migration and invasion. Our data suggest that targeting angiotensin II production or action may represent a valuable therapeutic option to prevent metastatic progression of invasive breast tumors.

  3. STRIPAK components determine mode of cancer cell migration and metastasis

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    Madsen, Chris D.; Hooper, Steven; Tozluoglu, Melda; Bruckbauer, Andreas; Fletcher, Georgina; Erler, Janine T.; Bates, Paul A.; Thompson, Barry; Sahai, Erik

    2017-01-01

    The contractile actomyosin cytoskeleton and its connection to the plasma membrane are critical for control of cell shape and migration. We identify three STRIPAK complex components, FAM40A, FAM40B, and STRN3, as regulators of the actomyosin cortex. We show that FAM40A negatively regulates the MST3 and MST4 kinases, which promote the co-localisation of the contractile actomyosin machinery with the Ezrin/Radixin/Moesin family proteins by phosphorylating the inhibitors of PPP1CB, PPP1R14A-D. Using computational modelling, in vitro cell migration assays and in vivo breast cancer metastasis assays we demonstrate that co-localisation of contractile activity and actin-plasma membrane linkage reduces cell speed on planar surfaces, but favours migration in confined environments similar to those observed in vivo. We further show that FAM40B mutations found in human tumours uncouple it from PP2A and enable it to drive a contractile phenotype, which may underlie its role in human cancer. PMID:25531779

  4. Integrin signaling modes controlling cell migration and metastasis

    NARCIS (Netherlands)

    Truong, Hoa Hoang

    2011-01-01

    The aim of this thesis is to address how integrin-mediated signaling regulates cellular processes that have profound effects on cell morphology, motility, cancer metastasis, and FN fibrillogenesis, and how these findings can be utilized for relevant medical purposes or advancement of drug discovery.

  5. Hypoxia promotes Rab5 activation, leading to tumor cell migration, invasion and metastasis.

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    Silva, Patricio; Mendoza, Pablo; Rivas, Solange; Díaz, Jorge; Moraga, Carolina; Quest, Andrew F G; Torres, Vicente A

    2016-05-17

    Hypoxia, a common condition of the tumor microenvironment, is associated with poor patient prognosis, tumor cell migration, invasion and metastasis. Recent evidence suggests that hypoxia alters endosome dynamics in tumor cells, leading to augmented cell proliferation and migration and this is particularly relevant, because endosomal components have been shown to be deregulated in cancer. The early endosome protein Rab5 is a small GTPase that promotes integrin trafficking, focal adhesion turnover, Rac1 activation, tumor cell migration and invasion. However, the role of Rab5 and downstream events in hypoxia remain unknown. Here, we identify Rab5 as a critical player in hypoxia-driven tumor cell migration, invasion and metastasis. Exposure of A549 human lung carcinoma, ZR-75, MDA-MB-231 and MCF-7 human breast cancer and B16-F10 mouse melanoma cells to hypoxia increased Rab5 activation, followed by its re-localization to the leading edge and association with focal adhesions. Importantly, Rab5 was required for hypoxia-driven cell migration, FAK phosphorylation and Rac1 activation, as shown by shRNA-targeting and transfection assays with Rab5 mutants. Intriguingly, the effect of hypoxia on both Rab5 activity and migration was substantially higher in metastatic B16-F10 cells than in poorly invasive B16-F0 cells. Furthermore, exogenous expression of Rab5 in B16-F0 cells predisposed to hypoxia-induced migration, whereas expression of the inactive mutant Rab5/S34N prevented the migration of B16-F10 cells induced by hypoxia. Finally, using an in vivo syngenic C57BL/6 mouse model, Rab5 expression was shown to be required for hypoxia-induced metastasis. In summary, these findings identify Rab5 as a key mediator of hypoxia-induced tumor cell migration, invasion and metastasis.

  6. Stromal Cell-Derived Factor-1 Promotes Cell Migration, Tumor Growth of Colorectal Metastasis

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    Otto Kollmar

    2007-10-01

    Full Text Available In a mouse model of established extrahepatic colorectal metastasis, we analyzed whether stromal cellderived factor (SDF 1 stimulates tumor cell migration in vitro, angiogenesis, tumor growth in vivo. METHODS: Using chemotaxis chambers, CT26.WT colorectal tumor cell migration was studied under stimulation with different concentrations of SDF-1. To evaluate angiogenesis, tumor growth in vivo, green fluorescent protein-transfected CT26.WT cells were implanted in dorsal skinfold chambers of syngeneic BALB/c mice. After 5 days, tumors were locally exposed to SDF-1. Cell proliferation, tumor microvascularization, growth were studied during a further 9-day period using intravital fluorescence microscopy, histology, immunohistochemistry. Tumors exposed to PBS only served as controls. RESULTS:In vitro, > 30% of unstimulated CT26.WT cells showed expression of the SDF-1 receptor CXCR4. On chemotaxis assay, SDF-1 provoked a dose-dependent increase in cell migration. In vivo, SDF-1 accelerated neovascularization, induced a significant increase in tumor growth. Capillaries of SDF-1-treated tumors showed significant dilation. Of interest, SDF-1 treatment was associated with a significantly increased expression of proliferating cell nuclear antigen, a downregulation of cleaved caspase-3. CONCLUSION: Our study indicates that the CXC chemokine SDF-1 promotes tumor cell migration in vitro, tumor growth of established extrahepatic metastasis in vivo due to angiogenesis-dependent induction of tumor cell proliferation, inhibition of apoptotic cell death.

  7. Luteolin inhibits lung metastasis, cell migration, and viability of triple-negative breast cancer cells

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    Cook, Matthew T; Liang, Yayun; Besch-Williford, Cynthia; Hyder, Salman M

    2017-01-01

    Most breast cancer-related deaths from triple-negative breast cancer (TNBC) occur following metastasis of cancer cells and development of tumors at secondary sites. Because TNBCs lack the three receptors targeted by current chemotherapeutic regimens, they are typically treated with extremely aggressive and highly toxic non-targeted treatment strategies. Women with TNBC frequently develop metastatic lesions originating from drug-resistant residual cells and have poor prognosis. For this reason, novel therapeutic strategies that are safer and more effective are sought. Luteolin (LU) is a naturally occurring, non-toxic plant compound that has proven effective against several types of cancer. With this in mind, we conducted in vivo and in vitro studies to determine whether LU might suppress metastasis of TNBC. In an in vivo mouse metastasis model, LU suppressed metastasis of human MDA-MB-435 and MDA-MB-231 (4175) LM2 TNBC cells to the lungs. In in vitro assays, LU inhibited cell migration and viability of MDA-MB-435 and MDA-MB-231 (4175) LM2 cells. Further, LU induced apoptosis in MDA-MB-231 (4175) LM2 cells. Relatively low levels (10 µM) of LU significantly inhibited vascular endothelial growth factor (VEGF) secretion in MDA-MB-231 (4175) LM2 cells, suggesting that it has the ability to suppress a potent angiogenic and cell survival factor. In addition, migration of MDA-MB-231 (4175) LM2 cells was inhibited upon exposure to an antibody against the VEGF receptor, KDR, but not by exposure to a VEGF165 antibody. Collectively, these data suggest that the anti-metastatic properties of LU may, in part, be due to its ability to block VEGF production and KDR-mediated activity, thereby inhibiting tumor cell migration. These studies suggest that LU deserves further investigation as a potential treatment option for women with TNBC. PMID:28096694

  8. Chemoattractant signaling between tumor cells and macrophages regulates cancer cell migration, metastasis and neovascularization.

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    Chad E Green

    Full Text Available Tumor-associated macrophages are known to influence cancer progression by modulation of immune function, angiogenesis, and cell metastasis, however, little is known about the chemokine signaling networks that regulate this process. Utilizing CT26 colon cancer cells and RAW 264.7 macrophages as a model cellular system, we demonstrate that treatment of CT26 cells with RAW 264.7 conditioned medium induces cell migration, invasion and metastasis. Inflammatory gene microarray analysis indicated CT26-stimulated RAW 264.7 macrophages upregulate SDF-1alpha and VEGF, and that these cytokines contribute to CT26 migration in vitro. RAW 264.7 macrophages also showed a robust chemotactic response towards CT26-derived chemokines. In particular, microarray analysis and functional testing revealed CSF-1 as the major chemoattractant for RAW 264.7 macrophages. Interestingly, in the chick CAM model of cancer progression, RAW 264.7 macrophages localized specifically to the tumor periphery where they were found to increase CT26 tumor growth, microvascular density, vascular disruption, and lung metastasis, suggesting these cells home to actively invading areas of the tumor, but not the hypoxic core of the tumor mass. In support of these findings, hypoxic conditions down regulated CSF-1 production in several tumor cell lines and decreased RAW 264.7 macrophage migration in vitro. Together our findings suggest a model where normoxic tumor cells release CSF-1 to recruit macrophages to the tumor periphery where they secrete motility and angiogenic factors that facilitate tumor cell invasion and metastasis.

  9. XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

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    Wang, Ting; Han, Shuai; Wu, Zhipeng; Han, Zhitao; Yan, Wangjun; Liu, Tielong; Wei, Haifeng; Song, Dianwen; Zhou, Wang, E-mail: brilliant212@163.com; Yang, Xinghai, E-mail: cnspineyang@163.com; Xiao, Jianru, E-mail: jianruxiao83@163.com

    2015-08-21

    Bone metastasis occurs in approximately 30–40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis. - Highlights: • XCR1 is overexpressed in bone metastasis compared with primary NSCLC. • XCR1 activation by XCL1 promotes lung cancer cell proliferation and migration. • JAK2/STAT3 is a novel potential downstream pathway of XCR1.

  10. Inhibition of miR-15b decreases cell migration and metastasis in colorectal cancer.

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    Li, Jian; Chen, Yuxiang; Guo, Xiong; Zhou, Ling; Jia, Zeming; Tang, Yaping; Lin, Ling; Liu, Weidong; Ren, Caiping

    2016-07-01

    Colorectal cancer (CRC) has a high prevalence and mortality rate. Biomarkers for predicting the recurrence of CRC are not clinically available. This study investigated the role of circulating miR-15b in the prediction of CRC recurrence and the associated mechanism. miR-15b levels in plasma and tissues were measured by real-time PCR. Metastasis suppressor-1 (MTSS1) and Klotho protein expression were detected by Western blot and immunohistochemistry. Invasion and migration of CRC tumor cells were measured by transwell plates. Liver metastasis was established by intraspleen injection of HCT116 cells. Plasma miR-15b levels were significantly higher in CRC patients than in healthy controls, in CRC patients with metastasis than in CRC patients without metastasis, and in CRC patients with recurrence than in CRC patients without recurrence in the 5-year follow-up. miR-15b level in CRC tumors was significantly higher than that in peritumoral tissues. High plasma miR-15b level and negative MTSS1 and Klotho expression in tumor tissues significantly correlated with poor survival. Inhibition of miR-15b activity by adenovirus carrying antimiR-15b sequence significantly increased MTSS1 and Klotho protein expression and subsequently decreased colony formation ability, invasion, and migration of HCT116 cells in vitro and liver metastasis of HCT116 tumors in vivo. In conclusion, high abundance of circulating miR-15b correlated with tumor metastasis, recurrence, and poor patient prognosis through downregulation of MTSS1 and Klotho protein expression.

  11. NME2 reduces proliferation, migration and invasion of gastric cancer cells to limit metastasis.

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    Yan-fei Liu

    Full Text Available Gastric cancer is one of the most common malignancies and has a high rate of metastasis. We hypothesize that NME2 (Nucleoside Diphosphate Kinase 2, which has previously been considered as an anti-metastatic gene, plays a role in the invasiveness of gastric cancer cells. Using a tissue chip technology and immunohistochemistry, we demonstrated that NME2 expression was associated with levels of differentiation of gastric cancer cells and their metastasis into the lymph nodes. When the NME2 gene product was over-expressed by ;in vitro stable transfection, cells from BGC823 and MKN45 gastric cancer cell lines had reduced rates of proliferation, migration, and invasion through the collagen matrix, suggesting an inhibitory activity of NME2 in the propagation and invasion of gastric cancer. NME2 could, therefore, severe as a risk marker for gastric cancer invasiveness and a potential new target for gene therapy to enhance or induce NME2 expression.

  12. Timosaponin AIII inhibits melanoma cell migration by suppressing COX-2 and in vivo tumor metastasis.

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    Kim, Ki Mo; Im, A-Rang; Kim, Seung Hyung; Hyun, Jin Won; Chae, Sungwook

    2016-02-01

    Melanoma is the leading cause of death from skin disease, due in large part to its propensity to metastasize. We examined the effects of timosaponin AIII, a compound isolated from Anemarrhena asphodeloides Bunge, on melanoma cancer cell migration and the molecular mechanisms underlying these effects using B16-F10 and WM-115 melanoma cells lines. Overexpression of COX-2, its metabolite prostaglandin E2 (PGE2), and PGE2 receptors (EP2 and EP4) promoted cell migration in vitro. Exposure to timosaponin AIII resulted in concentration-dependent inhibition of cell migration, which was associated with reduced levels of COX-2, PGE2, and PGE2 receptors. Transient transfection of COX-2 siRNA also inhibited cell migration. Exposure to 12-O-tetradecanoylphorbal-13-acetate enhanced cell migration, whereas timosaponin AIII inhibited 12-O-tetradecanoylphorbal-13-acetate-induced cell migration and reduced basal levels of EP2 and EP4. Moreover, timosaponin AIII inhibited activation of nuclear factor-kappa B (NF-κB), an upstream regulator of COX-2 in B16-F10 cells. Consistent with our in vitro findings, in vivo studies showed that timosaponin AIII treatment significantly reduced the total number of metastatic nodules in the mouse lung and improved histological alterations in B16-F10-injected C57BL/6 mice. In addition, C57BL/6 mice treated with timosaponin AIII showed reduced expression of COX-2 and NF-κB in the lung. Together, these results indicate that timosaponin AIII has the capacity to inhibit melanoma cell migration, an essential step in the process of metastasis, by inhibiting expression of COX-2, NF-κB, PGE2, and PGE2 receptors.

  13. The enamel matrix derivative (Emdogain) enhances human tongue carcinoma cells gelatinase production, migration and metastasis formation.

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    Laaksonen, Matti; Suojanen, Juho; Nurmenniemi, Sini; Läärä, Esa; Sorsa, Timo; Salo, Tuula

    2008-08-01

    Enamel matrix derivative Emdogain (EMD) is widely used in periodontal treatment to regenerate lost connective tissue and to improve the attachment of the teeth. Gelatinases (MMP-2 and -9) have an essential role in the promotion and progression of oral cancer growth and metastasis formation. We studied the effects of EMD on human tongue squamous cell carcinoma (HSC-3) cells in vitro and in vivo. In vitro, EMD (100 microg/ml and 200 microg/ml) remarkably induced the MMP-2 and -9 production from HSC-3 cells analysed by zymography and enzyme-linked immunosorbent assay. EMD also slightly induced the MMP-2 and -9 production from benign human mucosal keratinocytes (HMK). Furthermore, EMD clearly induced the transmigration of HSC-3 cells but had no effect on the HMK migration in transwell assays. The in vitro wound closure of HSC-3 cells was notably accelerated by EMD, whereas it had only minor effect on the wound closure of HMKs. The migration of both cell lines was inhibited by a selective cyclic anti-gelatinolytic peptide CTT-2. EMD had no effect on HSC-3 cell proliferation or apoptosis and only a limited effect on cell attachment to various extracellular matrix components. The in vivo mice experiment revealed that EMD substantially induced HSC-3 xenograft metastasis formation. Our results suggest that the use of EMD for patients with oral mucosal carcinomas or premalignant lesions should be carefully considered, possibly avoided.

  14. Emerging role of TRP channels in cell migration: from tumor vascularization to metastasis

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    Alessandra eFioro Pla

    2013-11-01

    Full Text Available Transient Receptor Potential (TRP channels modulate intracellular Ca2+ concentrations, controlling critical cytosolic and nuclear events that are involved in the initiation and progression of cancer. It is not, therefore, surprising that the expression of some TRP channels is altered during tumor growth and metastasis. Cell migration of both epithelial and endothelial cells is an essential step of the so-called metastatic cascade that leads to the spread of the disease within the body. It is in fact required for both tumor vascularization as well as for tumor cell invasion into adjacent tissues and intravasation into blood/lymphatic vessels. Studies from the last 15 years have unequivocally shown that the ion channles and the transport proteins also play important roles in cell migration. On the other hand, recent literature underlies a critical role for TRP channels in the migration process both in cancer cells as well as in tumor vascularization. This will be the main focus of our review. We will provide an overview of recent advances in this field describing TRP channels contribution to the process vascular and cancer cell migration, and we will systematically discuss relevant molecular mechanism involved.

  15. Galectin-4 Reduces Migration and Metastasis Formation of Pancreatic Cancer Cells.

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    Ana I Belo

    Full Text Available Galectin-4 (Gal-4 is a member of the galectin family of glycan binding proteins that shows a significantly higher expression in cystic tumors of the human pancreas and in pancreatic adenocarcinomas compared to normal pancreas. However, the putative function of Gal-4 in tumor progression of pancreatic cancer is still incompletely understood. In this study the role of Gal-4 in cancer progression was investigated, using a set of defined pancreatic cancer cell lines, Pa-Tu-8988S (PaTu-S and Pa-Tu-8988T (PaTu-T, as a model. These two cell lines are derived from the same liver metastasis of a human primary pancreatic adenocarcinoma, but differ in their growth characteristics and metastatic capacity. We demonstrated that Gal-4 expression is high in PaTu-S, which shows poor migratory properties, whereas much lower Gal-4 levels are observed in the highly metastatic cell line PaTu-T. In PaTu-S, Gal-4 is found in the cytoplasm, but it is also secreted and accumulates at the membrane at sites of contact with neighboring cells. Moreover, we show that Gal-4 inhibits metastasis formation by delaying migration of pancreatic cancer cells in vitro using a scratch assay, and in vivo using zebrafish (Danio rerio as an experimental model. Our data suggest that Gal-4 may act at the cell-surface of PaTu-S as an adhesion molecule to prevent release of the tumor cells, but has in addition a cytosolic function by inhibiting migration via a yet unknown mechanism.

  16. The PDZ protein TIP-1 facilitates cell migration and pulmonary metastasis of human invasive breast cancer cells in athymic mice

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    Han, Miaojun [Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Yunnan (China); Graduate School, Chinese Academy of Sciences, Beijing (China); Department of Radiation Oncology, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States); Wang, Hailun [Department of Radiation Oncology, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States); Zhang, Hua-Tang [Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Yunnan (China); Han, Zhaozhong, E-mail: zhaozhong.han@vanderbilt.edu [Department of Radiation Oncology, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States); Department of Cancer Biology, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States); Vanderbilt-Ingram Cancer Center, School of Medicine, Vanderbilt University, Nashville, TN 37232 (United States)

    2012-05-25

    Highlights: Black-Right-Pointing-Pointer This study has revealed novel oncogenic functions of TIP-1 in human invasive breast cancer. Black-Right-Pointing-Pointer Elevated TIP-1 expression levels in human breast cancers correlate to the disease prognosis. Black-Right-Pointing-Pointer TIP-1 knockdown suppressed the cell migration and pulmonary metastasis of human breast cancer cells. Black-Right-Pointing-Pointer TIP-1 knockdown suppressed the expression and functionality of motility-related genes. -- Abstract: Tax-interacting protein 1 (TIP-1, also known as Tax1bp3) inhibited proliferation of colon cancer cells through antagonizing the transcriptional activity of beta-catenin. However, in this study, elevated TIP-1 expression levels were detected in human invasive breast cancers. Studies with two human invasive breast cancer cell lines indicated that RNAi-mediated TIP-1 knockdown suppressed the cell adhesion, proliferation, migration and invasion in vitro, and inhibited tumor growth in mammary fat pads and pulmonary metastasis in athymic mice. Biochemical studies showed that TIP-1 knockdown had moderate and differential effects on the beta-catenin-regulated gene expression, but remarkably down regulated the genes for cell adhesion and motility in breast cancer cells. The decreased expression of integrins and paxillin was accompanied with reduced cell adhesion and focal adhesion formation on fibronectin-coated surface. In conclusion, this study revealed a novel oncogenic function of TIP-1 suggesting that TIP-1 holds potential as a prognostic biomarker and a therapeutic target in the treatment of human invasive breast cancers.

  17. Downregulation of AKT3 Increases Migration and Metastasis in Triple Negative Breast Cancer Cells by Upregulating S100A4.

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    Astrid Grottke

    Full Text Available Treatment of breast cancer patients with distant metastases represents one of the biggest challenges in today's gynecological oncology. Therefore, a better understanding of mechanisms promoting the development of metastases is of paramount importance. The serine/threonine kinase AKT was shown to drive cancer progression and metastasis. However, there is emerging data that single AKT isoforms (i.e. AKT1, AKT2 and AKT3 have different or even opposing functions in the regulation of cancer cell migration in vitro, giving rise to the hypothesis that inhibition of distinct AKT isoforms might have undesirable effects on cancer dissemination in vivo.The triple negative breast cancer cell line MDA-MB-231 was used to investigate the functional roles of AKT in migration and metastasis. AKT single and double knockdown cells were generated using isoform specific shRNAs. Migration was analyzed using live cell imaging, chemotaxis and transwell assays. The metastatic potential of AKT isoform knockdown cells was evaluated in a subcutaneous xenograft mouse model in vivo.Depletion of AKT3, but not AKT1 or AKT2, resulted in increased migration in vitro. This effect was even more prominent in AKT2,3 double knockdown cells. Furthermore, combined downregulation of AKT2 and AKT3, as well as AKT1 and AKT3 significantly increased metastasis formation in vivo. Screening for promigratory proteins revealed that downregulation of AKT3 increases the expression of S100A4 protein. In accordance, depletion of S100A4 by siRNA approach reverses the increased migration induced by knockdown of AKT3.We demonstrated that knockdown of AKT3 can increase the metastatic potential of triple negative breast cancer cells. Therefore, our results provide a rationale for the development of AKT isoform specific inhibitors.

  18. SIRT 1 Overexpression is Associated with Metastasis of Pancreatic Ductal Adenocarcinoma (PDAC) and Promotes Migration and Growth of PDAC Cells.

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    Li, Siqin; Hong, Hua; Lv, Huicheng; Wu, Guozhu; Wang, Zhigang

    2016-05-12

    BACKGROUND SIRT 1, as a class III histone deacetylase (HDAC), is implicated in the initiation and progression of malignancies. However, the association of SIRT 1 with tumorigenesis or progression of pancreatic ductal adenocarcinoma (PDAC) is not clear. MATERIAL AND METHODS In our study we investigated SIRT 1 expression in PDAC samples and evaluated the association of SIRT 1 level with the clinical and pathological characteristics of PDAC patients. We investigated the role of SIRT 1 in the migration and growth of PDAC PANC-1 or BxPC-3 cells using gain-of-function and loss-of-function approach. RESULTS We demonstrated that SIRT 1 mRNA level was significantly promoted in intra-tumor tissues compared to peri-tumor tissues of PDAC; and SIRT 1 overexpression was markedly associated with distant or lymph node (LN) metastasis of these PDAC tissues. Moreover, the in vitro wound healing assay demonstrated that SIRT 1 overexpression with lentivirus vector markedly promoted the migration of PANC-1 or BxPC-3 cells, whereas SIRT 1 knockdown using SIRT 1 specific siRNA transfection significantly inhibited the migration of PDAC cells. The colony forming assay confirmed SIRT 1 promotion of the growth of PANC-1 or BxPC-3 cells. CONCLUSIONS In summary, SIRT 1 overexpression is significantly associated with metastasis of PDAC, and overexpressed SIRT 1 plays an important role in pancreatic cancer cell migration and growth. Our data warrants further studies on SIRT 1 as a novel chemotherapeutic target in PDAC.

  19. PRK1/PKN1 controls migration and metastasis of androgen-independent prostate cancer cells.

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    Jilg, Cordula A; Ketscher, Anett; Metzger, Eric; Hummel, Barbara; Willmann, Dominica; Rüsseler, Vanessa; Drendel, Vanessa; Imhof, Axel; Jung, Manfred; Franz, Henriette; Hölz, Stefanie; Krönig, Malte; Müller, Judith M; Schüle, Roland

    2014-12-30

    The major threat in prostate cancer is the occurrence of metastases in androgen-independent tumor stage, for which no causative cure is available. Here we show that metastatic behavior of androgen-independent prostate tumor cells requires the protein-kinase-C-related kinase (PRK1/PKN1) in vitro and in vivo. PRK1 regulates cell migration and gene expression through its kinase activity, but does not affect cell proliferation. Transcriptome and interactome analyses uncover that PRK1 regulates expression of migration-relevant genes by interacting with the scaffold protein sperm-associated antigen 9 (SPAG9/JIP4). SPAG9 and PRK1 colocalize in human cancer tissue and are required for p38-phosphorylation and cell migration. Accordingly, depletion of either ETS domain-containing protein Elk-1 (ELK1), an effector of p38-signalling or p38 depletion hinders cell migration and changes expression of migration-relevant genes as observed upon PRK1-depletion. Importantly, a PRK1 inhibitor prevents metastases in mice, showing that the PRK1-pathway is a promising target to hamper prostate cancer metastases in vivo. Here we describe a novel mechanism controlling the metastatic behavior of PCa cells and identify PRK1 as a promising therapeutic target to treat androgen-independent metastatic prostate cancer.

  20. Metastasis-associated phosphatase PRL-2 regulates tumor cell migration and invasion.

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    Wang, Y; Lazo, J S

    2012-02-16

    The phosphatase of regenerating liver (PRL) family, comprising PRL-1, PRL-2 and PRL-3, is a group of prenylated phosphatases that are candidate cancer biomarkers and therapeutic targets. Although several studies have documented that altered expression of PRL-1 or PRL-3 can influence cell proliferation, migration and invasion, there is a dearth of knowledge about the biological functions of PRL-2. Thus, in the current study we have evaluated the role of PRL-2 in cell migration and invasion in human cancer cells. We found that four human lung cancer cells, including A549 cells, overexpress PRL-2 when compared with normal lung cells. PRL-2 knockdown by RNA interference markedly inhibited cell migration and invasion, and this inhibition can be restored by overexpressing the short interference RNA (siRNA)-resistant vector HA-PRL-2m. PRL-2 suppression by siRNA decreased p130Cas and vinculin expression, and decreased extracellular signal-regulated kinase (ERK) phosphorylation, while increasing the phosphorylation of ezrin on tyrosine 146. We found no significant changes in total p53, Akt and c-Src expression levels or their phosphorylation status, suggesting that PRL-2 knockdown could inhibit tumor cell migration and invasion through a Src-independent p130Cas signaling pathway. Ectopic expression of wild-type PRL-2, a catalytic inactive C101S mutant and a C-terminal CAAX deletion revealed a requirement for both the PRL-2 catalytic functionality and prenylation site. Expression of wild-type but not mutant forms of PRL-2 caused ERK phosphorylation and nuclear translocation. These results support a model in which PRL-2 promotes cell migration and invasion through an ERK-dependent signaling pathway.

  1. Over-expression of miR-106b promotes cell migration and metastasis in hepatocellular carcinoma by activating epithelial-mesenchymal transition process.

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    Wing Lung Yau

    Full Text Available Hepatocellular carcinoma (HCC is one the the most fatal cancers worldwide. The poor prognosis of HCC is mainly due to the developement of distance metastasis. To investigate the mechanism of metastasis in HCC, an orthotopic HCC metastasis animal model was established. Two sets of primary liver tumor cell lines and corresponding lung metastasis cell lines were generated. In vitro functional analysis demonstrated that the metastatic cell line had higher invasion and migration ability when compared with the primary liver tumor cell line. These cell lines were subjected to microRNA (miRNAs microarray analysis to identify differentially expressed miRNAs which were associated with the developement of metastasis in vivo. Fifteen human miRNAs, including miR-106b, were differentially expressed in 2 metastatic cell lines compared with the primary tumor cell lines. The clinical significance of miR-106b in 99 HCC clinical samples was studied. The results demonstrated that miR-106b was over-expressed in HCC tumor tissue compared with adjacent non-tumor tissue (p = 0.0005, and overexpression of miR-106b was signficantly correlated with higher tumor grade (p = 0.018. Further functional studies demonstrated that miR-106b could promote cell migration and stress fiber formation by over-expressing RhoGTPases, RhoA and RhoC. In vivo functional studies also showed that over-expression of miR-106b promoted HCC metastasis. These effects were related to the activation of the epithelial-mesenchymal transition (EMT process. Our results suggested that miR-106b expression contributed to HCC metastasis by activating the EMT process promoting cell migration in vitro and metastasis in vivo.

  2. MicroRNA-340 inhibits the migration, invasion, and metastasis of breast cancer cells by targeting Wnt pathway.

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    Mohammadi-Yeganeh, Samira; Paryan, Mahdi; Arefian, Ehsan; Vasei, Mohammad; Ghanbarian, Hossein; Mahdian, Reza; Karimipoor, Morteza; Soleimani, Masoud

    2016-07-01

    MicroRNAs (miRNAs) play a key role in tumor metastasis based on their capacity to regulate the expression of tumor-related genes. Over-expression of key genes such as c-MYC and CTNNB1 (encoding β-catenin) in Wnt/β-catenin-dependent and ROCK1 in Wnt/β-catenin-independent signaling pathways (Rho/Rho-associated kinase (ROCK) signaling pathway) has already been identified as the hallmarks of many tumors, and their role in breast cancer has also been investigated and confirmed. miR-340 characterization as an onco-suppressor miRNA has been previously reported. However, the mechanism by which it inhibits metastasis has not been completely elucidated. Quantitative real-time PCR (qPCR), Western blot, and luciferase assays were used to confirm the effect of miR-340 on the 3'-untranslated region (UTR) of the target genes. Lentiviral particles containing miR-340 were also used to evaluate the effect of miR-340 restoration on cell proliferation, migration, and invasion in vitro in the invasive MDA-MB-231 cell line. By applying bioinformatic approaches for the prediction of miRNAs targeting 3'-UTRs of CTNNB1, c-MYC, and ROCK1, we found out that miR-340 could dramatically down-regulate metastasis by targeting Wnt signaling in breast cancer cells. In the current study, analyzing miR-340 by reverse transcription quantitative PCR (RT-qPCR) in MDA-MB-231 showed that it was remarkably down-regulated in the metastatic breast cancer cell line. We found that restoration of miR-340 in the invasive breast cancer cell line, MDA-MB-231, suppresses the expression of the target genes' messenger RNA (mRNA) and protein and, as a result, inhibits tumor cell invasion and metastasis. Our findings highlight the ability of bioinformatic approaches to find miRNAs targeting specific genes. By bioinformatic analysis, we confirmed the important role of miR-340 as a pivotal regulator of breast cancer metastasis in targeting previously validated (ROCK1) and potentially novel genes, i.e., (CTNNB1 and c-MYC).

  3. Human adipose tissue-derived stromal/stem cells promote migration and early metastasis of triple negative breast cancer xenografts.

    Directory of Open Access Journals (Sweden)

    Brian G Rowan

    Full Text Available BACKGROUND: Fat grafting is used to restore breast defects after surgical resection of breast tumors. Supplementing fat grafts with adipose tissue-derived stromal/stem cells (ASCs is proposed to improve the regenerative/restorative ability of the graft and retention. However, long term safety for ASC grafting in proximity of residual breast cancer cells is unknown. The objective of this study was to determine the impact of human ASCs derived from abdominal lipoaspirates of three donors, on a human breast cancer model that exhibits early metastasis. METHODOLOGY/PRINCIPAL FINDINGS: Human MDA-MB-231 breast cancer cells represents "triple negative" breast cancer that exhibits early micrometastasis to multiple mouse organs [1]. Human ASCs were derived from abdominal adipose tissue from three healthy female donors. Indirect co-culture of MDA-MB-231 cells with ASCs, as well as direct co-culture demonstrated that ASCs had no effect on MDA-MB-231 growth. Indirect co-culture, and ASC conditioned medium (CM stimulated migration of MDA-MB-231 cells. ASC/RFP cells from two donors co-injected with MDA-MB-231/GFP cells exhibited a donor effect for stimulation of primary tumor xenografts. Both ASC donors stimulated metastasis. ASC/RFP cells were viable, and integrated with MDA-MB-231/GFP cells in the tumor. Tumors from the co-injection group of one ASC donor exhibited elevated vimentin, matrix metalloproteinase-9 (MMP-9, IL-8, VEGF and microvessel density. The co-injection group exhibited visible metastases to the lung/liver and enlarged spleen not evident in mice injected with MDA-MB-231/GFP alone. Quantitation of the total area of GFP fluorescence and human chromosome 17 DNA in mouse organs, H&E stained paraffin sections and fluorescent microscopy confirmed multi-focal metastases to lung/liver/spleen in the co-injection group without evidence of ASC/RFP cells. CONCLUSIONS: Human ASCs derived from abdominal lipoaspirates of two donors stimulated metastasis of

  4. Laminin-511: a multi-functional adhesion protein regulating cell migration, tumor invasion and metastasis.

    Science.gov (United States)

    Pouliot, Normand; Kusuma, Nicole

    2013-01-01

    Laminins are major constituents of basement membranes. At least 16 isoforms have now been described, each with distinct spatio-temporal expression patterns and functions. The laminin-511 heterotrimer (α5β1γ1) is one of the more recent isoforms to be identified and a potent adhesive and pro-migratory substrate for a variety of normal and tumor cell lines in vitro. As our understanding of its precise function in normal tissues and in pathologies is rapidly unraveling, current evidence suggests an important regulatory role in cancer. This review describes published data on laminin-511 expression in several malignancies and experimental evidence from both in vitro and in vivo studies supporting its functional role during tumor progression. A particular emphasis is put on more recent studies from our laboratory and that of others indicating that laminin-511 contributes to tumor dissemination and metastasis in advanced breast carcinomas and other tumor types. Collectively, the experimental evidence suggests that high expression of laminin-511 has prognostic significance and that targeting tumor-laminin-511 interactions may have therapeutic potential in advanced cancer patients.

  5. Downregulation of CXCR4 by SDF-KDEL in SBC-5 cells inhibits their migration in vitro and organ metastasis in vivo.

    Science.gov (United States)

    Ma, Ningqiang; Pang, Hailin; Shen, Weiwei; Zhang, Feng; Cui, Zaoxun; Wang, Junyan; Wang, Jianlin; Liu, Lili; Zhang, Helong

    2015-02-01

    Metastasis is the principal cause of morbidity and mortality in cancer patients. The master genes that govern organ-selective metastasis remain elusive. We compared the expression levels of C-X-C chemokine receptor type 4 (CXCR4) in the human small cell lung cancer (SCLC) cells, SBC-5 and SBC-3, by flow cytometric analysis and found that CXCR4 was expressed at markedly higher levels in the SBC-5 cells which can produce multiple organ metastasis, particularly bone metastasis compared to the SBC-3 cells. Stromal-derived-factor-1 (SDF-1)-CXCR4 has been shown to regulate cell migration and metastasis in a various types of cancer; however, the roles of SDF-1-CXCR4 in the organ-selective metastasis of SCLC in vivo remain to be elucidated. Thus, in this study, we constructed a phenotype of SBC-5 cells in which CXCR4 was knocked out using the intrakine strategy and found that the downregulation of CXCR4 inhibited cell migration and invasion, but did not affect cell proliferation or apoptosis in vitro. In in vivo experiments, the knockout of CXCR4 suppressed the development of metastastic lesions in the lungs, liver and bone, but did not decrease metastasis to the kidneys. Our data demonstrate that CXCR4 is a candidate gene involved in the development of metastastic lesions in specific organs, such as the lungs, bone and liver, which can secrete high concentrations of SDF-1, the sole ligand of CXCR4. Thus, CXCR4 may prove to be a promising target for the prevention and effective treatment of metastastic lesions due to SCLC.

  6. The Sal-like 4 - integrin α6β1 network promotes cell migration for metastasis via activation of focal adhesion dynamics in basal-like breast cancer cells.

    Science.gov (United States)

    Itou, Junji; Tanaka, Sunao; Li, Wenzhao; Iida, Atsuo; Sehara-Fujisawa, Atsuko; Sato, Fumiaki; Toi, Masakazu

    2017-01-01

    During metastasis, cancer cell migration is enhanced. However, the mechanisms underlying this process remain elusive. Here, we addressed this issue by functionally analyzing the transcription factor Sal-like 4 (SALL4) in basal-like breast cancer cells. Loss-of-function studies of SALL4 showed that this transcription factor is required for the spindle-shaped morphology and the enhanced migration of cancer cells. SALL4 also up-regulated integrin gene expression. The impaired cell migration observed in SALL4 knockdown cells was restored by overexpression of integrin α6 and β1. In addition, we clarified that integrin α6 and β1 formed a heterodimer. At the molecular level, loss of the SALL4 - integrin α6β1 network lost focal adhesion dynamics, which impairs cell migration. Over-activation of Rho is known to inhibit focal adhesion dynamics. We observed that SALL4 knockdown cells exhibited over-activation of Rho. Aberrant Rho activation was suppressed by integrin α6β1 expression, and pharmacological inhibition of Rho activity restored cell migration in SALL4 knockdown cells. These results indicated that the SALL4 - integrin α6β1 network promotes cell migration via modulation of Rho activity. Moreover, our zebrafish metastasis assays demonstrated that this gene network enhances cell migration in vivo. Our findings identify a potential new therapeutic target for the prevention of metastasis, and provide an improved understanding of cancer cell migration.

  7. Trafficking and cell migration.

    Science.gov (United States)

    Ulrich, Florian; Heisenberg, Carl-Philipp

    2009-07-01

    The migration of single cells and epithelial sheets is of great importance for gastrulation and organ formation in developing embryos and, if misregulated, can have dire consequences e.g. during cancer metastasis. A keystone of cell migration is the regulation of adhesive contacts, which are dynamically assembled and disassembled via endocytosis. Here, we discuss some of the basic concepts about the function of endocytic trafficking during cell migration: transport of integrins from the cell rear to the leading edge in fibroblasts; confinement of signalling to the front of single cells by endocytic transport of growth factors; regulation of movement coherence in multicellular sheets by cadherin turnover; and shaping of extracellular chemokine gradients. Taken together, endocytosis enables migrating cells and tissues to dynamically modulate their adhesion and signalling, allowing them to efficiently migrate through their extracellular environment.

  8. Structure-based design of an urokinase-type plasminogen activator receptor-derived peptide inhibiting cell migration and lung metastasis.

    Science.gov (United States)

    Carriero, Maria Vincenza; Longanesi-Cattani, Immacolata; Bifulco, Katia; Maglio, Ornella; Lista, Liliana; Barbieri, Antonio; Votta, Giuseppina; Masucci, Maria Teresa; Arra, Claudio; Franco, Renato; De Rosa, Mario; Stoppelli, Maria Patrizia; Pavone, Vincenzo

    2009-09-01

    The urokinase-type plasminogen activator receptor (uPAR) plays a central role in sustaining the malignant phenotype and promoting tumor metastasis. The Ser(88)-Arg-Ser-Arg-Tyr(92) is the minimum chemotactic sequence of uPAR required to induce the same intracellular signaling as its ligand uPA. Here, we describe the generation of new peptide inhibitors of cell migration and invasion derived from SRSRY by a drug design approach. Ac-Arg-Glu-Arg-Phe-NH(2) (i.e., RERF), which adopts a turned structure in solution, was selected for its ability to potently prevent SRSRY-directed cell migration. Fluorescein-RERF associates with very high affinity to RBL-2H3 rat basophilic leukemia cells expressing the human formyl peptide receptor (FPR). Accordingly, femtomolar concentrations of RERF prevent agonist-dependent internalization of FPR and inhibit N-formyl-Met-Leu-Phe-dependent migration in a dose-dependent manner. In the absence of FPR, fluorescein-RERF binds to cell surface at picomolar concentrations in an alphav integrin-dependent manner. The involvement of vitronectin receptor is further supported by the findings that 100 pmol/L RERF selectively inhibits vitronectin-dependent RBL-2H3 cell migration and prevents SRSRY-triggered uPAR/alphav association. Furthermore, RERF reduces the speed of wound closure and the extent of Matrigel invasion by human fibrosarcoma HT1080 cells without affecting cell proliferation. Finally, a 3- to 5-fold reduction of lung metastasis number and size in nude mice following i.v. injection of green fluorescent protein-expressing HT1080 cells in the presence of 3.32 mg/kg RERF is observed. Our findings indicate that RERF effectively prevents malignant cell invasion in vivo with no signs of toxicity and may represent a promising prototype drug for anticancer therapy.

  9. Over-expression of TRIM37 promotes cell migration and metastasis in hepatocellular carcinoma by activating Wnt/β-catenin signaling

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Jianxin; Yu, Chao; Chen, Meiyuan; Tian, She; Sun, Chengyi, E-mail: chenyisun11@163.com

    2015-09-04

    Hepatocellular carcinoma (HCC) is the most common cancer in the world especially in East Asia and Africa. Advanced stage, metastasis and frequent relapse are responsible for the poor prognosis of HCC. However, the precise mechanisms underlying HCC remained unclear. So it is urgent to identify the pathological processes and relevant molecules of HCC. TRIM37 is an E3 ligase and has been observed deregulated expression in various tumors. Recent studies of TRIM37 have implicated that TRIM37 played critical roles in cell proliferation and other processes. In the present study, we demonstrated that TRIM37 expression was notably up-regulated in HCC samples and was associated with advanced stage and tumor volume, which all indicating the poor outcomes. We also found that TRIM37 could serve as an independent prognostic factor of HCC. During the course of in vitro and in vivo work, we showed that TRIM37 promoted HCC cells migration and metastasis by inducing EMT. Furthermore, we revealed that the effect of TRIM37 mediated EMT in HCC cells was achieved by the activation of Wnt/β-catenin signaling. These finding may provide insight into the understanding of TRIM37 as a novel critical factor of HCC and a candidate target for HCC treatment. - Highlights: • Highly expression of TRIM37 is found in HCC samples compared with nontumorous samples. • TRIM37 expression is correlated with advanced HCC stages and could be an independent prognostic factor. • TRIM37 promotes cell proliferation and metastasis. • We report an E3 ligase TRIM37 affects Wnt/β-catenin signaling.

  10. Chemistry and biology of the compounds that modulate cell migration.

    Science.gov (United States)

    Tashiro, Etsu; Imoto, Masaya

    2016-03-01

    Cell migration is a fundamental step for embryonic development, wound repair, immune responses, and tumor cell invasion and metastasis. Extensive studies have attempted to reveal the molecular mechanisms behind cell migration; however, they remain largely unclear. Bioactive compounds that modulate cell migration show promise as not only extremely powerful tools for studying the mechanisms behind cell migration but also as drug seeds for chemotherapy against tumor metastasis. Therefore, we have screened cell migration inhibitors and analyzed their mechanisms for the inhibition of cell migration. In this mini-review, we introduce our chemical and biological studies of three cell migration inhibitors: moverastin, UTKO1, and BU-4664L.

  11. SDA, a DNA aptamer inhibiting E- and P-selectin mediated adhesion of cancer and leukemia cells, the first and pivotal step in transendothelial migration during metastasis formation.

    Directory of Open Access Journals (Sweden)

    Rassa Faryammanesh

    Full Text Available Endothelial (E- and platelet (P- selectin mediated adhesion of tumor cells to vascular endothelium is a pivotal step of hematogenous metastasis formation. Recent studies have demonstrated that selectin deficiency significantly reduces metastasis formation in vivo. We selected an E- and P-Selectin specific DNA Aptamer (SDA via SELEX (Systematic Evolution of Ligands by EXponential enrichment with a K(d value of approximately 100 nM and the capability of inhibiting the interaction between selectin and its ligands. Employing human colorectal cancer (HT29 and leukemia (EOL-1 cell lines we could demonstrate an anti-adhesive effect for SDA in vitro. Under physiological shear stress conditions in a laminar flow adhesion assay, SDA inhibited dynamic tumor cell adhesion to immobilized E- or P-selectin. The stability of SDA for more than two hours allowed its application in cell-cell adhesion assays in cell culture medium. When adhesion of HT29 cells to TNFα-stimulated E-selectin presenting human pulmonary microvascular endothelial cells was analyzed, inhibition via SDA could be demonstrated as well. In conclusion, SDA is a potential new therapeutic agent that antagonizes selectin-mediated adhesion during metastasis formation in human malignancies.

  12. Pericytes limit tumor cell metastasis

    DEFF Research Database (Denmark)

    Xian, Xiaojie; Håkansson, Joakim; Ståhlberg, Anders

    2006-01-01

    Previously we observed that neural cell adhesion molecule (NCAM) deficiency in beta tumor cells facilitates metastasis into distant organs and local lymph nodes. Here, we show that NCAM-deficient beta cell tumors grew leaky blood vessels with perturbed pericyte-endothelial cell-cell interactions...... and deficient perivascular deposition of ECM components. Conversely, tumor cell expression of NCAM in a fibrosarcoma model (T241) improved pericyte recruitment and increased perivascular deposition of ECM molecules. Together, these findings suggest that NCAM may limit tumor cell metastasis by stabilizing...... the microvessel wall. To directly address whether pericyte dysfunction increases the metastatic potential of solid tumors, we studied beta cell tumorigenesis in primary pericyte-deficient Pdgfb(ret/ret) mice. This resulted in beta tumor cell metastases in distant organs and local lymph nodes, demonstrating a role...

  13. Invasive cancer cells and metastasis

    Science.gov (United States)

    Mierke, Claudia Tanja

    2013-12-01

    the biophysical state of the primary tumor cell. To determine the cytoskeletal dynamics they chose magnetic twisting cytometry, where the spontaneous motion of surface bound marker beads was measured, which is a measure for the cytoskeletal remodeling dynamics. The group of Katarina Wolf measured the stiffness of the cell nucleus because it is the largest and stiffest organelle, which may hinder the migration of invasive tumor cells through dense connective tissue [2]. They combined atomic force confocal microscopy for measurement of bulk nuclear stiffness (the inverse of the compressibility) with simultaneous visualization of the cantilever-nucleus contact as well as monitoring of the cell's fate. The dynamics of tissue topology such as the mixing of compartments during cancer invasion and metastasis were theoretically analyzed by Lance L Munn [3]. In particular, he presented a mathematical model of tissue repair and tumor growth based on collective cell migration that simulates a wide range of tumor behaviors using correct tissue compartmentalization and connectivity. In the future, the topological analysis could be helpful for tumor diagnosis or monitoring tumor therapy. The group of Cynthia A Reinhart-King analyzed how the topological guidance of a 3D tumor cell migration at an interface of collagen densities affects cell motility [4]. In particular, they mimicked the heterogeneities in density of the tumor stroma by preparing gels with an interface of high and low density collagen gels and investigated how this affects cell motility. The author's review paper details the effect of focal adhesion proteins such as focal adhesion kinase (FAK) on cell motility and how this effect is driven by mechanical alterations of cells expressing FAK compared to cells with FAK knock-out [5]. In particular, it focused on mechanical properties regulated by FAK in comparison to the mechano-regulating protein vinculin. This article highlights that both focal adhesion proteins

  14. Cancer stem cells and metastasis.

    Science.gov (United States)

    Sampieri, Katia; Fodde, Riccardo

    2012-06-01

    Cancer stem cells (CSCs) represent a subpopulation of tumour cells endowed with self-renewal and multi-lineage differentiation capacity but also with an innate resistance to cytotoxic agents, a feature likely to pose major clinical challenges towards the complete eradication of minimal residual disease in cancer patients. Operationally, CSCs are defined by their tumour-propagating ability when serially transplanted into immune-compromised mice and by their capacity to fully recapitulate the original heterogeneity of cell types observed in the primary lesions they are derived from. CSCs were first identified in haematopoietic malignancies and later in a broad spectrum of solid tumours including those of the breast, colon and brain. Notably, several CSC characteristics are relevant to metastasis, such as motility, invasiveness and, as mentioned above, resistance to DNA damage-induced apoptosis. Here, we have reviewed the current literature on the relation between CSCs and metastasis formation. Preliminary studies on cancer cell lines and patient-derived material suggest a rate-limiting role for stem-like cells in the processes of tumour cell dissemination and metastasis formation. However, additional studies are needed to deliver formal proof of their identity as the cell of origin of recurrences at distant organ sites. Nevertheless, several studies have already provided pre-clinical evidence of the efficacy of novel therapies directed against disseminated CSCs.

  15. G Protein Coupled Receptor Kinase 3 Regulates Breast Cancer Migration, Invasion, and Metastasis.

    Directory of Open Access Journals (Sweden)

    Matthew J Billard

    Full Text Available Triple negative breast cancer (TNBC is a heterogeneous disease that has a poor prognosis and limited treatment options. Chemokine receptor interactions are important modulators of breast cancer metastasis; however, it is now recognized that quantitative surface expression of one important chemokine receptor, CXCR4, may not directly correlate with metastasis and that its functional activity in breast cancer may better inform tumor pathogenicity. G protein coupled receptor kinase 3 (GRK3 is a negative regulator of CXCR4 activity, and we show that GRK expression correlates with tumorigenicity, molecular subtype, and metastatic potential in human tumor microarray analysis. Using established human breast cancer cell lines and an immunocompetent in vivo mouse model, we further demonstrate that alterations in GRK3 expression levels in tumor cells directly affect migration and invasion in vitro and the establishment of distant metastasis in vivo. The effects of GRK3 modulation appear to be specific to chemokine-mediated migration behaviors without influencing tumor cell proliferation or survival. These data demonstrate that GRK3 dysregulation may play an important part in TNBC metastasis.

  16. Regulator of calcineurin 1 modulates cancer cell migration in vitro

    OpenAIRE

    Espinosa, Allan V.; Shinohara, Motoo; Porchia,Leonardo M; Chung, Yun Jae; McCarty, Samantha; Saji, Motoyasu; Ringel, Matthew D.

    2009-01-01

    Metastasis suppressors and other regulators of cell motility play an important role in tumor invasion and metastases. We previously identified that activation of the G protein coupled receptor 54 (GPR54) by the metastasis suppressor metastin inhibits cell migration in association with overexpression of Regulator of calcineurin 1 (RCAN1), an endogenous regulator of calcineurin. Calcineurin inhibitors also blocked cell migration in vitro and RCAN1 protein levels were reduced in nodal metastases...

  17. Metastasis Is Cell Motility Disease

    Institute of Scientific and Technical Information of China (English)

    Kazuyuki ITOH

    2009-01-01

    @@ Multidisciplinary approach (surgery, chemotherapy and radiation) for the primary site of cancer is now almost established, however, recurrence, inva-sion and metastasis are still life threatening, thus the effort of fighting against metastasis is critical and crucial.

  18. Prostate cancer and metastasis initiating stem cells

    Institute of Scientific and Technical Information of China (English)

    Kathleen Kelly; Juan Juan Yin

    2008-01-01

    Androgen refractory prostate cancer metastasis is a major clinical challenge.Mechanism-based approaches to treating prostate cancer metastasis require an understanding of the developmental origin of the metastasis-initiating cell.Properties of prostate cancer metastases such as plasticity with respect to differentiated phenotype and androgen independence are consistent with the transformation of a prostate epithelial progenitor or stem cell leading to metastasis.This review focuses upon current evidence and concepts addressing the identification and properties of normal prostate stem or progenitor cells and their transformed counterparts.

  19. Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth

    Directory of Open Access Journals (Sweden)

    Maria E. Gonzalez

    2017-01-01

    Full Text Available Increased collagen deposition by breast cancer (BC-associated mesenchymal stem/multipotent stromal cells (MSC promotes metastasis, but the mechanisms are unknown. Here, we report that the collagen receptor discoidin domain receptor 2 (DDR2 is essential for stromal-BC communication. In human BC metastasis, DDR2 is concordantly upregulated in metastatic cancer and multipotent mesenchymal stromal cells. In MSCs isolated from human BC metastasis, DDR2 maintains a fibroblastic phenotype with collagen deposition and induces pathological activation of DDR2 signaling in BC cells. Loss of DDR2 in MSCs impairs their ability to promote DDR2 phosphorylation in BC cells, as well as BC cell alignment, migration, and metastasis. Female ddr2-deficient mice homozygous for the slie mutation show inefficient spontaneous BC metastasis. These results point to a role for mesenchymal stem cell DDR2 in metastasis and suggest a therapeutic approach for metastatic BC.

  20. Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth.

    Science.gov (United States)

    Gonzalez, Maria E; Martin, Emily E; Anwar, Talha; Arellano-Garcia, Caroline; Medhora, Natasha; Lama, Arjun; Chen, Yu-Chih; Tanager, Kevin S; Yoon, Euisik; Kidwell, Kelley M; Ge, Chunxi; Franceschi, Renny T; Kleer, Celina G

    2017-01-31

    Increased collagen deposition by breast cancer (BC)-associated mesenchymal stem/multipotent stromal cells (MSC) promotes metastasis, but the mechanisms are unknown. Here, we report that the collagen receptor discoidin domain receptor 2 (DDR2) is essential for stromal-BC communication. In human BC metastasis, DDR2 is concordantly upregulated in metastatic cancer and multipotent mesenchymal stromal cells. In MSCs isolated from human BC metastasis, DDR2 maintains a fibroblastic phenotype with collagen deposition and induces pathological activation of DDR2 signaling in BC cells. Loss of DDR2 in MSCs impairs their ability to promote DDR2 phosphorylation in BC cells, as well as BC cell alignment, migration, and metastasis. Female ddr2-deficient mice homozygous for the slie mutation show inefficient spontaneous BC metastasis. These results point to a role for mesenchymal stem cell DDR2 in metastasis and suggest a therapeutic approach for metastatic BC.

  1. Upregulated expression of CAP1 is associated with tumor migration and metastasis in hepatocellular carcinoma.

    Science.gov (United States)

    Liu, Yanhua; Cui, Xiaopeng; Hu, Baoying; Lu, Cuihua; Huang, Xiaodong; Cai, Jing; He, Song; Lv, Liting; Cong, Xia; Liu, Guoliang; Zhang, Yixin; Ni, Runzhou

    2014-03-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers that exhibits high incidences of intrahepatic metastasis and tumor recurrence. Adenylate cyclase-associated protein 1 (CAP1), a protein involved in the regulation of actin filaments, was recently reported to play a role in cell motility and the pathology of pancreatic cancer. In this study, we examined a potential role of CAP1 in HCC progression, and found that CAP1 was overexpressed in HCC specimens compared with adjacent noncancerous liver tissues by Western blot analysis and real-time PCR assay. Further, immunohistochemical analysis in 107 HCC specimens revealed that overexpression of CAP1 was closely correlated only with tumor metastasis, but not with other clinicopathologic parameters. Univariate and multivariate survival analyses showed that CAP1 could be an independent prognostic factor for patients' survival. In addition, immunofluorescent assay demonstrated that CAP1 was colocalized with actin in the leading edge of lamellipodium in HCC cells. Importantly, knocking-down the expression of CAP1 using small interfering RNA (siRNA) targeting CAP1 led to impaired migration of HCC cells. Collectively, our results indicated that upregulated expression of CAP1 might contribute heavily to the metastasis of HCC.

  2. Analysing immune cell migration.

    Science.gov (United States)

    Beltman, Joost B; Marée, Athanasius F M; de Boer, Rob J

    2009-11-01

    The visualization of the dynamic behaviour of and interactions between immune cells using time-lapse video microscopy has an important role in modern immunology. To draw robust conclusions, quantification of such cell migration is required. However, imaging experiments are associated with various artefacts that can affect the estimated positions of the immune cells under analysis, which form the basis of any subsequent analysis. Here, we describe potential artefacts that could affect the interpretation of data sets on immune cell migration. We propose how these errors can be recognized and corrected, and suggest ways to prevent the data analysis itself leading to biased results.

  3. Collective cell migration: a mechanistic perspective.

    Science.gov (United States)

    Vedula, Sri Ram Krishna; Ravasio, Andrea; Lim, Chwee Teck; Ladoux, Benoit

    2013-11-01

    Collective cell migration is fundamental to gaining insights into various important biological processes such as wound healing and cancer metastasis. In particular, recent in vitro studies and in silico simulations suggest that mechanics can explain the social behavior of multicellular clusters to a large extent with minimal knowledge of various cellular signaling pathways. These results suggest that a mechanistic perspective is necessary for a comprehensive and holistic understanding of collective cell migration, and this review aims to provide a broad overview of such a perspective.

  4. Human neutrophils facilitate tumor cell transendothelial migration.

    LENUS (Irish Health Repository)

    Wu, Q D

    2012-02-03

    Tumor cell extravasation plays a key role in tumor metastasis. However, the precise mechanisms by which tumor cells migrate through normal vascular endothelium remain unclear. In this study, using an in vitro transendothelial migration model, we show that human polymorphonuclear neutrophils (PMN) assist the human breast tumor cell line MDA-MB-231 to cross the endothelial barrier. We found that tumor-conditioned medium (TCM) downregulated PMN cytocidal function, delayed PMN apoptosis, and concomitantly upregulated PMN adhesion molecule expression. These PMN treated with TCM attached to tumor cells and facilitated tumor cell migration through different endothelial monolayers. In contrast, MDA-MB-231 cells alone did not transmigrate. FACScan analysis revealed that these tumor cells expressed high levels of intercellular adhesion molecule-1 (ICAM-1) but did not express CD11a, CD11b, or CD18. Blockage of CD11b and CD18 on PMN and of ICAM-1 on MDA-MB-231 cells significantly attenuated TCM-treated, PMN-mediated tumor cell migration. These tumor cells still possessed the ability to proliferate after PMN-assisted transmigration. These results indicate that TCM-treated PMN may serve as a carrier to assist tumor cell transendothelial migration and suggest that tumor cells can exploit PMN and alter their function to facilitate their extravasation.

  5. Emergence of oligarchy in collective cell migration

    Science.gov (United States)

    Schumacher, Linus; Maini, Philip; Baker, Ruth

    Identifying the principles of collective cell migration has the potential to help prevent birth defects, improve regenerative therapies and develop model systems for cancer metastasis. In collaboration with experimental biologists, we use computational simulations of a hybrid model, comprising individual-based stochastic cell movement coupled to a reaction-diffusion equation for a chemoattractant, to explore the role of cell specialisation in the guidance of collective cell migration. In the neural crest, an important migratory cell population in vertebrate embryo development, we present evidence that just a few cells are guiding group migration in a cell-induced chemoattractant gradient that determines the switch between ``leader'' and ``follower'' behaviour in individual cells. This leads us to more generally consider under what conditions cell specialisation might become advantageous for collective migration. Alternatively, individual cell responses to locally different microenvironmental conditions could create the (artefactual) appearance of heterogeneity in a population of otherwise identical cellular agents. We explore these questions using a self-propelled particle model as a minimal description for collective cell migration in two and three dimensions.

  6. Gastric metastasis by lung small cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    Giovanni Casella; Camillo Di Bella; Antonino Roberto Cambareri; Carmelo Antonio Buda; Gianluigi Corti; Filippo Magri; Stefano Crippa; Vittorio Baldini

    2006-01-01

    Metastatic tumors of the gastrointestinal tract are rare. We describe a case of gastric metastasis due to primary lung cancer, revealed by an upper gastrointestinal endoscopy (UGIE). Haematogenous metastases to the stomach are a rare event. To our knowledge, only 55 cases have been described in the international literature. In these patients, the prognosis is very poor. We report herein a case of gastric metastasis by lung small cell carcinoma,with a review of the literature about this rare entity.

  7. Gastric metastasis by lung small cell carcinoma

    Science.gov (United States)

    Casella, Giovanni; Bella, Camillo Di; Cambareri, Antonino Roberto; Buda, Carmelo Antonio; Corti, Gianluigi; Magri, Filippo; Crippa, Stefano; Baldini, Vittorio

    2006-01-01

    Metastatic tumors of the gastrointestinal tract are rare. We describe a case of gastric metastasis due to primary lung cancer, revealed by an upper gastrointestinal endoscopy (UGIE). Haematogenous metastases to the stomach are a rare event. To our knowledge, only 55 cases have been described in the international literature. In these patients, the prognosis is very poor. We report herein a case of gastric metastasis by lung small cell carcinoma, with a review of the literature about this rare entity. PMID:16810769

  8. Metastasis regulation by PPARD expression in cancer cells

    Science.gov (United States)

    Zuo, Xiangsheng; Xu, Weiguo; Xu, Min; Tian, Rui; Moussalli, Micheline J.; Mao, Fei; Zheng, Xiaofeng; Wang, Jing; Morris, Jeffrey S.; Eng, Cathy; Maru, Dipen M.; Rashid, Asif; Broaddus, Russell; Wei, Daoyan; Hung, Mien-Chie; Sood, Anil K.

    2017-01-01

    Peroxisome proliferator–activated receptor–δ (PPARD) is upregulated in many major human cancers, but the role that its expression in cancer cells has in metastasis remains poorly understood. Here, we show that specific PPARD downregulation or genetic deletion of PPARD in cancer cells significantly repressed metastasis in various cancer models in vivo. Mechanistically, PPARD promoted angiogenesis via interleukin 8 in vivo and in vitro. Analysis of transcriptome profiling of HCT116 colon cancer cells with or without genetic deletion of PPARD and gene expression patterns in The Cancer Genome Atlas colorectal adenocarcinoma database identified novel pro-metastatic genes (GJA1, VIM, SPARC, STC1, SNCG) as PPARD targets. PPARD expression in cancer cells drastically affected epithelial-mesenchymal transition, migration, and invasion, further underscoring its necessity for metastasis. Clinically, high PPARD expression in various major human cancers (e.g., colorectal, lung, breast) was associated with significantly reduced metastasis-free survival. Our results demonstrate that PPARD, a druggable protein, is an important molecular target in metastatic cancer. PMID:28097239

  9. Osteopontin knockdown suppresses non-small cell lung cancer cell invasion and metastasis

    Institute of Scientific and Technical Information of China (English)

    SUN Bing-sheng; YOU Jian; LI Yue; ZHANG Zhen-fa; WANG Chang-li

    2013-01-01

    Background Osteopontin (OPN) was identified as one of the leading genes that promote the metastasis of malignant tumor.However,the mechanism by which OPN mediates metastasis in non-small cell lung cancer (NSCLC) remains unknown.The aim of the study is to investigate the biological significance and the related molecular mechanism of OPN expression in lung cancer cell line.Methods Lentiviral-mediated RNA interference was applied to inhibit OPN expression in metastatic human NSCLC cell line (A549).The invasion,proliferation,and metastasis were evaluated OPN-silenced in A549 cells in vitro and in vivo.The related mechanism was further investigated.Results Interestingly,OPN knockdown significantly suppressed the invasiveness of A549 cells,but had only a minor effect on the cellular migration and proliferation.Moreover,we demonstrated that OPN knockdown significantly reduced the levels of matrix metalloproteinase (MMP)-2 and urokinase plasminogen activator (uPA),and led to an obviousinhibition of both in vitro invasion and in vivo lung metastasis of A549 cells (P <0.001).Conclusions Our data demonstrate that OPN contributes to A549 cell metastasis by stimulating cell invasion,independent of cellular migration and proliferation.OPN could be a new treatment target of NSCLC.

  10. Nuclear stiffening inhibits migration of invasive melanoma cells

    OpenAIRE

    Ribeiro, Alexandre J. S.; Khanna, Payal; Sukumar, Aishwarya; Dong, Cheng; Dahl, Kris Noel

    2014-01-01

    During metastasis, melanoma cells must be sufficiently deformable to squeeze through extracellular barriers with small pore sizes. We visualize and quantify deformability of single cells using micropipette aspiration and examine the migration potential of a population of melanoma cells using a flow migration apparatus. We artificially stiffen the nucleus with recombinant overexpression of Δ50 lamin A, which is found in patients with Hutchison Gilford progeria syndrome and in aged individuals....

  11. Modeling traction forces in collective cell migration

    Science.gov (United States)

    Zimmermann, Juliane; Basan, Markus; Hayes, Ryan L.; Rappel, Wouter-Jan; Levine, Herbert

    2015-03-01

    Collective cell migration is an important process in embryonic development, wound healing, and cancer metastasis. We have developed a particle-based simulation for collective cell migration that describes flow patterns and finger formation at the tissue edge observed in wound healing experiments. We can apply methods for calculating intercellular stress to our simulation model, and have thereby provided evidence for the validity of a stress reconstitution method from traction forces used in experiments. To accurately capture experimentally measured traction forces and stresses in the tissue, which are mostly tensile, we have to include intracellular acto-myosin contraction into our simulation. We can then reproduce the experimentally observed behavior of cells moving around a circular obstacle, and suggest underlying mechanisms for cell-cell alignment and generation of traction force patterns.

  12. Microfluidic device with dual mechanical cues for cell migration investigation.

    Science.gov (United States)

    Tsai, Chin-Hsiung; Kuo, Po-Ling

    2013-01-01

    Cell migration plays an important role in numerous physiological and pathological conditions, such as angiogenesis, wound healing and cancer metastasis. Understanding the fundamental mechanisms of cell migration is crucial to develop strategies for disease treatment and regenerative medicine. Several biomechanical cues have been well studied about their effects on guiding cell migration. However, the effects of dual or multiple cues on cell migration are barely addressed. In this work, we developed a microfluidic-based device to study the combinatory effects of osmotic and stiffness gradient on cell migration. Computer simulation and experimental validation showed that the device was capable of providing stable osmotic and stiffness gradient to cultured cells at the same time. Preliminary results suggest that our device has a valuable potential in studying cell migration in complex conditions which better recapitulate the complex environmental conditions in vivo.

  13. The Biological Effects of Dickkopf1 on Small Cell Lung Cancer Cells and Bone Metastasis.

    Science.gov (United States)

    Pang, Hailin; Ma, Ningqiang; Jiao, Mi; Shen, Weiwei; Xin, Bo; Wang, Tongfei; Zhang, Feng; Liu, Lili; Zhang, Helong

    2017-01-02

    The bone is among the most common sites of metastasis in patients with lung cancer. Over 30%-40% of lung cancers can develop bone metastasis, and no effective therapeutic methods exist in clinic cases. Wnt/β-catenin signaling and Dickkopf1 (DKK1) play important roles in the progression of lung cancer, which preferentially metastasizes to the skeleton. However, the role of DKK1 in osteotropism of small cell lung cancer (SCLC) remains to be elucidated. This study aimed to define the role of DKK1 in SCLC bone metastasis and investigate the underlying mechanisms. Our results demonstrated that the expression level of DKK1 was dramatically higher in bone metastatic SCLC cells (SBC-5 cell line) compared with that in cells without bone metastatic ability (SBC-3 cell line). Therefore, we hypothesized that DKK1 was involved in the bone metastasis of SCLC. We then suppressed the DKK1 expression in SBC-5 cells by RNAi and found that downregulation of DKK1 can inhibit cell proliferation, colony formation, cell migration, and invasion, but increase the apoptosis rate. Downregulation of DKK1 did not affect the cell cycle progression of SBC-5 cells in vitro. In vivo, downregulated DKK1 in SBC-5 cells resulted in attenuated bone metastasis. These results indicated that DKK1 may be an important regulator in bone metastases of SCLC, and targeting DKK1 may be an effective method to prevent and treat skeleton metastases in SCLC cases.

  14. Expression of aquaporin-1 in SMMC-7221 liver carcinoma cells promotes cell migration

    Institute of Scientific and Technical Information of China (English)

    LI Yongming; FENG Xuechao; YANG Hong; MA Tonghui

    2006-01-01

    Migration of tumor cells is a crucial step in tumor invasion and metastasis. Here we provide evidence that aquaporin expression is involved in tumor cell migration. RT-PCR, immunofluorescence and Western blot analysis demonstrated the AQP1 protein expression on the plasma membrane of SMMC-7221 human hepatoma cells. SMMC-7221 cell clones with high (SMMC-7221hPf) and low (SMMC-7221/Pf) water permeability were identified by functional assays with corresponding high and low AQP1 expression. Cell migration rate was remarkably higher in SMMC-7221hPf cells than SMMC-7221/Pf cells, assessed by Boyden chamber and wound healing assays, whereas cell growth and adhesion were not different. Adenovirus-mediated AQP1 expression in SMMC-7221/Pf cells increased their water permeability and migration rate. These results provide the first evidence that aquaporin-mediated membrane water permeability enhances tumor cell migration and may be associated with tumor invasion and metastasis.

  15. Rho family proteins in cell adhesion and cell migration.

    Science.gov (United States)

    Evers, E E; Zondag, G C; Malliri, A; Price, L S; ten Klooster, J P; van der Kammen, R A; Collard, J G

    2000-06-01

    Cell migration and the regulation of cadherin-mediated homotypic cell-cell interactions are critical events during development, morphogenesis and wound healing. Aberrations in signalling pathways involved in the regulation of cell migration and cadherin-mediated cell-cell adhesion contribute to tumour invasion and metastasis. The rho family proteins, including cdc42, rac1 and rhoA, regulate signalling pathways that mediate the distinct actin cytoskeleton changes required for both cellular motility and cell-cell adhesion. Recent studies indicate that rac directly influences rho activity at the GTPase level and that the reciprocal balance between rac and rho activity can determine epithelial or mesenchymal cell morphology and migratory behaviour of epithelial (tumour) cells.

  16. Fibronectin 1 promotes migration and invasion of papillary thyroid cancer and predicts papillary thyroid cancer lymph node metastasis

    Science.gov (United States)

    Xia, Shujun; Wang, Chuandong; Postma, Emily Louise; Yang, Yanhua; Ni, Xiaofeng; Zhan, Weiwei

    2017-01-01

    Lymph node metastasis (LNM) is common in papillary thyroid cancer (PTC), and is an indicator of recurrence. The detailed molecular mechanism of LNM in PTC has not been well described. This study aimed to investigate the role of fibronectin 1 in PTC LNM and its clinical relevance. The expression of fibronectin 1 was confirmed in PTC tissues and cell lines. A correlation analysis was conducted and a receiver-operating characteristic curve obtained. The effect of fibronectin 1 on the proliferation of PTC cell lines was performed using a colony-formation assay and Cell Counting Kit 8. Cell-cycle analysis was performed with a flow-cytometry assay. Migration and invasion ability were evaluated by transwell and wound-healing assays. Fibronectin 1 was overexpressed in metastasized PTC. Overexpressed fibronectin 1 was positively correlated with PTC LNM. Receiver-operating characteristic analysis showed that the diagnostic accuracy of fibronectin 1 was 81.1%, with sensitivity of 80% and specificity of 82%. Overexpression of fibronectin 1 promoted proliferation, migration, and invasion in PTC. Fibronectin 1 plays a critical role in PTC metastasis by modulating the proliferation, migration, and invasion ability of PTC cells, and it is a valuable diagnostic biomarker for predicting PTC LNM. PMID:28367057

  17. Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan

    Science.gov (United States)

    Maishi, Nako; Ohba, Yusuke; Akiyama, Kosuke; Ohga, Noritaka; Hamada, Jun-ichi; Nagao-Kitamoto, Hiroko; Alam, Mohammad Towfik; Yamamoto, Kazuyuki; Kawamoto, Taisuke; Inoue, Nobuo; Taketomi, Akinobu; Shindoh, Masanobu; Hida, Yasuhiro; Hida, Kyoko

    2016-01-01

    Tumour blood vessels are gateways for distant metastasis. Recent studies have revealed that tumour endothelial cells (TECs) demonstrate distinct phenotypes from their normal counterparts. We have demonstrated that features of TECs are different depending on tumour malignancy, suggesting that TECs communicate with surrounding tumour cells. However, the contribution of TECs to metastasis has not been elucidated. Here, we show that TECs actively promote tumour metastasis through a bidirectional interaction between tumour cells and TECs. Co-implantation of TECs isolated from highly metastatic tumours accelerated lung metastases of low metastatic tumours. Biglycan, a small leucine-rich repeat proteoglycan secreted from TECs, activated tumour cell migration via nuclear factor-κB and extracellular signal–regulated kinase 1/2. Biglycan expression was upregulated by DNA demethylation in TECs. Collectively, our results demonstrate that TECs are altered in their microenvironment and, in turn, instigate tumour cells to metastasize, which is a novel mechanism for tumour metastasis. PMID:27295191

  18. New dimensions in cell migration

    NARCIS (Netherlands)

    Friedl, P.; Sahai, E.; Weiss, S.; Yamada, K.M.

    2012-01-01

    Studies of cell migration in three-dimensional (3D) cell culture systems and in vivo have revealed several differences when compared with cell migration in two dimensions, including their morphology and mechanical and signalling control. Here, researchers assess the contribution of 3D models to our

  19. Arctigenin Inhibits Lung Metastasis of Colorectal Cancer by Regulating Cell Viability and Metastatic Phenotypes.

    Science.gov (United States)

    Han, Yo-Han; Kee, Ji-Ye; Kim, Dae-Seung; Mun, Jeong-Geon; Jeong, Mi-Young; Park, Sang-Hyun; Choi, Byung-Min; Park, Sung-Joo; Kim, Hyun-Jung; Um, Jae-Young; Hong, Seung-Heon

    2016-08-27

    Arctigenin (ARC) has been shown to have an anti-cancer effect in various cell types and tissues. However, there have been no studies concerning metastatic colorectal cancer (CRC). In this study, we investigated the anti-metastatic properties of ARC on colorectal metastasis and present a potential candidate drug. ARC induced cell cycle arrest and apoptosis in CT26 cells through the intrinsic apoptotic pathway via MAPKs signaling. In several metastatic phenotypes, ARC controlled epithelial-mesenchymal transition (EMT) through increasing the expression of epithelial marker E-cadherin and decreasing the expressions of mesenchymal markers; N-cadherin, vimentin, β-catenin, and Snail. Moreover, ARC inhibited migration and invasion through reducing of matrix metalloproteinase-2 (MMP-2) and MMP-9 expressions. In an experimental metastasis model, ARC significantly inhibited lung metastasis of CT26 cells. Taken together, our study demonstrates the inhibitory effects of ARC on colorectal metastasis.

  20. Arctigenin Inhibits Lung Metastasis of Colorectal Cancer by Regulating Cell Viability and Metastatic Phenotypes

    Directory of Open Access Journals (Sweden)

    Yo-Han Han

    2016-08-01

    Full Text Available Arctigenin (ARC has been shown to have an anti-cancer effect in various cell types and tissues. However, there have been no studies concerning metastatic colorectal cancer (CRC. In this study, we investigated the anti-metastatic properties of ARC on colorectal metastasis and present a potential candidate drug. ARC induced cell cycle arrest and apoptosis in CT26 cells through the intrinsic apoptotic pathway via MAPKs signaling. In several metastatic phenotypes, ARC controlled epithelial-mesenchymal transition (EMT through increasing the expression of epithelial marker E-cadherin and decreasing the expressions of mesenchymal markers; N-cadherin, vimentin, β-catenin, and Snail. Moreover, ARC inhibited migration and invasion through reducing of matrix metalloproteinase-2 (MMP-2 and MMP-9 expressions. In an experimental metastasis model, ARC significantly inhibited lung metastasis of CT26 cells. Taken together, our study demonstrates the inhibitory effects of ARC on colorectal metastasis.

  1. [Intrascrotal metastasis in a renal cell carcinoma].

    Science.gov (United States)

    Calleja Escudero, J; Pascual Samaniego, M; Martín Blanco, S; de Castro Olmedo, C; Gonzalo, V; Fernández del Busto, E

    2004-04-01

    The present article reports a case of intrascrotal metastasis of renal adenocarcinoma. This is an unusual case. A 66-year-old male patient undewent right radical nephrectomy and cavotomy for renal cell carcinoma with renal vein infiltration and thrombus in cava. Six months later the patient present with a nodulous enlargement intrascrotal and roots of penis. And he died 15 moths after nephrectomy. Usually intrascrotal metastases are a late event in the course after detection of a renal carcinoma.

  2. MiR-132 prohibits proliferation, invasion, migration, and metastasis in breast cancer by targeting HN1

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Zhan-Guo, E-mail: zhang_zhanguo@hotmail.com; Chen, Wei-Xun, E-mail: chenweixunclark@163.com; Wu, Yan-Hui, E-mail: wuyanhui84@126.com; Liang, Hui-Fang, E-mail: lianghuifang1997@126.com; Zhang, Bi-Xiang, E-mail: bixiangzhang@163.com

    2014-11-07

    Highlights: • MiR-132 is down-regulated in breast cancer tissues and cell lines. • MiR-132 directly regulates HN1 by binding its 3′ UTR. • MiR-132 shows regulatory role in proliferation, invasion, migration and metastasis. • HN1 is involved in miR-132-mediated cell behavior. • Aberrant HN1 is associated with worse overall survival of breast cancer patients. - Abstract: Accumulating evidence indicates that miRNAs play critical roles in tumorigenesis and cancer progression. This study aims to investigate the role and the underlying mechanism of miR-132 in breast cancer. Here, we report that miR-132 is significantly down-regulated in breast cancer tissues and cancer cell lines. Additional study identifies HN1 as a novel direct target of miR-132. MiR-132 down-regulates HN1 expression by binding to the 3′ UTR of HN1 transcript, thereby, suppressing multiple oncogenic traits such as cancer cell proliferation, invasion, migration and metastasis in vivo and in vitro. Overexpression of HN1 restores miR-132-suppressed malignancy. Importantly, higher HN1 expression is significantly associated with worse overall survival of breast cancer patients. Taken together, our data demonstrate a critical role of miR-132 in prohibiting cell proliferation, invasion, migration and metastasis in breast cancer through direct suppression of HN1, supporting the potential utility of miR-132 as a novel therapeutic strategy against breast cancer.

  3. Cell migration towards CXCL12 in leukemic cells compared to breast cancer cells.

    Science.gov (United States)

    Mills, Shirley C; Goh, Poh Hui; Kudatsih, Jossie; Ncube, Sithembile; Gurung, Renu; Maxwell, Will; Mueller, Anja

    2016-04-01

    Chemotaxis or directed cell migration is mediated by signalling events initiated by binding of chemokines to their cognate receptors and the activation of a complex signalling cascade. The molecular signalling pathways involved in cell migration are important to understand cancer cell metastasis. Therefore, we investigated the molecular mechanisms of CXCL12 induced cell migration and the importance of different signalling cascades that become activated by CXCR4 in leukemic cells versus breast cancer cells. We identified Src kinase as being essential for cell migration in both cancer types, with strong involvement of the Raf/MEK/ERK1/2 pathway. We did not detect any involvement of Ras or JAK2/STAT3 in CXCL12 induced migration in Jurkat cells. Preventing PKC activation with inhibitors does not affect migration in Jurkat cells at all, unlike in the adherent breast cancer cell line MCF-7 cells. However, in both cell lines, knock down of PKCα prevents migration towards CXCL12, whereas the expression of PKCζ is less crucial for migration. PI3K activation is essential in both cell types, however LY294002 usage in MCF-7 cells does not block migration significantly. These results highlight the importance of verifying specific signalling pathways in different cell settings and with different approaches.

  4. Metastasis in renal cell carcinoma: Biology and implications for therapy

    Directory of Open Access Journals (Sweden)

    Jun Gong

    2016-10-01

    Full Text Available Although multiple advances have been made in systemic therapy for renal cell carcinoma (RCC, metastatic RCC remains incurable. In the current review, we focus on the underlying biology of RCC and plausible mechanisms of metastasis. We further outline evolving strategies to combat metastasis through adjuvant therapy. Finally, we discuss clinical patterns of metastasis in RCC and how distinct systemic therapy approaches may be considered based on the anatomic location of metastasis.

  5. Leader cells regulate collective cell migration via Rac activation in the downstream signaling of integrin beta 1 and PI3K

    OpenAIRE

    YAMAGUCHI, Naoya; Mizutani, Takeomi; Kawabata, Kazushige; Haga, Hisashi

    2015-01-01

    Collective cell migration plays a crucial role in several biological processes, such as embryonic development, wound healing, and cancer metastasis. Here, we focused on collectively migrating Madin-Darby Canine Kidney (MDCK) epithelial cells that follow a leader cell on a collagen gel to clarify the mechanism of collective cell migration. First, we removed a leader cell from the migrating collective with a micromanipulator. This then caused disruption of the cohesive migration of cells that f...

  6. Invadopodia Are Required for Cancer Cell Extravasation and Are a Therapeutic Target for Metastasis

    Directory of Open Access Journals (Sweden)

    Hon S. Leong

    2014-09-01

    Full Text Available Tumor cell extravasation is a key step during cancer metastasis, yet the precise mechanisms that regulate this dynamic process are unclear. We utilized a high-resolution time-lapse intravital imaging approach to visualize the dynamics of cancer cell extravasation in vivo. During intravascular migration, cancer cells form protrusive structures identified as invadopodia by their enrichment of MT1-MMP, cortactin, Tks4, and importantly Tks5, which localizes exclusively to invadopodia. Cancer cells extend invadopodia through the endothelium into the extravascular stroma prior to their extravasation at endothelial junctions. Genetic or pharmacological inhibition of invadopodia initiation (cortactin, maturation (Tks5, or function (Tks4 resulted in an abrogation of cancer cell extravasation and metastatic colony formation in an experimental mouse lung metastasis model. This provides direct evidence of a functional role for invadopodia during cancer cell extravasation and distant metastasis and reveals an opportunity for therapeutic intervention in this clinically important process.

  7. Overexpression of p28GANK accelerates the metastasis of oesophageal squamous cell carcinoma.

    Science.gov (United States)

    Tang, Shanhong; Qin, Jianping; Liu, Weihui; Zheng, Xiushan; Wu, Xiaoling; Xu, Hui; Qiao, Lijuan; Fan, Quanshui; Zeng, Weizheng; Jiang, Mingde

    2015-06-01

    The present study aimed to evaluate the effects of p28GANK expression on the metastasis of oesophageal squamous cell carcinoma (ESCC) tissues and to investigate its roles in the metastasis of highly invasive and non‑invasive ESCC cell lines. Quantitative polymerase chain reaction (qPCR) and immunohistochemical analyses were performed to assess p28GANK mRNA and protein expression in ESCC tissues and to analyse its significance in ESCC metastasis. qPCR and western blot analyses were used to detect p28GANK mRNA and protein expression in highly invasive and non‑invasive cell lines. Subsequently, lentivirus‑mediated p28GANK short interfering RNA (siRNA) was transfected into highly invasive ESCC cells, and Transwell assays were performed to analyse the effects of p28GANK knockdown on their migration and invasion. The mean expression levels of p28GANK mRNA in the ESCC tissues of patients with metastasis were significantly higher than those in the ESCC specimens from patients without metastasis. p28GANK expression in ESCC tissues was correlated with T‑stage, lymph node metastasis and lymphatic invasion. The mRNA and protein expression levels of p28GANK were significantly higher in highly invasive cell lines compared with those of matched, non‑invasive cell lines. Lentivirus‑mediated siRNA knockdown of p28GANK markedly decreased p28GANK expression in EC109‑P and EC9706‑P cells and supressed the metastasis of ESCC cells in vitro. In conclusion, p28GANK expression was increased in metastatic ESCC tissues and cells, and p28GANK knockdown decreased the metastatic ability of ESCC cells. These results suggested that p28GANK may be a potential therapeutic marker for ESCC metastasis.

  8. The thioredoxin system in breast cancer cell invasion and migration.

    Science.gov (United States)

    Bhatia, Maneet; McGrath, Kelly L; Di Trapani, Giovanna; Charoentong, Pornpimol; Shah, Fenil; King, Mallory M; Clarke, Frank M; Tonissen, Kathryn F

    2016-08-01

    Metastasis is the most life threatening aspect of breast cancer. It is a multi-step process involving invasion and migration of primary tumor cells with a subsequent colonization of these cells at a secondary location. The aim of the present study was to investigate the role of thioredoxin (Trx1) in the invasion and migration of breast cancer cells and to assess the strength of the association between high levels of Trx1 and thioredoxin reductase (TrxR1) expression with breast cancer patient survival. Our results indicate that the expression of both Trx1 and TrxR1 are statistically significantly increased in breast cancer patient cells compared with paired normal breast tissue from the same patient. Over-expression of Trx1 in MDA-MB-231 breast cancer cell lines enhanced cell invasion in in vitro assays while expression of a redox inactive mutant form of Trx1 (designated 1SS) or the antisense mRNA inhibited cell invasion. Addition of exogenous Trx1 also enhanced cell invasion, while addition of a specific monoclonal antibody that inhibits Trx1 redox function decreased cell invasion. Over-expression of intracellular Trx1 did not increase cell migration but expression of intracellular 1SS inhibited migration. Addition of exogenous Trx1 enhanced cell migration while 1SS had no effect. Treatment with auranofin inhibited TrxR activity, cell migration and clonogenic activity of MDA-MB-231 cells, while increasing reactive oxygen species (ROS) levels. Analysis of 25 independent cohorts with 5910 patients showed that Trx1 and TrxR1 were both associated with a poor patient prognosis in terms of overall survival, distant metastasis free survival and disease free survival. Therefore, targeting the Trx system with auranofin or other specific inhibitors may provide improved breast cancer patient outcomes through inhibition of cancer invasion and migration.

  9. The thioredoxin system in breast cancer cell invasion and migration

    Directory of Open Access Journals (Sweden)

    Maneet Bhatia

    2016-08-01

    Full Text Available Metastasis is the most life threatening aspect of breast cancer. It is a multi-step process involving invasion and migration of primary tumor cells with a subsequent colonization of these cells at a secondary location. The aim of the present study was to investigate the role of thioredoxin (Trx1 in the invasion and migration of breast cancer cells and to assess the strength of the association between high levels of Trx1 and thioredoxin reductase (TrxR1 expression with breast cancer patient survival. Our results indicate that the expression of both Trx1 and TrxR1 are statistically significantly increased in breast cancer patient cells compared with paired normal breast tissue from the same patient. Over-expression of Trx1 in MDA-MB-231 breast cancer cell lines enhanced cell invasion in in vitro assays while expression of a redox inactive mutant form of Trx1 (designated 1SS or the antisense mRNA inhibited cell invasion. Addition of exogenous Trx1 also enhanced cell invasion, while addition of a specific monoclonal antibody that inhibits Trx1 redox function decreased cell invasion. Over-expression of intracellular Trx1 did not increase cell migration but expression of intracellular 1SS inhibited migration. Addition of exogenous Trx1 enhanced cell migration while 1SS had no effect. Treatment with auranofin inhibited TrxR activity, cell migration and clonogenic activity of MDA-MB-231 cells, while increasing reactive oxygen species (ROS levels. Analysis of 25 independent cohorts with 5910 patients showed that Trx1 and TrxR1 were both associated with a poor patient prognosis in terms of overall survival, distant metastasis free survival and disease free survival. Therefore, targeting the Trx system with auranofin or other specific inhibitors may provide improved breast cancer patient outcomes through inhibition of cancer invasion and migration.

  10. Effect and mechanism of the Twist gene on invasion and metastasis of gastric carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    Geng-Qiu Luo; Jing-He Li; Ji-Fang Wen; Yan-Hong Zhou; Yong-Bin Hu; Jian-Hua Zhou

    2008-01-01

    AIM: To study the effect of the transfected Twist gene on invasion and metastasis of gastric carcinoma cells and the possible mechanisms involved.METHODS: Human gastric carcinoma MKN28 cells were stably transfected with Twist sense plasmid, and MKN45 cells were stably transfected with Twist antisense plasmid using the lipofectamine transfection technique.RT-PCR,Western blotting, ENSA, gelatin zymography assay, and in vitro invasion and migration assays were performed.Nude mice metastasis models were established by the abdominal cavity transfer method.RESULTS: Cell models (TwistS-MKN28) that steadily expressed high Twist protein were obtained.Compared with MKN28 and pcDNA3-MKN28 cells, adherence,migration and invasion ability of TwistS-MKN28 cells were clearly raised.The number of cancer nodules was increased significantly in the abdominal cavity and liver of nude mice inoculated with TwistS-MKN28 cells.Overexpression of Twist in MKN28 cells increased Tcf-4/Lef DNA binding activity, and promoted expression of Tcf-4's downstream target genes cyclin Dt and HMP-2.However, suppression of Twist (TwistAS-NKN45) inhibited MKN45 cell invasion and the expression of cyclin D1 was reduced.The activity of MMP-2 was also decreased.CONCLUSION: These results indicate that Twist promotes gastric cancer cell migration, invasion and metastasis, and Twist may play an important role in Wnt/Tcf-4 signaling.

  11. Breast metastasis from small cell lung carcinoma

    Institute of Scientific and Technical Information of China (English)

    Shi-ping LUH; Chih KUO; Thomas Chang-yao TSAO

    2008-01-01

    Breast metastases from extramammary neoplasms are very rare. We presented a 66 year-old female with metastasis of small cell lung carcinoma to the breast. She presented with consolidation over the left upper lobe of her lung undetermined after endobronchial or video-assisted thoracoscopic surgery (VATS) biopsy, and this was treated effectively after antibiotic therapy at initial stage. The left breast lumps were noted 4 months later, and she underwent a modified radical mastectomy under the impression of primary breast carcinoma. However, the subsequent chest imaging revealed re-growing mass over the left mediastinum and hilum, and cells with the same morphological and staining features were found from specimens of transbronchial brushing and biopsy. An accurate diagnosis to distinguish a primary breast carcinoma from metastatic one is very important because the therapeutic planning and the outcome between them are different.

  12. Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3 inflammasome

    Energy Technology Data Exchange (ETDEWEB)

    Ahmad, Israr; Muneer, Kashiff M.; Tamimi, Iman A.; Chang, Michelle E.; Ata, Muhammad O. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, AL (United States); Yusuf, Nabiha, E-mail: nabiha@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, AL (United States); Veteran Affairs Medical Center, Birmingham, University of Alabama at Birmingham, AL (United States); Comprehensive Cancer Center, University of Alabama at Birmingham, AL (United States)

    2013-07-01

    The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1β and IL-18 secretion. The NLRP3 (NACHT, LRR, and pyrin domain-containing protein 3) inflammasome is constitutively assembled and activated in human melanoma cells. We have examined the inhibitory effect of thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone), a major ingredient of black seed obtained from the plant Nigella sativa on metastatic human (A375) and mouse (B16F10) melanoma cell lines. We have assessed whether thymoquinone inhibits metastasis of melanoma cells by targeting NLRP3 subunit of inflammasomes. Using an in vitro cell migration assay, we found that thymoquinone inhibited the migration of both human and mouse melanoma cells. The inhibitory effect of thymoquinone on metastasis was also observed in vivo in B16F10 mouse melanoma model. The inhibition of migration of melanoma cells by thymoquinone was accompanied by a decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by thymoquinone resulted in inhibition of IL-1β and IL-18. Treatment of mouse melanoma cells with thymoquinone also inhibited NF-κB activity. Furthermore, inhibition of reactive oxygen species (ROS) by thymoquinone resulted in partial inactivation of NLRP3 inflammasome. Thus, thymoquinone exerts its inhibitory effect on migration of human and mouse melanoma cells by inhibition of NLRP3 inflammasome. Thus, our results indicate that thymoquinone can be a potential immunotherapeutic agent not only as an adjuvant therapy for melanoma, but also, in the control and prevention of metastatic melanoma. - Highlights: • Thymoquinone causes inhibition of migration of melanoma cells. • Thymoquinone causes inhibition of metastasis in vivo. • Thymoquinone causes inhibition of migration by activation of NLRP3 inflammasome.

  13. Collective dynamics of cell migration and cell rearrangements

    Science.gov (United States)

    Kabla, Alexandre

    Understanding multicellular processes such as embryo development or cancer metastasis requires to decipher the contributions of local cell autonomous behaviours and long range interactions with the tissue environment. A key question in this context concerns the emergence of large scale coordination in cell behaviours, a requirement for collective cell migration or convergent extension. I will present a few examples where physical and mechanical aspects play a significant role in driving tissue scale dynamics. Geometrical confinement is one of the key external factors influencing large scale coordination during collective migration. Using a combination of in vitro experiments and numerical simulations, we show that the velocity correlation length, measured in unconfined conditions, provides a convenient length scale to predict the dynamic response under confinement. The same length scale can also be used to quantify the influence range of directional cues within the cell population. Heterogeneity within motile cell populations is frequently associated with an increase in their invasive capability and appears to play an important role during cancer metastasis. Using in silico experiments, we studied the way cell invasion is influenced by both the degree of cell coordination and the amount of variability in the motile force of the invading cells. Results suggest that mechanical heterogeneity dramatically enhances the invasion rate through an emerging cooperative process between the stronger and weaker cells, accounting for a number of observed invasion phenotypes. Effective convergent extension requires on a consistent orientation of cell intercalation at the tissue scale, most often in relation with planar cell polarity mechanisms to define the primary axes of deformation. Using a novel modelling approach for cells mechanical interactions, we studied the dynamics of substrate free motile cell populations. Ongoing work shows in particular that nematic order emerges

  14. LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6.

    Science.gov (United States)

    Ketscher, A; Jilg, C A; Willmann, D; Hummel, B; Imhof, A; Rüsseler, V; Hölz, S; Metzger, E; Müller, J M; Schüle, R

    2014-10-06

    Lysine-specific demethylase 1 (LSD1) was shown to control gene expression and cell proliferation of androgen-dependent prostate cancer (PCa) cells, whereas the role of LSD1 in androgen-independent metastatic prostate cancer remains elusive. Here, we show that depletion of LSD1 leads to increased migration and invasion of androgen-independent PCa cells. Transcriptome and cistrome analyses reveal that LSD1 regulates expression of lysophosphatidic acid receptor 6 (LPAR6) and cytoskeletal genes including the focal adhesion adaptor protein paxillin (PXN). Enhanced LPAR6 signalling upon LSD1 depletion promotes migration with concomitant phosphorylation of PXN. In mice LPAR6 overexpression enhances, whereas knockdown of LPAR6 abolishes metastasis of androgen-independent PCa cells. Taken together, we uncover a novel mechanism of how LSD1 controls metastasis and identify LPAR6 as a promising therapeutic target to treat metastatic prostate cancer.

  15. Cardamonin Inhibits Metastasis of Lewis Lung Carcinoma Cells by Decreasing mTOR Activity.

    Directory of Open Access Journals (Sweden)

    Pei-Guang Niu

    Full Text Available The mammalian target of rapamycin (mTOR regulates the motility and invasion of cancer cells. Cardamonin is a chalcone that exhibits anti-tumor activity. The previous study had proved that the anti-tumor effect of cardamonin was associated with mTOR inhibition. In the present study, the anti-metastatic effect of cardamonin and its underlying molecule mechanisms were investigated on the highly metastatic Lewis lung carcinoma (LLC cells. The proliferation, invasion and migration of LLC cells were measured by MTT, transwell and wound healing assays, respectively. The expression and activation of mTOR- and adhesion-related proteins were assessed by Western blotting. The in vivo effect of cardamonin on the metastasis of the LLC cells was investigated by a mouse model. Treated with cardamonin, the proliferation, invasion and migration of LLC cells were significantly inhibited. The expression of Snail was decreased by cardamonin, while that of E-cadherin was increased. In addition, cardamonin inhibited the activation of mTOR and its downstream target ribosomal S6 kinase 1 (S6K1. Furthermore, the tumor growth and its lung metastasis were inhibited by cardamonin in C57BL/6 mice. It indicated that cardamonin inhibited the invasion and metastasis of LLC cells through inhibiting mTOR. The metastasis inhibitory effect of cardamonin was correlated with down-regulation of Snail and up-regulation of E-cadherin.

  16. Osteoactivin Promotes Migration of Oral Squamous Cell Carcinomas.

    Science.gov (United States)

    Arosarena, Oneida A; Dela Cadena, Raul A; Denny, Michael F; Bryant, Evan; Barr, Eric W; Thorpe, Ryan; Safadi, Fayez F

    2016-08-01

    Nearly 50% of patients with oral squamous cell carcinoma (OSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell adhesion, migration, and invasion. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies. The aims were to determine how integrin interactions modulate OA-induced OSCC cell migration; and to investigate OA effects on cell survival and proliferation. We confirmed OA mRNA and protein overexpression in OSCC cell lines. We assessed OA's interactions with integrins using adhesion inhibition assays, fluorescent immunocytochemistry and co-immunoprecipitation. We investigated OA-mediated activation of mitogen-activated protein kinases (MAPKs) and cell survival. Integrin inhibition effects on OA-mediated cell migration were determined. We assessed effects of OA knock-down on cell migration and proliferation. OA is overexpressed in OSCC cell lines, and serves as a migration-promoting adhesion molecule. OA co-localized with integrin subunits, and co-immunoprecipitated with the subunits. Integrin blocking antibodies, especially those directed against the β1 subunit, inhibited cell adhesion (P = 0.03 for SCC15 cells). Adhesion to OA activated MAPKs in UMSCC14a cells and OA treatment promoted survival of SCC15 cells. Integrin-neutralizing antibodies enhanced cell migration with OA in the extracellular matrix. OA knock-down resulted in decreased proliferation of SCC15 and SCC25 cells, but did not inhibit cell migration. OA in the extracellular matrix promotes OSCC cell adhesion and migration, and may be a novel target in the prevention of HNSCC spread. J. Cell. Physiol. 231: 1761-1770, 2016. © 2015 Wiley Periodicals, Inc.

  17. Kaempferol modulates the metastasis of human non-small cell lung cancer cells by inhibiting epithelial-mesenchymal transition

    Directory of Open Access Journals (Sweden)

    Meng Hang

    2015-06-01

    Full Text Available The present study was done to determine whether kaempferol, a natural polyphenol of the flavonoid family, affects Epithelial-Mesenchymal Transition (EMT in non-small cell lung cancer cells. Kaempferol not only inhibited cancer cell proliferation and migration in a dose-dependent manner but also modulated the expression of EMT-related proteins E-cadherin and vimentin which are indispensible to cellular motility, invasiveness and metastasis. These results indicate that kaempferol suppresses non-small cell lung cancer migration by modulating the expression of EMT proteins. Therefore, kaempferol may be useful as a potential anticancer agent for non-small cell lung cancer.

  18. Cell migration in confined environments.

    Science.gov (United States)

    Irimia, Daniel

    2014-01-01

    We describe a protocol for measuring the speed of human neutrophils migrating through small channels, in conditions of mechanical confinement comparable to those experienced by neutrophils migrating through tissues. In such conditions, we find that neutrophils move persistently, at constant speed for tens of minutes, enabling precise measurements at single cells resolution, for large number of cells. The protocol relies on microfluidic devices with small channels in which a solution of chemoattractant and a suspension of isolated neutrophils are loaded in sequence. The migration of neutrophils can be observed for several hours, starting within minutes after loading the neutrophils in the devices. The protocol is divided into four main steps: the fabrication of the microfluidic devices, the separation of neutrophils from whole blood, the preparation of the assay and cell loading, and the analysis of data. We discuss the practical steps for the implementation of the migration assays in biology labs, the adaptation of the protocols to various cell types, including cancer cells, and the supplementary device features required for precise measurements of directionality and persistence during migration.

  19. Migrastatin analogues inhibit canine mammary cancer cell migration and invasion.

    Directory of Open Access Journals (Sweden)

    Kinga Majchrzak

    Full Text Available BACKGROUND: Cancer spread to other organs is the main cause of death of oncological patients. Migration of cancer cells from a primary tumour is the crucial step in the complex process of metastasis, therefore blocking this process is currently the main treatment strategy. Metastasis inhibitors derived from natural products, such as, migrastatin, are very promising anticancer agents. Thus, the aim of our study was to investigate the effect of six migrastatin analogues (MGSTA-1 to 6 on migration and invasion of canine mammary adenocarcinoma cell lines isolated from primary tumours and their metastases to the lungs. Canine mammary tumours constitute a valuable tool for studying multiple aspect of human cancer. RESULTS: OUR RESULTS SHOWED THAT TWO OF SIX FULLY SYNTHETIC ANALOGUES OF MIGRASTATIN: MGSTA-5 and MGSTA-6 were potent inhibitors of canine mammary cancer cells migration and invasion. These data were obtained using the wound healing test, as well as trans-well migration and invasion assays. Furthermore, the treatment of cancer cells with the most effective compound (MGSTA-6 disturbed binding between filamentous F-actin and fascin1. Confocal microscopy analyses revealed that treatment with MGSTA-6 increased the presence of unbound fascin1 and reduced co-localization of F-actin and fascin1 in canine cancer cells. Most likely, actin filaments were not cross-linked by fascin1 and did not generate the typical filopodial architecture of actin filaments in response to the activity of MGSTA-6. Thus, administration of MGSTA-6 results in decreased formation of filopodia protrusions and stress fibres in canine mammary cancer cells, causing inhibition of cancer migration and invasion. CONCLUSION: Two synthetic migrastatin analogues (MGSTA-5 and MGSTA-6 were shown to be promising compounds for inhibition of cancer metastasis. They may have beneficial therapeutic effects in cancer therapy in dogs, especially in combination with other anticancer drugs

  20. A Discrete Cell Migration Model

    Energy Technology Data Exchange (ETDEWEB)

    Nutaro, James J [ORNL; Kruse, Kara L [ORNL; Ward, Richard C [ORNL; O' Quinn, Elizabeth [Wofford College; Woerner, Matthew M [ORNL; Beckerman, Barbara G [ORNL

    2007-01-01

    Migration of vascular smooth muscle cells is a fundamental process in the development of intimal hyperplasia, a precursor to development of cardiovascular disease and a potential response to injury of an arterial wall. Boyden chamber experiments are used to quantify the motion of cell populations in response to a chemoattractant gradient (i.e., cell chemotaxis). We are developing a mathematical model of cell migration within the Boyden chamber, while simultaneously conducting experiments to obtain parameter values for the migration process. In the future, the model and parameters will be used as building blocks for a detailed model of the process that causes intimal hyperplasia. The cell migration model presented in this paper is based on the notion of a cell as a moving sensor that responds to an evolving chemoattractant gradient. We compare the results of our three-dimensional hybrid model with results from a one-dimensional continuum model. Some preliminary experimental data that is being used to refine the model is also presented.

  1. The Interplay between Signaling and Metabolism in Breast Cancer Cell Motility and Metastasis

    Science.gov (United States)

    Tsarfaty, Ilan

    2013-03-01

    The initiation and growth of tumor metastases require tumor cells go through a transition between collective-to-individual cell migration. Understanding the molecular, cellular and physical mechanisms of these different migration modes is limited. We focus on the tumor cell migration induced by Hepatocyte Growth Factor / Scatter Factor (HGF/SF) - Met-signaling, a master regulator of cell motility in normal and malignant processes. Met has been implicated in tumorigenesis and metastasis and several Met targeting agents have been introduced into the clinic, and are currently in all phases of clinical trials Our analysis demonstrates that Met signaling dramatically alter the morpho-kinetic dynamics of collective migration of tumor cells. It induce a ``wave'' of increasing velocities that propagates back from the leading edge, increases cells' orientation and cooperation capabilities. In parallel Met signaling induces amoeboid cell motility that increased cell individuality. The decision making regarding the motility mode is dependent on the extent of activation of unique signal and metabolic cues. We present a combination of molecular imaging, conceptual and modeling framework for the analysis and assessment of the collective mesenchymal to epithelial versus amoeboid motility. Combined together our analysis can contribute to the understanding of metastasis and personalizing anti Met targeted therapy.

  2. Isolated renal metastasis from squamous cell lung cancer

    Directory of Open Access Journals (Sweden)

    Cai Jun

    2013-01-01

    Full Text Available Abstract Renal metastasis from non-small cell lung cancer is rather uncommon. The mechanism underlying the occurrence of metastasis in this site is still not well understood. We report a case of a 53-year-old Chinese woman who had moderately differentiated squamous cell carcinoma of the lung. After a ten months post-surgery interval of disease free survival, computed tomography (CT scan found that left renal parenchymal was occupied by a mass, confirmed by kidney biopsy to be a metastasis from squamous cell lung carcinoma. Based on this case, we are warned to be cautious in diagnosis and treatment when renal lesion are detected.

  3. CD147 and AGR2 expression promote cellular proliferation and metastasis of head and neck squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Sweeny, Larissa, E-mail: larissasweeny@gmail.com [Department of Surgery, University of Alabama, Division of Otolaryngology-Head and Neck Surgery, 1670 University Boulevard, Volker Hall G082, Birmingham, Alabama (United States); Liu, Zhiyong; Bush, Benjamin D.; Hartman, Yolanda [Department of Surgery, University of Alabama, Division of Otolaryngology-Head and Neck Surgery, 1670 University Boulevard, Volker Hall G082, Birmingham, Alabama (United States); Zhou, Tong [Department of Medicine, Division of Immunology and Rheumatology, 1825 University Boulevard, Shelby Biomedical Research Building 302, Birmingham, Alabama (United States); Rosenthal, Eben L., E-mail: oto@uab.edu [Department of Surgery, University of Alabama, Division of Otolaryngology-Head and Neck Surgery, 1670 University Boulevard, Volker Hall G082, Birmingham, Alabama (United States)

    2012-08-15

    The signaling pathways facilitating metastasis of head and neck squamous cell carcinoma (HNSCC) cells are not fully understood. CD147 is a transmembrane glycoprotein known to induce cell migration and invasion. AGR2 is a secreted peptide also known to promote cell metastasis. Here we describe their importance in the migration and invasion of HNSCC cells (FADU and OSC-19) in vitro and in vivo. In vitro, knockdown of CD147 or AGR2 decreased cellular proliferation, migration and invasion. In vivo, knockdown of CD147 or AGR2 expression decreased primary tumor growth as well as regional and distant metastasis. -- Highlights: Black-Right-Pointing-Pointer We investigated AGR2 in head and neck squamous cell carcinoma for the first time. Black-Right-Pointing-Pointer We explored the relationship between AGR2 and CD147 for the first time. Black-Right-Pointing-Pointer AGR2 and CD147 appear to co-localize in head and squamous cell carcinoma samples. Black-Right-Pointing-Pointer Knockdown of both AGR2 and CD147 reduced migration and invasion in vitro. Black-Right-Pointing-Pointer Knockdown of both AGR2 and CD147 decreased metastasis in vivo.

  4. Salinomycin treatment reduces metastatic tumor burden by hampering cancer cell migration

    OpenAIRE

    Kopp, Florian; Hermawan, Adam; Oak, Prajakta Shirish; Herrmann, Annika; Wagner, Ernst; Roidl, Andreas

    2014-01-01

    Background: Tumor spreading is the major threat for cancer patients. The recently published anti-cancer drug salinomycin raised hope for an improved treatment by targeting therapy-refractory cancer stem cells. However, an unambiguous role of salinomycin against cancer cell migration and metastasis formation remains elusive. Findings: We report that salinomycin effectively inhibits cancer cell migration in a variety of cancer types as determined by Boyden chamber assays. Additionally, cells we...

  5. Nuclear envelope rupture and repair during cancer cell migration

    Science.gov (United States)

    Denais, Celine M.; Gilbert, Rachel M.; Isermann, Philipp; McGregor, Alexandra L.; te Lindert, Mariska; Weigelin, Bettina; Davidson, Patricia M.; Friedl, Peter; Wolf, Katarina; Lammerding, Jan

    2016-01-01

    During cancer metastasis, tumor cells penetrate tissues through tight interstitial spaces, requiring extensive deformation of the cell and its nucleus. Here, we investigated tumor cell migration in confining microenvironments in vitro and in vivo. Nuclear deformation caused localized loss of nuclear envelope (NE) integrity, which led to the uncontrolled exchange of nucleo-cytoplasmic content, herniation of chromatin across the NE, and DNA damage. The incidence of NE rupture increased with cell confinement and with depletion of nuclear lamins, NE proteins that structurally support the nucleus. Cells restored NE integrity using components of the endosomal sorting complexes required for transport-III (ESCRT-III) machinery. Our findings indicate that cell migration incurs substantial physical stress on the NE and its content, requiring efficient NE and DNA damage repair for survival. PMID:27013428

  6. Contribution to Study About Metastasis of Oral Squamous Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Fernanda Ferreira LOPES

    2006-09-01

    Full Text Available Objective: This paper is a retrospective study with aim of collecting information about neoplasm metastasis of oral squamous cell carcinoma. Method: The registry of patients with the histopathology diagnose of oral squamous cell carcinoma in Oncology Institute Aldenora Belo (IMOAB in São Luis - MA, from 1992 to 2004, was analyzed and 18 cases were selected. Results: The most common anatomical region of primary neoplasm was tongue, following by buccal floor and cheek. In related to anatomical area compromised by metastasis, the cervical ones were the most frequent, followed by tongue and buccal floor. Conclusion: It concluded that the tongue was the most common site of oral squamous cell carcinoma, where frequently, shows metastasis, and the most common loco-regional metastasis was on cervical area, especially.

  7. Isothiocyanates induce oxidative stress and suppress the metastasis potential of human non-small cell lung cancer cells

    Directory of Open Access Journals (Sweden)

    Zhou Qinghua

    2010-06-01

    Full Text Available Abstract Background Isothiocyanates are natural compounds found in consumable cruciferous vegetables. They have been shown to inhibit chemical carcinogenesis by a wide variety of chemical carcinogens in animal models. Recent studies have also shown that isothiocyanates have antitumor activity, inhibiting the growth of several types of cultured human cancer cells. Our previous study showed that PEITC inhibited human leukemia cells growth by inducing apoptosis. However, the effect of isothiocyanates on lung cancer cell metastasis has not been studied. In the present study, we investigated the inhibitory effects of BITC and PEITC on metastatic potential of highly metastatic human lung cancer L9981 cells. Methods Cell migration and invasion were measured by wound healing assay and transwell chemotaxis assay. Expression of metastasis-related genes was assessed by quantitative RT-PCR and Western blotting. The mechanisms of action were evaluated by flow cytometry, reporter assay and Western blotting. Results Our data showed that both BITC and PEITC inhibited L9981 cell growth in a dose-dependent manner, the IC50 values were 5.0 and 9.7 μM, respectively. Cell migrations were reduced to 8.1% and 16.5% of control, respectively; and cell invasions were reduced to 2.7% and 7.3% of control, respectively. Metastasis-related genes MMP-2, Twist and β-catenin were also modulated. BITC and PEITC inhibited cell survival signaling molecules Akt and NFκB activation. Moreover, BITC and PEITC increased ROS generation and caused GSH depletion. Pretreatment with NAC blocked BITC and PEITC induced ROS elevation and NFκB inhibition. Conclusion Our results indicated that BITC and PEITC suppress lung cancer cell metastasis potential by modulation of metastasis-related gene expression, inhibition of Akt/NFκB pathway. Induction of oxidative stress may play an important role.

  8. Extrahepatic synthesis of coagulation factor Ⅶ by colorectal cancer cells promotes tumor invasion and metastasis

    Institute of Scientific and Technical Information of China (English)

    TANG Jian-qiang; FAN Qing; WU Wen-han; JIA Zhi-chao; LI Hui; YANG Yin-mo; LIU Yu-cun; WAN Yuan-lian

    2010-01-01

    Background Blood coagulation factor Ⅶ (FⅦ) is physiologically synthesized in the liver and released into the blood. Binding of FⅦ to tissue factor (TF) is related to the metastatic potential of tumor cells, also a significant risk factor in the development of hepatic metastasis in patients with colorectal cancer (CRC). It has been found that some cancer cells can produce FⅦ extrahepatically. However, litte is known about FⅦ and CRC. We therefore hypothesized that CRC cells may synthese FⅦ, leading to tumor invasion and metastasis.Methods We detected the expression of FⅦ protein in 55 CRC specimens by immunohistochemical staining. The FⅦ mRNA in 45 of 55 CRC cases, 6 colon cancer cell lines and one hepatoma cell line was measured by real-time reverse transcription-PCR (RT-PCR). Transwell invasion assays were performed to evaluate the changes of cell migration and invasion of LoVo cancer cells in vitro. We further observed the likely effectors regulated by the TF/FⅦa complex Western blotting assay.Results Extrahepatic synthesis of FⅦ was detected in the cytoplasm of 32 (58.2%) CRC specimens byimmunohistochemistry, but not in normal mucosa. Liver metastasis (P=0.003) and TNM staging (P=0.005) were significantly correlated with FⅦ antigen expression. The positive ratios in stages Ⅰ, Ⅱ, Ⅲ and Ⅳ were 33.3%, 40.0%,52.4% and 87.5%, respectively. The expression of FⅦ mRNA in CRC with hepatic metastasis was significantly higher than CRC without hepatic metastasis (5.33±2.88 vs. 1.47±0.51, P=0.03). Ectopic FⅦa induced a slight increase (1.34-fold) in the number of migrating cells, which was inhibited by the specific TF antibody. The formation of TF/FⅦacomplex resulted in a marked increase in the expression of matrix metalloproteinases (MMP)-2 (3.5-fold) and MMP-9(4.7-fold) in a time-dependent and dose-dependent manner.Conclusions Extrahepatic synthesis of FⅦ by CRC cells may promote tumor invasion and metastasis. MMPs, as downstream

  9. Effects of Curcumin on Invasion and Metastasis in the Human Cervical Cancer Cells Caski

    Institute of Scientific and Technical Information of China (English)

    Fang XU; Xiao-ling MU; Jing ZHAO

    2009-01-01

    Objective: To explore the effects of curcumin on invasion and metastasis in the human cervical cancer cells Caski.Methods: Caski cells were treated with 10, 25, 50μmol/L curcumin for 24, 48, 72 h. Proliferation of Caski cells was measured with MTT assay. When treated with 50μmol/L curcumin for 72 h, the expressions of MMP-2, MT1-MMP and NF-κB of cells were detected by Western-blot, and invasion and metastasis of Caski cells were evaluated with transwell chamber.Results: After being treated with 10μmol/L, 25μmol/L, 50μmol/L curcumin for 24, 48 and 72 h, the proliferation of Caski cells was inhibited in a dose-and time-dependent manner. The expression of MMP-2, MT1-MMP and NF-κB were decreased when being treated with 50μmol/L curcumin for 72 h. After treatment with 50μmol/L curcumin, in invasion assay, the number of cells in curcumin treated group to migrate to filter coated with Matrigel was reduced compared with control group(P<0.05). Meanwhile, in migration assay, the number of cells in curcumin treated group to migrate to filter was also decreased compared with control group (P<0.05).Conclusion: Curcumin could affect the invasion and metastasis of the human cervical cancer cells Caski. Inhibiting the expression of MMP-2, MT1-MMP and NF-κB was probably one of its molecular mechanisms.

  10. DIXDC1 activates the Wnt signaling pathway and promotes gastric cancer cell invasion and metastasis.

    Science.gov (United States)

    Tan, Cong; Qiao, Fan; Wei, Ping; Chi, Yayun; Wang, Weige; Ni, Shujuan; Wang, Qifeng; Chen, Tongzhen; Sheng, Weiqi; Du, Xiang; Wang, Lei

    2016-04-01

    DIXDC1 (Dishevelled-Axin domain containing 1) is a DIX (Dishevelled-Axin) domain-possessing protein that promotes colon cancer cell proliferation and increases the invasion and migration ability of non-small-cell lung cancer via the PI3K pathway. As a positive regulator of the Wnt/β-catenin pathway, the biological role of DIXDC1 in human gastric cancer and the relationship between DIXDC1 and the Wnt pathway are unclear. In the current study, the upregulation of DIXDC1 was detected in gastric cancer and was associated with advanced TNM stage cancer, lymph node metastasis, and poor prognosis. We also found that the overexpression of DIXDC1 could promote the invasion and migration of gastric cancer cells. The upregulation of MMPs and the downregulation of E-cadherin were found to be involved in the process. DIXDC1 enhanced β-catenin nuclear accumulation, which activated the Wnt pathway. Additionally, the inhibition of β-catenin in DIXDC1-overexpressing cells reversed the metastasis promotion effects of DIXDC1. These results demonstrate that the expression of DIXDC1 is associated with poor prognosis of gastric cancer patients and that DIXDC1 promotes gastric cancer invasion and metastasis through the activation of the Wnt pathway; E-cadherin and MMPs are also involved in this process. © 2015 Wiley Periodicals, Inc.

  11. Mechanobiology of cell migration in the context of dynamic two-way cell-matrix interactions.

    Science.gov (United States)

    Kurniawan, Nicholas A; Chaudhuri, Parthiv Kant; Lim, Chwee Teck

    2016-05-24

    Migration of cells is integral in various physiological processes in all facets of life. These range from embryonic development, morphogenesis, and wound healing, to disease pathology such as cancer metastasis. While cell migratory behavior has been traditionally studied using simple assays on culture dishes, in recent years it has been increasingly realized that the physical, mechanical, and chemical aspects of the matrix are key determinants of the migration mechanism. In this paper, we will describe the mechanobiological changes that accompany the dynamic cell-matrix interactions during cell migration. Furthermore, we will review what is to date known about how these changes feed back to the dynamics and biomechanical properties of the cell and the matrix. Elucidating the role of these intimate cell-matrix interactions will provide not only a better multi-scale understanding of cell motility in its physiological context, but also a more holistic perspective for designing approaches to regulate cell behavior.

  12. Immunosuppressive cells in tumor immune escape and metastasis.

    Science.gov (United States)

    Liu, Yang; Cao, Xuetao

    2016-05-01

    Tumor immune escape and the initiation of metastasis are critical steps in malignant progression of tumors and have been implicated in the failure of some clinical cancer immunotherapy. Tumors develop numerous strategies to escape immune surveillance or metastasize: Tumors not only modulate the recruitment and expansion of immunosuppressive cell populations to develop the tumor microenvironment or pre-metastatic niche but also switch the phenotype and function of normal immune cells from a potentially tumor-reactive state to a tumor-promoting state. Immunosuppressive cells facilitate tumor immune escape by inhibiting antitumor immune responses and furthermore promote tumor metastasis by inducing immunosuppression, promoting tumor cell invasion and intravasation, establishing a pre-metastatic niche, facilitating epithelial-mesenchymal transition, and inducing angiogenesis at primary tumor or metastatic sites. Numerous translational studies indicate that it is possible to inhibit tumor immune escape and prevent tumor metastasis by blocking immunosuppressive cells and eliminating immunosuppressive mechanisms that are induced by either immunosuppressive cells or tumor cells. Furthermore, many clinical trials targeting immunosuppressive cells have also achieved good outcome. In this review, we focus on the underlying mechanisms of immunosuppressive cells in promoting tumor immune escape and metastasis, discuss our current understanding of the interactions between immunosuppressive cells and tumor cells in the tumor microenvironment, and suggest future research directions as well as potential clinical strategies in cancer immunotherapy.

  13. Cell-stiffness-induced mechanosignaling - a key driver of leukocyte transendothelial migration

    NARCIS (Netherlands)

    A. Schaefer; P.L. Hordijk

    2015-01-01

    The breaching of cellular and structural barriers by migrating cells is a driving factor in development, inflammation and tumor cell metastasis. One of the most extensively studied examples is the extravasation of activated leukocytes across the vascular endothelium, the inner lining of blood vessel

  14. Downregulation of COX-2 and CYP 4A signaling by isoliquiritigenin inhibits human breast cancer metastasis through preventing anoikis resistance, migration and invasion.

    Science.gov (United States)

    Zheng, Hao; Li, Ying; Wang, Yuzhong; Zhao, Haixia; Zhang, Jing; Chai, Hongyan; Tang, Tian; Yue, Jiang; Guo, Austin M; Yang, Jing

    2014-10-01

    Flavonoids exert extensive in vitro anti-invasive and in vivo anti-metastatic activities. Anoikis resistance occurs at multiple key stages of the metastatic cascade. Here, we demonstrate that isoliquiritigenin (ISL), a flavonoid from Glycyrrhiza glabra, inhibits human breast cancer metastasis by preventing anoikis resistance, migration and invasion through downregulating cyclooxygenase (COX)-2 and cytochrome P450 (CYP) 4A signaling. ISL induced anoikis in MDA-MB-231 and BT-549 human breast cancer cells as evidenced by flow cytometry and the detection of caspase cleavage. Moreover, ISL inhibited the mRNA expression of phospholipase A2, COX-2 and CYP 4A and decreased the secretion of prostaglandin E2 (PGE2) and 20-hydroxyeicosatetraenoic acid (20-HETE) in detached MDA-MB-231 cells. In addition, it decreased the levels of phospho-PI3K (Tyr(458)), phospho-PDK (Ser(241)) and phospho-Akt (Thr(308)). Conversely, the exogenous addition of PGE2, WIT003 (a 20-HETE analog) and an EP4 agonist (CAY10580) or overexpression of constitutively active Akt reversed ISL-induced anoikis. ISL exerted the in vitro anti-migratory and anti-invasive activities, whereas the addition of PGE2, WIT003 and CAY10580 or overexpression of constitutively active Akt reversed the in vitro anti-migratory and anti-invasive activities of ISL in MDA-MB-231 cells. Notably, ISL inhibited the in vivo lung metastasis of MDA-MB-231 cells, together with decreased intratumoral levels of PGE2, 20-HETE and phospho-Akt (Thr(308)). In conclusion, ISL inhibits breast cancer metastasis by preventing anoikis resistance, migration and invasion via downregulating COX-2 and CYP 4A signaling. It suggests that ISL could be a promising multi-target agent for preventing breast cancer metastasis, and anoikis could represent a novel mechanism through which flavonoids may exert the anti-metastatic activities.

  15. MiR-888 regulates side population properties and cancer metastasis in breast cancer cells.

    Science.gov (United States)

    Huang, Shengjian; Chen, Liangbiao

    2014-08-01

    Cancer stem cells (CSCs) have recently been reported to possess properties related to cancer metastasis. However, the mechanism by which microRNAs (miRNAs) regulate these properties remains unclear. This study aims to investigate a correlation between miRNAs and the side population (SP) of human breast cancer cell line MCF-7 with CSC properties. miR-888 was found in our previous study to be up-regulated in SP cells and predicted to target E-Cadherin directly, indicating a potential role in maintaining SP properties and regulating the epithelial-mesenchymal transition (EMT) and cancer metastasis. After the over-expression of miR-888 in MCF-7 cells and knock-down of its expression in SP cells, we found that miR-888 played a role in maintaining CSC-related properties. Next, miR-888 was found to regulate the EMT process by targeting related gene expression. Lastly, MCF-7 cells over-expressing miR-888 exhibited a significant reduction in their ability to adhere to the extracellular matrix and an increased potential for migration and invasion, whereas knock-down of miR-888 expression in SP cells reversed these trends. In conclusion, miR-888 maintains SP properties and regulates EMT and metastasis in MCF-7 cells, potentially by targeting E-Cadherin expression.

  16. Anti-metastasis effect of fucoidan from Undaria pinnatifida sporophylls in mouse hepatocarcinoma Hca-F cells.

    Science.gov (United States)

    Wang, Peisheng; Liu, Zhichao; Liu, Xianli; Teng, Hongming; Zhang, Cuili; Hou, Lin; Zou, Xiangyang

    2014-01-01

    Metastasis is one of the major causes of cancer-related death. It is a complex biological process involving multiple genes, steps, and phases. It is also closely connected to many biological activities of cancer cells, such as growth, invasion, adhesion, hematogenous metastasis, and lymphatic metastasis. Fucoidan derived from Undaria pinnatifida sporophylls (Ups-fucoidan) is a sulfated polysaccharide with more biological activities than other fucoidans. However, there is no information on the effects of Ups-fucoidan on tumor invasion and metastasis. We used the mouse hepatocarcinoma Hca-F cell line, which has high invasive and lymphatic metastasis potential in vitro and in vivo, to examine the effect of Ups-fucoidan on cancer cell invasion and metastasis. Ups-fucoidan exerted a concentration- and time-dependent inhibitory effect on tumor metastasis in vivo and inhibited Hca-F cell growth, migration, invasion, and adhesion capabilities in vitro. Ups-fucoidan inhibited growth and metastasis by downregulating vascular endothelial growth factor (VEGF) C/VEGF receptor 3, hepatocyte growth factor/c-MET, cyclin D1, cyclin-dependent kinase 4, phosphorylated (p) phosphoinositide 3-kinase, p-Akt, p-extracellular signal regulated kinase (ERK) 1/2, and nuclear transcription factor-κB (NF-κB), and suppressed adhesion and invasion by downregulating L-Selectin, and upregulating protein levels of tissue inhibitor of metalloproteinases (TIMPs). The results suggest that Ups-fucoidan suppresses Hca-F cell growth, adhesion, invasion, and metastasis capabilities and that these functions are mediated through the mechanism involving inactivation of the NF-κB pathway mediated by PI3K/Akt and ERK signaling pathways.

  17. Anti-metastasis effect of fucoidan from Undaria pinnatifida sporophylls in mouse hepatocarcinoma Hca-F cells.

    Directory of Open Access Journals (Sweden)

    Peisheng Wang

    Full Text Available Metastasis is one of the major causes of cancer-related death. It is a complex biological process involving multiple genes, steps, and phases. It is also closely connected to many biological activities of cancer cells, such as growth, invasion, adhesion, hematogenous metastasis, and lymphatic metastasis. Fucoidan derived from Undaria pinnatifida sporophylls (Ups-fucoidan is a sulfated polysaccharide with more biological activities than other fucoidans. However, there is no information on the effects of Ups-fucoidan on tumor invasion and metastasis. We used the mouse hepatocarcinoma Hca-F cell line, which has high invasive and lymphatic metastasis potential in vitro and in vivo, to examine the effect of Ups-fucoidan on cancer cell invasion and metastasis. Ups-fucoidan exerted a concentration- and time-dependent inhibitory effect on tumor metastasis in vivo and inhibited Hca-F cell growth, migration, invasion, and adhesion capabilities in vitro. Ups-fucoidan inhibited growth and metastasis by downregulating vascular endothelial growth factor (VEGF C/VEGF receptor 3, hepatocyte growth factor/c-MET, cyclin D1, cyclin-dependent kinase 4, phosphorylated (p phosphoinositide 3-kinase, p-Akt, p-extracellular signal regulated kinase (ERK 1/2, and nuclear transcription factor-κB (NF-κB, and suppressed adhesion and invasion by downregulating L-Selectin, and upregulating protein levels of tissue inhibitor of metalloproteinases (TIMPs. The results suggest that Ups-fucoidan suppresses Hca-F cell growth, adhesion, invasion, and metastasis capabilities and that these functions are mediated through the mechanism involving inactivation of the NF-κB pathway mediated by PI3K/Akt and ERK signaling pathways.

  18. Focal Adhesion-Independent Cell Migration.

    Science.gov (United States)

    Paluch, Ewa K; Aspalter, Irene M; Sixt, Michael

    2016-10-06

    Cell migration is central to a multitude of physiological processes, including embryonic development, immune surveillance, and wound healing, and deregulated migration is key to cancer dissemination. Decades of investigations have uncovered many of the molecular and physical mechanisms underlying cell migration. Together with protrusion extension and cell body retraction, adhesion to the substrate via specific focal adhesion points has long been considered an essential step in cell migration. Although this is true for cells moving on two-dimensional substrates, recent studies have demonstrated that focal adhesions are not required for cells moving in three dimensions, in which confinement is sufficient to maintain a cell in contact with its substrate. Here, we review the investigations that have led to challenging the requirement of specific adhesions for migration, discuss the physical mechanisms proposed for cell body translocation during focal adhesion-independent migration, and highlight the remaining open questions for the future.

  19. Human Umbilical Cord Mesenchymal Stem Cells Promote Breast Cancer Metastasis by Interleukin-8- and Interleukin-6-Dependent Induction of CD44(+)/CD24(-) Cells.

    Science.gov (United States)

    Ma, Fengxia; Chen, Dandan; Chen, Fang; Chi, Ying; Han, Zhibo; Feng, Xiaoming; Li, Xue; Han, Zhongchao

    2015-01-01

    Although emerging evidence links mesenchymal stem cells (MSCs) with cancer metastasis, the underlying mechanisms are poorly understood. In the present study, we found that human umbilical cord-derived MSCs (UC-MSCs) promoted MCF-7 cell migration in vitro and metastasis in vivo. To explore the mechanisms, the characteristics of MCF-7 cells cocultured with UC-MSCs were assessed. The expression and secretion of interleukin-8 (IL-8) and IL-6 were induced in MCF-7 cells cocultured with UC-MSCs. However, neutralization of IL-8 or IL-6 secreted by UC-MSCs could attenuate the enhanced expression of IL-8 and IL-6 in MCF-7 cells cocultured with UC-MSCs, which subsequently alleviated the enhanced migration. Similar to UC-MSCs, exogenous human recombinant IL-8 or IL-6 also promoted IL-8 and IL-6 expression and MCF-7 cell migration. In addition to enhanced IL-8 and IL-6 expression, MCF-7 cells cocultured with UC-MSCs displayed enhanced mammosphere-forming ability and increased percentage of CD44(+)/CD24(-) cells. However, epithelial-to-mesenchymal transition (EMT) was not observed in MCF-7 cells cocultured with UC-MSCs. Taken together, these results suggested that IL-8 and IL-6 secreted by UC-MSCs activated the autocrine IL-8 and IL-6 signaling in MCF-7 cells and induced CD44(+)/CD24(-) cells, which subsequently promoted MCF-7 cell migration in vitro and metastasis in vivo.

  20. Plasticity between Epithelial and Mesenchymal States Unlinks EMT from Metastasis-Enhancing Stem Cell Capacity

    Directory of Open Access Journals (Sweden)

    Evelyne Beerling

    2016-03-01

    Full Text Available Forced overexpression and/or downregulation of proteins regulating epithelial-to-mesenchymal transition (EMT has been reported to alter metastasis by changing migration and stem cell capacity of tumor cells. However, these manipulations artificially keep cells in fixed states, while in vivo cells may adapt transient and reversible states. Here, we have tested the existence and role of epithelial-mesenchymal plasticity in metastasis of mammary tumors without artificially modifying EMT regulators. In these tumors, we found by intravital microscopy that the motile tumor cells have undergone EMT, while their epithelial counterparts were not migratory. Moreover, we found that epithelial-mesenchymal plasticity renders any EMT-induced stemness differences, as reported previously, irrelevant for metastatic outgrowth, because mesenchymal cells that arrive at secondary sites convert to the epithelial state within one or two divisions, thereby obtaining the same stem cell potential as their arrived epithelial counterparts. We conclude that epithelial-mesenchymal plasticity supports migration but additionally eliminates stemness-enhanced metastatic outgrowth differences.

  1. Selectins mediate small cell lung cancer systemic metastasis.

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    Franziska Heidemann

    Full Text Available Metastasis formation is the major reason for the extremely poor prognosis in small cell lung cancer (SCLC patients. The molecular interaction partners regulating metastasis formation in SCLC are largely unidentified, however, from other tumor entities it is known that tumor cells use the adhesion molecules of the leukocyte adhesion cascade to attach to the endothelium at the site of the future metastasis. Using the human OH-1 SCLC line as a model, we found that these cells expressed E- and P-selectin binding sites, which could be in part attributed to the selectin binding carbohydrate motif sialyl Lewis A. In addition, protein backbones known to carry these glycotopes in other cell lines including PSGL-1, CD44 and CEA could be detected in in vitro and in vivo grown OH1 SCLC cells. By intravital microscopy of murine mesenterial vasculature we could capture SCLC cells while rolling along vessel walls demonstrating that SCLC cells mimic leukocyte rolling behavior in terms of selectin and selectin ligand interaction in vivo indicating that this mechanism might indeed be important for SCLC cells to seed distant metastases. Accordingly, formation of spontaneous distant metastases was reduced by 50% when OH-1 cells were xenografted into E-/P-selectin-deficient mice compared with wild type mice (p = 0.0181. However, as metastasis formation was not completely abrogated in selectin deficient mice, we concluded that this adhesion cascade is redundant and that other molecules of this cascade mediate metastasis formation as well. Using several of these adhesion molecules as interaction partners presumably make SCLC cells so highly metastatic.

  2. Andrographolide Inhibits Proliferation and Metastasis of SGC7901 Gastric Cancer Cells

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    Lei Dai

    2017-01-01

    Full Text Available To explore the mechanisms by which andrographolide inhibits gastric cancer cell proliferation and metastasis, we employed the gastric cell line SGC7901 to investigate the anticancer effects of andrographolide. The cell survival ratio, cell migration and invasion, cell cycle, apoptosis, and matrix metalloproteinase activity were assessed. Moreover, western blotting and real-time PCR were used to examine the protein expression levels and the mRNA expression levels, respectively. The survival ratio of cells decreased with an increasing concentration of andrographolide in a dose-dependent manner. Consistent results were also obtained using an apoptosis assay, as detected by flow cytometry. The cell cycle was blocked at the G2/M2 phase by andrographolide treatment, and the proportion of cells arrested at G1/M was enhanced as the dose increased. Similarly, wound healing and Transwell assays showed reduced migration and invasion of the gastric cancer cells at various concentrations of andrographolide. Andrographolide can inhibit cell proliferation, invasion, and migration, block the cell cycle, and promote apoptosis in SGC7901 cells. The mechanisms may include upregulated expression of Timp-1/2, cyclin B1, p-Cdc2, Bax, and Bik and downregulated expression of MMP-2/9 and antiapoptosis protein Bcl-2.

  3. Andrographolide Inhibits Proliferation and Metastasis of SGC7901 Gastric Cancer Cells

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    Dai, Lei; Wang, Gang

    2017-01-01

    To explore the mechanisms by which andrographolide inhibits gastric cancer cell proliferation and metastasis, we employed the gastric cell line SGC7901 to investigate the anticancer effects of andrographolide. The cell survival ratio, cell migration and invasion, cell cycle, apoptosis, and matrix metalloproteinase activity were assessed. Moreover, western blotting and real-time PCR were used to examine the protein expression levels and the mRNA expression levels, respectively. The survival ratio of cells decreased with an increasing concentration of andrographolide in a dose-dependent manner. Consistent results were also obtained using an apoptosis assay, as detected by flow cytometry. The cell cycle was blocked at the G2/M2 phase by andrographolide treatment, and the proportion of cells arrested at G1/M was enhanced as the dose increased. Similarly, wound healing and Transwell assays showed reduced migration and invasion of the gastric cancer cells at various concentrations of andrographolide. Andrographolide can inhibit cell proliferation, invasion, and migration, block the cell cycle, and promote apoptosis in SGC7901 cells. The mechanisms may include upregulated expression of Timp-1/2, cyclin B1, p-Cdc2, Bax, and Bik and downregulated expression of MMP-2/9 and antiapoptosis protein Bcl-2.

  4. Efficient cell migration requires global chromatin condensation.

    Science.gov (United States)

    Gerlitz, Gabi; Bustin, Michael

    2010-07-01

    Cell migration is a fundamental process that is necessary for the development and survival of multicellular organisms. Here, we show that cell migration is contingent on global condensation of the chromatin fiber. Induction of directed cell migration by the scratch-wound assay leads to decreased DNaseI sensitivity, alterations in the chromatin binding of architectural proteins and elevated levels of H4K20me1, H3K27me3 and methylated DNA. All these global changes are indicative of increased chromatin condensation in response to induction of directed cell migration. Conversely, chromatin decondensation inhibited the rate of cell migration, in a transcription-independent manner. We suggest that global chromatin condensation facilitates nuclear movement and reshaping, which are important for cell migration. Our results support a role for the chromatin fiber that is distinct from its known functions in genetic processes.

  5. Trophoblast glycoprotein promotes pancreatic ductal adenocarcinoma cell metastasis through Wnt/planar cell polarity signaling.

    Science.gov (United States)

    He, Ping; Jiang, Shuheng; Ma, Mingze; Wang, Yang; Li, Rongkun; Fang, Fang; Tian, Guangang; Zhang, Zhigang

    2015-07-01

    Trophoblast glycoprotein (TPBG), a 72 kDa glycoprotein was identified using a monoclonal antibody, which specifically binds human trophoblast. The expression of TPBG in normal tissues is limited; however, it is upregulated in numerous types of cancer. When TPBG is expressed at a high level, this usually indicates a poor clinical outcome. In the present study, it was demonstrated that TPBG was more commonly observed in human pancreatic ductal adenocarcinoma (PDAC) compared with normal pancreatic tissue. Immunohistochemical analysis of PDAC tissue microarrays indicated that the expression of TPBG in PDAC tissues was closely correlated with the tumor-node-metastasis stage of the tumor. Silencing of TPBG in PDAC cell lines resulted in a decreased ability of cancer cell migration and invasion. Further investigation demonstrated that the Wnt/planar cell polarity signaling pathway was suppressed, as the expression of Wnt5a and the activation of c-Jun N-terminal kinase was inhibited following TPBG knockdown. In conclusion, the present study provided evidence that TPBG is involved in PDAC metastasis, and that TPBG and its associated signaling pathways may be a suitable target for PDAC therapy.

  6. JAM-C promotes lymphangiogenesis and nodal metastasis in non-small cell lung cancer.

    Science.gov (United States)

    Hao, SongNan; Yang, YanMei; Liu, Yan; Yang, ShuCai; Wang, Geng; Xiao, JianBing; Liu, HuiDong

    2014-06-01

    This study aims to investigate lymphatic metastasis-related genes in non-small cell lung carcinomas (NSCLC). NSCLC tissue was analyzed for expression of junctional adhesion molecule-C (JAM-C) protein. Our data revealed novel associations between JAM-C overexpression in primary tumors and lymphatic microvessel density (LMVD), lymph node metastasis, and poorer overall survival and recurrence-free survival. We used the highly metastatic human lung adenocarcinoma cell line Anip973 and its parental line AGZY83-a, which has a low metastatic capacity, in vivo and vitro. We found that JAM-C played an important role in different metastasis capacity of lymph node. JAM-C affected tumor growth, LNM, JAM-C, VEGF-C, vasculature, and ERK1/2 phosphorylation (p-ERK1/2). β1 integrin was involved in lymph node metastasis. Moreover, JAM-C knockdown in highly metastatic Anip973 decreased cell migration in scratch-wound assays. The JAM-C knockdown in Anip973 cells and JAM-C cDNA in AGZY83-a cells regulated the vascular endothelial growth factor C (VEGF-C) expression. Immunofluorescence showed that blocked VEGF-C expression in JAM-C shRNA Anip973 cells were restored after JAM-C treatment. JAM-C-induced VEGF-C in JAM-C cDNA AGZY83-a cells was also effectively inhibited by treatment with an antibody specifically against JAM-C. Use of media from Anip973 cells, AGZY83-a, and A549cells lung cancer cells that overexpressed or downregulated JAM-C was demonstrated to affect activity of VEGF-C-induced β1 integrin subunit or ERK activity in human dermal lymphatic endothelial cells (HDLEC) treated with VEGF-C or inhibitory antibody to JAM-C. Overall, these results indicate that JAM-C could mediate metastasis as it contributes to VEGF-C expression in cancer cells. JAM-C affects β1and ERK activation in HDLEC, thus promoting lymphangiogenesis and nodal metastasis. Our findings indicate that JAM-C may be a therapeutic target for preventing and treating lymphatic metastases.

  7. Holothurian glycosaminoglycan inhibits metastasis via inhibition of P-selectin in B16F10 melanoma cells.

    Science.gov (United States)

    Yue, Zhiqiang; Wang, Aiyun; Zhu, Zhijie; Tao, Li; Li, Yao; Zhou, Liang; Chen, Wenxing; Lu, Yin

    2015-12-01

    P-selectin-mediated tumor cell adhesion to platelets is a well-established stage in the process of tumor metastasis. Through computerized structural analysis, we found a marine-derived polysaccharide, holothurian glycosaminoglycan (hGAG), behaved as a ligand-competitive inhibitor of P-selectin, indicating its potential to disrupt the binding of P-selectin to cell surface receptor and activation of downstream regulators of tumor cell migration. Our experimental data demonstrated that hGAG significantly inhibited P-selectin-mediated adhesion of tumor cells to platelets and tumor cell migration in vitro and reduced subsequent pulmonary metastasis in vivo. Furthermore, abrogation of the P-selectin-mediated adhesion of tumor cells led to down-regulation of protein levels of integrins, FAK and MMP-2/9 in B16F10 cells, which is a crucial molecular mechanism of hGAG to inhibit tumor metastasis. In conclusion, hGAG has emerged as a novel anti-cancer agent via blocking P-selectin-mediated malignant events of tumor metastasis.

  8. EGF receptor signalling is essential for electric-field-directed migration of breast cancer cells.

    Science.gov (United States)

    Pu, Jin; McCaig, Colin D; Cao, Lin; Zhao, Zhiqiang; Segall, Jeffrey E; Zhao, Min

    2007-10-01

    The mechanisms by which cancer cells migrate to metastasise are not fully understood. Breast cancers are accompanied by electrical depolarisation of tumour epithelial cells. The electrical changes can be detected on the skin and are used to differentiate malignant from benign breast tumours. Could the electrical signals play a role in metastasis by promoting tumour cell migration? We report that electric fields stimulate and direct migration of human breast cancer cells. Importantly, these effects were more significant in highly metastatic tumour cells than in low metastatic tumour cells. Electric-field-enhanced directional migration correlates well with the expression level of EGF receptor (EGFR/ErbB1). To confirm this, we transfected low metastatic clone MTC cells with human ErbB1, which significantly increased the electrotactic response. Inhibition of ErbB1 completely abolished the directional response of MTLn3 cells to an electric field. Transfection of MTLn3 cells and MDA-MB-435 cells with expression vectors for ErbB family members ErbB1, ErbB2 and ErbB3 also significantly enhanced EF-induced migration. These results suggest that electric signals might play a role in metastasis of breast cancers by enhancing cell migration through the ErbB-signalling pathway.

  9. Collective cell migration during inflammatory response

    Science.gov (United States)

    Wu, Di; Stroka, Kimberly; Aranda-Espinoza, Helim

    2012-02-01

    Wound scratch healing assays of endothelial cell monolayers is a simple model to study collective cell migration as a function of biological signals. A signal of particular interest is the immune response, which after initial wounding in vivo causes the release of various inflammatory factors such as tumor necrosis alpha (TNF-α). TNF-α is an innate inflammatory cytokine that can induce cell growth, cell necrosis, and change cell morphology. We studied the effects of TNF-α on collective cell migration using the wound healing assays and measured several migration metrics, such as rate of scratch closure, velocities of leading edge and bulk cells, closure index, and velocity correlation functions between migrating cells. We observed that TNF-α alters all migratory metrics as a function of the size of the scratch and TNF-α content. The changes observed in migration correlate with actin reorganization upon TNF-α exposure.

  10. Slit2 Inhibits Growth and Metastasis of Fibrosarcoma and Squamous Cell Carcinoma

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    Hee Kyung Kim

    2008-12-01

    Full Text Available Slits are a group of secreted glycoproteins that play a role in the regulation of cell migration. Previous studies suggested that Slit2 might be a tumor-suppressor gene. However, it remained to be determined whether Slit2 suppressed tumor growth and metastasis in animal models. We showed that Slit2 expression was decreased or abolished in human esophageal squamous cell carcinomas (SCCs compared to normal tissues by in situ hybridization. Stable transfection of human SCC A431 and fibrosarcoma HT1080 cells with Slit2 gene suppressed tumor growth in athymic nude mice. Apoptosis in Slit2-transfected tumors was increased, whereas proliferating cells were decreased, suggesting a mechanism for Slit2-mediated tumor suppression. This was supported by further analysis indicating that antiapoptotic molecules Bcl-2 and Bcl-xl and cell cycle molecules Cdk6 and Cyclin D1 were down-regulated in Slit2-transfected tumors. Furthermore, wound healing and Matrigel invasion assays showed that the transfection with Slit2 inhibited tumor cell migration and invasion. Slit2-transfected tumors showed a high level of keratin 8/18 and a low level of N-cadherin expression compared to empty vector-transfected tumors. More importantly, Slit2 transfection suppressed the metastasis of HT1080 tumor cells in lungs after intravenous inoculation. Collectively, our study has demonstrated that Slit2 inhibits tumor growth and metastasis of fibrosarcoma and SCC and that its effect on cell cycle and apoptosis signal pathways is an important mechanism for Slit2-mediated tumor suppression.

  11. Slit2 inhibits growth and metastasis of fibrosarcoma and squamous cell carcinoma.

    Science.gov (United States)

    Kim, Hee Kyung; Zhang, Hong; Li, Hui; Wu, Tsung-Teh; Swisher, Stephen; He, Donggou; Wu, Lizhi; Xu, Jianmin; Elmets, Craig A; Athar, Mohammad; Xu, Xìao-chun; Xu, Hui

    2008-12-01

    Slits are a group of secreted glycoproteins that play a role in the regulation of cell migration. Previous studies suggested that Slit2 might be a tumor-suppressor gene. However, it remained to be determined whether Slit2 suppressed tumor growth and metastasis in animal models. We showed that Slit2 expression was decreased or abolished in human esophageal squamous cell carcinomas (SCCs) compared to normal tissues by in situ hybridization. Stable transfection of human SCC A431 and fibrosarcoma HT1080 cells with Slit2 gene suppressed tumor growth in athymic nude mice. Apoptosis in Slit2-transfected tumors was increased, whereas proliferating cells were decreased, suggesting a mechanism for Slit2-mediated tumor suppression. This was supported by further analysis indicating that antiapoptotic molecules Bcl-2 and Bcl-xl and cell cycle molecules Cdk6 and Cyclin D1 were down-regulated in Slit2-transfected tumors. Furthermore, wound healing and Matrigel invasion assays showed that the transfection with Slit2 inhibited tumor cell migration and invasion. Slit2-transfected tumors showed a high level of keratin 8/18 and a low level of N-cadherin expression compared to empty vector-transfected tumors. More importantly, Slit2 transfection suppressed the metastasis of HT1080 tumor cells in lungs after intravenous inoculation. Collectively, our study has demonstrated that Slit2 inhibits tumor growth and metastasis of fibrosarcoma and SCC and that its effect on cell cycle and apoptosis signal pathways is an important mechanism for Slit2-mediated tumor suppression.

  12. Leukemia stem cells in drug resistance and metastasis

    Institute of Scientific and Technical Information of China (English)

    DENG Chao-hua; ZHANG Qiu-ping

    2010-01-01

    Objective To review the central role of leukemia stem cells (LSCs) in drug resistance and metastasis, aiming to provide key insights into leukemogenic pathology and developing novel therapeutic strategies against the relapse of leukemia.Data sources The data used in this review were obtained mainly from the studies reported in PubMed using the key terms "tumor-initiating cells", "leukemia stem cells", "drug resistance" and "metastasis".Study selection Relevant articles on studies of leukemia stem cells were selected.Results Increasing numbers of studies have suggested the importance of cancer stem cells (CSCs) in the initiation and maintenance of cancer, especially in leukemia. This review has summarized the origin, characteristics, isolation and identification of LSCs. It highlights the crucial role of LSCs in drug resistance and metastasis of leukemia by illustrating possible mechanisms and aims to provide novel therapeutic strategies for LSCs-targeted treatment.Conclusion LSCs play a crucial role in drug resistance and metastasis of leukemia and new promising LSCs-targeted therapies warrant investigation in both experimental models and clinical practice.

  13. Microfluidic chip with integrated electrical cell-impedance sensing for monitoring single cancer cell migration in three-dimensional matrixes.

    Science.gov (United States)

    Nguyen, Tien Anh; Yin, Tsung-I; Reyes, Diego; Urban, Gerald A

    2013-11-19

    Cell migration has been recognized as one hallmark of malignant tumor progression. By integrating the method of electrical cell-substrate impedance sensing (ECIS) with the Boyden chamber design, the state-of-the-art techniques provide kinetic information about cell migration and invasion processes in three-dimensional (3D) extracellular matrixes. However, the information related to the initial stage of cell migration with single-cell resolution, which plays a unique role in the metastasis-invasion cascade of cancer, is not yet available. In this paper, we present a microfluidic device integrated with ECIS for investigating single cancer cell migration in 3D matrixes. Using microfluidics techniques without the requirement of physical connections to off-chip pneumatics, the proposed sensor chip can efficiently capture single cells on microelectrode arrays for sequential on-chip 2D or 3D cell culture and impedance measurement. An on-chip single-cell migration assay was successfully demonstrated within several minutes. Migration of single metastatic MDA-MB-231 cells in their initial stage can be monitored in real time; it shows a rapid change in impedance magnitude of approximately 10 Ω/s, whereas no prominent impedance change is observed for less-metastasis MCF-7 cells. The proposed sensor chip, allowing for a rapid and selective detection of the migratory properties of cancer cells at the single-cell level, could be applied as a new tool for cancer research.

  14. Effect of 7-hydroxystaurosporine on glioblastoma cell invasion and migration

    Institute of Scientific and Technical Information of China (English)

    Qing-hui MENG; Li-xin ZHOU; Jia-lin LUO; Jian-ping CAO; Jian TONG; Sai-jun FAN

    2005-01-01

    Aim: To investigate the effect of 7-hydroxystaurosporine (UCN-01), a selective protein kinase C (PKC) inhibitor, on cell growth, migration, and invasion in inva sive human glioblastoma U-87MG cells. Methods: PKC activity was determined based on the PKC-catalyzed transfer of the 32p-phosphate group from [g-32p]ATP into a PKC-specific peptide substrate. Cell viability was measured by MTT assay.Cell invasion and migration were evaluated by a Boyden chamber assay and scratch wound assay, respectively. Protein expression was analyzed using Western blot assay. The formation of 3-dimensional cellular aggregates was examined by a cell-cell aggregation assay. Results: UCN-01 treatment resulted in concentration- and time-dependent inhibition of U-87MG cell growth at higher doses (> 100 nmol/L), and reduced cell invasion and migration capability at less cytotoxic doses (<100 nmol/L). UCN-01 significantly repressed PKC activity. Consistent with this result, UCN-01 blocked cell invasion stimulated by phorbel 12-myristate13-acetate (PMA) and ethanol (EtOH), 2 PKC activators. Enforced expression of the tumor suppressor genes BRCA1 and PTEN increased the anti-invasion potential of UCN-01. Exposure to UCN-01 caused a dose-dependent increase in cell adhesion molecule E-cadherin. The effect of UCN-01 on the formation of cell-cell aggregation was significantly reduced by the addition of an anti-E-cadherin antibody. Conclusion: UCN-01 inhibits the invasion and migration of human glioma cells. Accordingly, UCN-01 can have potential clinical applications for the treatment of human glioma metastasis.

  15. Staphylococcal Superantigen-like 10 Inhibits CXCL12-Induced Human Tumor Cell Migration

    NARCIS (Netherlands)

    Walenkamp, Annemiek M. E.; Boer, Ingrid G. J.; Bestebroer, Jovanka; Rozeveld, Dennie; Timmer-Bosscha, Hetty; Hemrika, Wieger; van Strijp, Jos A. G.; de Haas, Carla J. C.

    2009-01-01

    PURPOSE: Tumor cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. CXCR4 is the most widely expressed chemokine receptor in many different types of cancer and has been linked to tumor dissemination and poo

  16. Small interfering RNA targeting ILK inhibits metastasis in human tongue cancer cells through repression of epithelial-to-mesenchymal transition

    Energy Technology Data Exchange (ETDEWEB)

    Xing, Yu [College of Laboratory Medicine, Chongqing Medical University, Chongqing (China); Laboratory of Forensic Medicine and Biomedical Information, Chongqing Medical University, Chongqing (China); Qi, Jin [The Affiliated Hospital of Stomatology, Chongqing Medical University (China); Deng, Shixiong [College of Laboratory Medicine, Chongqing Medical University, Chongqing (China); Laboratory of Forensic Medicine and Biomedical Information, Chongqing Medical University, Chongqing (China); Wang, Cheng [Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing (China); Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing (China); Zhang, Luyu [Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing (China); Chen, Junxia, E-mail: chjunxia@126.com [Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing (China); Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing (China)

    2013-08-01

    Integrin-linked kinase (ILK) is a multifunctional serine/threonine kinase. Accumulating evidences suggest that ILK are involved in cell–matrix interactions, cell proliferation, invasion, migration, angiogenesis and Epithelial–mesenchymal transition (EMT). However, the underlying mechanisms remain largely unknown. EMT has been postulated as a prerequisite for metastasis. The reports have demonstrated that EMT was implicated in metastasis of oral squamous cell carcinomas. Therefore, here we further postulate that ILK might participate in EMT of tongue cancer. We showed that ILK siRNA inhibited EMT with low N-cadherin, Vimentin, Snail, Slug and Twist as well as high E-cadherin expression in vivo and in vitro. We found that knockdown of ILK inhibited cell proliferation, migration and invasion as well as changed cell morphology. We also demonstrated that ILK siRNA inhibited phosphorylation of downstream signaling targets Akt and GSK3β as well as reduced expression of MMP2 and MMP9. Furthermore, we found that the tongue tumor with high metastasis capability showed higher ILK, Vimentin, Snail, Slug and Twist as well as lower E-cadherin expression in clinical specimens. Finally, ILK siRNA led to the suppression for tumorigenesis and metastasis in vivo. Our findings suggest that ILK could be a novel diagnostic and therapeutic target for tongue cancer. Highlights: • ILK siRNA influences cell morphology, cell cycle, migration and invasion. • ILK siRNA affects the expression of proteins associated with EMT. • ILK expression is related to EMT in clinical human tongue tumors. • ILK siRNA inhibits metastasis of the tongue cancer cells through suppressing EMT.

  17. Usp7 promotes medulloblastoma cell survival and metastasis by activating Shh pathway.

    Science.gov (United States)

    Zhan, Meixiao; Sun, Xiaohan; Liu, Jinxiao; Li, Yan; Li, Yong; He, Xu; Zhou, Zizhang; Lu, Ligong

    2017-03-04

    The ubiquitin-specific protease Usp7 plays roles in multiple cellular processes through deubiquitinating and stabilizing numerous substrates, including P53, Pten and Gli. Aberrant Usp7 activity has been implicated in many disorders and tumorigenesis, making it as a potential target for therapeutic intervention. Although it is clear that Usp7 is involved in many types of cancer, its role in regulating medulloblastoma (MB) is still unknown. In this study, we show that knockdown of Usp7 inhibits the proliferation and migration of MB cells, while Usp7 overexpression exerts an opposite effect. Furthermore, we establish Usp7 knockout MB cell line using the CRISPR/Cas9 system and further confirm that Usp7 knockout also blocks MB cell proliferation and metastasis. In addition, we reveal that knockdown of Usp7 compromises Shh pathway activity and decrease Gli protein levels, while P53 level and P53 target gene expression have no obvious changes. Finally, we find that Usp7 inhibitors apparently inhibit MB cell viability and migration. Taken together, our findings suggest that Usp7 is important for MB cell proliferation and metastasis by activating Shh pathway, and is a putative therapeutic target for MBs.

  18. Functional screening with a live cell imaging-based random cell migration assay.

    Science.gov (United States)

    van Roosmalen, Wies; Le Dévédec, Sylvia E; Zovko, Sandra; de Bont, Hans; van de Water, Bob

    2011-01-01

    Cell migration, essential in cancer progression, is a complex process comprising a number of spatiotemporally regulated and well-coordinated mechanisms. In order to study (random) cell migration in the context of responses to various external cues (such as growth factors) or intrinsic cell signaling, a number of different tools and approaches have been developed. In order to unravel the key pathways and players involved in the regulation of (cancer) cell migration, a systematical mapping of the players/pathways is required. For this purpose, we developed a cell migration assay based on automatic high-throughput microscopy screen. This approach allows for screening of hundreds of genes, e.g., those encoding various kinases and phosphatases but can also be used for screening of drugs libraries. Moreover, we have developed an automatic analysis pipeline comprising of (a) automatic data acquisition (movie) and (b) automatic analysis of the acquired movies of the migrating cells. Here, we describe various facets of this approach. Since cell migration is essential in progression of cancer metastasis, we describe two examples of experiments performed on highly motile (metastatic) cancer cells.

  19. Expression and phosphorylation of stathmin correlate with cell migration in esophageal squamous cell carcinoma.

    Science.gov (United States)

    Liu, Fei; Sun, Yu-Lin; Xu, Yang; Liu, Fang; Wang, Li-Shun; Zhao, Xiao-Hang

    2013-02-01

    Microtubules play extensive roles in cellular processes, including cell motility. Stathmin is an important protein which destabilizes microtubules. The essential function of stathmin is closely associated with its phosphorylation status. Stathmin is overexpressed in many human cancers and has a significant relationship with clinical characteristics such as grade, tumor size and prognosis. We demonstrated that stathmin was overexpressed in ESCC tissues using both 2-DE and immunohistochemistry analysis. In addition, overexpression of stathmin was significantly correlated with histological grade in ESCC. However, no correlation was found with age, gender and lymph node metastasis. Knockdown of stathmin with siRNA impaired cell migration in KYSE30 and KYSE410 cells. When EC0156 cells were treated with paclitaxel, stathmin was stably phosphorylated and migration was impaired. These observations suggest that stathmin may have a more important function in ESCC development and migration. The present study provides further understanding of the importance of stathmin in ESCC therapy or diagnosis.

  20. Effect of DPC4 Gene on Invasion and Metastasis of Colorectal Carcinoma Cells

    Institute of Scientific and Technical Information of China (English)

    De-Sheng XIAO; Ji-Fang WEN; Jing-He LI; Kuan-Song WANG; Zhong-Liang HU; Jian-Hua ZHOU; Zheng-Hao DENG; Ying LIU

    2006-01-01

    To investigate the effect of DPC4 gene on invasion and metastasis of colorectal carcinoma cells, the expression of DPC4 was detected in sixty-three samples of colorectal tumors and seven cases of colorectal mucosa. The biological behavior of tumors expressing DPC4 was evaluated (including tumor staging, differentiation degree and metastasis), pcDNA3.1-DPC4 plasmid was constructed and transferred into HCT116 cells not expressing DPC4. The cell models (DPC4+-HCT116) steadily expressing DPC4 were obtained. Compared with HCT116 and pcDNA3.1-HCT116 cells, the doubling time of DPC4+-HCT 116 cells was lengthened obviously (P<0.01), the apoptosis rate of DPC4+-HCT116 cells was significantly increased (P<0.01), the cloning efficiency, cell adherency, migration and invasion ability of DPC4+-HCT116 cells were dropped obviously (P<0.01). The number of cancer nodules was decreased significantly in abdominal cavity and liver of the nude mice inoculated with DPC4+-HCT116 cells. The activity of MMP-9 and MMP-2 was detected by gelatin zymography. In comparison with HCT116 and pcDNA3.1-HCT116 cells, the activity of MMP-9 was decreased in DPC4+-HCT116 cells. Therefore, the down-regulation of DPC4 expression may be associated with the carcinogenesis of colorectal carcinoma. DPC4 may inhibit the proliferation of colon cancer cell by restraining growth and inducing apoptosis, and the invasion and metastasis of colorectal carcinoma cells. MMP-9 may be one of the downstream target genes regulated by DPC4.

  1. Fisetin inhibits migration, invasion and epithelial-mesenchymal transition of LMP1-positive nasopharyngeal carcinoma cells.

    Science.gov (United States)

    Li, Rong; Zhao, Yinhai; Chen, Jin; Shao, Songjun; Zhang, Xiujuan

    2014-02-01

    Fisetin (3,3',4',7-tetrahydroxyflavone) has been reported to possess certain anticancer properties. It may inhibit tumor cell proliferation, metastasis and induce apoptosis. However, the effects of fisetin in preventing the metastasis of nasopharyngeal carcinoma (NPC) cells remain to be determined. The epithelial-mesenchymal transition (EMT) is involved in several metastatic malignancies including NPC. It has been reported that the Epstein-Barr virus latent membrane protein-1 (LMP1) induced EMT and is associated with the metastasis of NPC. The aim of this study was to examine the effects of fisetin in preventing the migration and invasion of LMP1-expressing NPC cells (CNE1-LMP1 cells), as well as to investigate whether fisetin may inhibit the molecular changes associated with EMT induced by LMP1. The investigation demonstrated that fisetin suppressed the migration and invasion of CNE1-LMP1 cells under non-cytotoxic concentrations. Fisetin inhibited molecular changes associated with EMT induced by LMP1, upregulated the epithelial marker, E-cadherin protein, and downregulated the mesenchymal marker, vimentin protein, levels. Fisetin also significantly reduced the levels of Twist protein, an EMT regulator. The investigation suggested that fisetin inhibits the migration and invasion of LMP1-positive NPC cells, and the molecular mechanism involves fisetin reversing the EMT induced by LMP1 and downregulates the expression of Twist. This study indicated that fisetin serves as a potential candidate for the treatment of cancer metastasis.

  2. Downregulation of COX-2 and CYP 4A signaling by isoliquiritigenin inhibits human breast cancer metastasis through preventing anoikis resistance, migration and invasion

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    Zheng, Hao; Li, Ying [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Wang, Yuzhong [Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079 (China); Zhao, Haixia [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Zhang, Jing [Animal Experimental Center of Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Tang, Tian [Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Yue, Jiang [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Guo, Austin M., E-mail: Austin_Guo@nymc.edu [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Department of Pharmacology, New York Medical College, Valhalla, NY 10595 (United States); Yang, Jing, E-mail: yangjingliu2013@163.com [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China)

    2014-10-01

    Flavonoids exert extensive in vitro anti-invasive and in vivo anti-metastatic activities. Anoikis resistance occurs at multiple key stages of the metastatic cascade. Here, we demonstrate that isoliquiritigenin (ISL), a flavonoid from Glycyrrhiza glabra, inhibits human breast cancer metastasis by preventing anoikis resistance, migration and invasion through downregulating cyclooxygenase (COX)-2 and cytochrome P450 (CYP) 4A signaling. ISL induced anoikis in MDA-MB-231 and BT-549 human breast cancer cells as evidenced by flow cytometry and the detection of caspase cleavage. Moreover, ISL inhibited the mRNA expression of phospholipase A2, COX-2 and CYP 4A and decreased the secretion of prostaglandin E{sub 2} (PGE{sub 2}) and 20-hydroxyeicosatetraenoic acid (20-HETE) in detached MDA-MB-231 cells. In addition, it decreased the levels of phospho-PI3K (Tyr{sup 458}), phospho-PDK (Ser{sup 241}) and phospho-Akt (Thr{sup 308}). Conversely, the exogenous addition of PGE{sub 2}, WIT003 (a 20-HETE analog) and an EP4 agonist (CAY10580) or overexpression of constitutively active Akt reversed ISL-induced anoikis. ISL exerted the in vitro anti-migratory and anti-invasive activities, whereas the addition of PGE{sub 2}, WIT003 and CAY10580 or overexpression of constitutively active Akt reversed the in vitro anti-migratory and anti-invasive activities of ISL in MDA-MB-231 cells. Notably, ISL inhibited the in vivo lung metastasis of MDA-MB-231 cells, together with decreased intratumoral levels of PGE{sub 2}, 20-HETE and phospho-Akt (Thr{sup 308}). In conclusion, ISL inhibits breast cancer metastasis by preventing anoikis resistance, migration and invasion via downregulating COX-2 and CYP 4A signaling. It suggests that ISL could be a promising multi-target agent for preventing breast cancer metastasis, and anoikis could represent a novel mechanism through which flavonoids may exert the anti-metastatic activities. - Highlights: • Isoliquiritigenin induces anoikis and suppresses

  3. Tumor-stroma interaction: Revealing fibroblast-secreted exosomes as potent regulators of Wnt-planar cell polarity signaling in cancer metastasis.

    Science.gov (United States)

    Luga, Valbona; Wrana, Jeffrey L

    2013-12-01

    Cancer-associated fibroblasts (CAF) regulate tumor progression, but their role in cancer metastasis remains largely unexplored. Exosomes are secreted microvesicles that are emerging as potent mediators of cell-cell communication that are of particular importance in tumor-stroma interactions. The Wnt-planar cell polarity (PCP) pathway is the primary regulator of convergent extension cell movements during vertebrate development, but the role of this signaling pathway in cancer cell migration and metastasis has been unclear. Recently, we revealed that fibroblasts secrete exosomes that promote breast cancer cell (BCC) protrusive activity, motility, and metastasis by activating autocrine Wnt-PCP signaling in BCCs. Moreover, we showed that Wnt ligands produced by BCCs tether to fibroblast exosomes upon trafficking of exosomes in BCCs. These findings have several implications that motivate promising future research in the fields of tumor-stroma communication, exosome function, and Wnt-PCP signaling in cancer metastasis.

  4. Atrial natriuretic peptide prevents cancer metastasis through vascular endothelial cells.

    Science.gov (United States)

    Nojiri, Takashi; Hosoda, Hiroshi; Tokudome, Takeshi; Miura, Koichi; Ishikane, Shin; Otani, Kentaro; Kishimoto, Ichiro; Shintani, Yasushi; Inoue, Masayoshi; Kimura, Toru; Sawabata, Noriyoshi; Minami, Masato; Nakagiri, Tomoyuki; Funaki, Soichiro; Takeuchi, Yukiyasu; Maeda, Hajime; Kidoya, Hiroyasu; Kiyonari, Hiroshi; Shioi, Go; Arai, Yuji; Hasegawa, Takeshi; Takakura, Nobuyuki; Hori, Megumi; Ohno, Yuko; Miyazato, Mikiya; Mochizuki, Naoki; Okumura, Meinoshin; Kangawa, Kenji

    2015-03-31

    Most patients suffering from cancer die of metastatic disease. Surgical removal of solid tumors is performed as an initial attempt to cure patients; however, surgery is often accompanied with trauma, which can promote early recurrence by provoking detachment of tumor cells into the blood stream or inducing systemic inflammation or both. We have previously reported that administration of atrial natriuretic peptide (ANP) during the perioperative period reduces inflammatory response and has a prophylactic effect on postoperative cardiopulmonary complications in lung cancer surgery. Here we demonstrate that cancer recurrence after curative surgery was significantly lower in ANP-treated patients than in control patients (surgery alone). ANP is known to bind specifically to NPR1 [also called guanylyl cyclase-A (GC-A) receptor]. In mouse models, we found that metastasis of GC-A-nonexpressing tumor cells (i.e., B16 mouse melanoma cells) to the lung was increased in vascular endothelium-specific GC-A knockout mice and decreased in vascular endothelium-specific GC-A transgenic mice compared with control mice. We examined the effect of ANP on tumor metastasis in mice treated with lipopolysaccharide, which mimics systemic inflammation induced by surgical stress. ANP inhibited the adhesion of cancer cells to pulmonary arterial and micro-vascular endothelial cells by suppressing the E-selectin expression that is promoted by inflammation. These results suggest that ANP prevents cancer metastasis by inhibiting the adhesion of tumor cells to inflamed endothelial cells.

  5. Inhibitory effects of Leucaena leucocephala on the metastasis and invasion of human oral cancer cells.

    Science.gov (United States)

    Chung, Hsiao-Hang; Chen, Mu-Kuan; Chang, Yu-Chao; Yang, Shun-Fa; Lin, Chia-Chieh; Lin, Chiao-Wen

    2017-02-09

    Oral cancer is one of the most common cancers worldwide, and metastasis is recognized as a major factor causing its low survival rate. The inhibition of metastasis progress and the improvement of the survival rate for oral cancer are critical research objectives. Leucaena leucocephala from the mimosa branch Leucaena genus is native to Central and South America and has been used as a traditional remedy for treating various disorders. Previous studies have demonstrated antioxidant, anti-inflammatory as well as anticancer properties of L. leucocephala plant materials. However, the molecular mechanism underlying the anticancer effect induced by L. leucocephala remains unclear. In this study, we investigated the effect of L. leucocephala extract (LLE) on SCC-9 and SAS oral cancer cells and examined the potential inhibitory mechanisms involved. The results indicated that LLE attenuated the migration and invasion abilities of both SCC-9 and SAS cells by reducing the activity and protein expression of matrix metalloproteinases-2 (MMP-2). Regarding mitogen-activated protein kinase (MAPK) pathways, the phosphorylation of ERK1/2 and p38 exhibited a significant inhibitory effect in the presence of LLE. The application of ERK inhibitor and p38 inhibitor confirmed that both signalling transduction pathways were involved in the inhibition of cell metastasis. These data indicate that L. leucocephala could be a potent therapeutic agent for the prevention and treatment of oral cancer and a prominent plant source for anticancer research in the future.

  6. Polymorphonuclear cells stimulate the migration and metastatic potential of rat sarcoma cells.

    Science.gov (United States)

    Remedi, María Mónica; Donadio, Ana Carolina; Chiabrando, Gustavo Alberto

    2009-02-01

    The tumour microenvironment, which is largely composed of inflammatory cells, is a crucial participant in the neoplastic process through the promotion of cell proliferation, survival and migration. Neutrophil polymorphonuclear cells (PMNs) induce inflammatory reactions that can be either cytotoxic for tumour cells or can promote tumour growth and metastasis. Previously, we have reported a spontaneous metastasis tumour model that has tumour PMNs infiltration, and metastasis, to liver and spleen. The aim of this study was to evaluate the PMNs influences on the tumour cell invasion and metastatic properties. We analysed intercellular adhesion molecule-1 (ICAM-1), urokinase-type plasminogen activator receptor (uPAR), MT1-MMP (membrane type 1-matrix metalloproteinase) and MMP2 protein expression in TuE-t cells cultured with PMNs or PMNs-conditioned medium isolated from tumour bearing and normal rats. The interaction between tumour cells and PMNs induced a decrease in ICAM-1 expression in tumour cells as well as an increase in MMP2 and tumour cell motility. Besides, conserved expression of uPAR and MT1-MMP in tumour cells was also demonstrated. The up-regulation in MMP2 associated with uPAR and MT1-MMP conserved expression may be related to an increased extracellular matrix proteolysis. These results showed that the interaction of tumour cells with PMNs could favour tumour cell spreading through the promotion of a tumour invasive phenotype.

  7. Doxycycline reverses epithelial-to-mesenchymal transition and suppresses the proliferation and metastasis of lung cancer cells.

    Science.gov (United States)

    Qin, Yuan; Zhang, Qiang; Lee, Shan; Zhong, Wei-Long; Liu, Yan-Rong; Liu, Hui-Juan; Zhao, Dong; Chen, Shuang; Xiao, Ting; Meng, Jing; Jing, Xue-Shuang; Wang, Jing; Sun, Bo; Dai, Ting-Ting; Yang, Cheng; Sun, Tao; Zhou, Hong-Gang

    2015-12-01

    The gelatinase inhibitor doxycycline is the prototypical antitumor antibiotic. We investigated the effects of doxycycline on the migration, invasion, and metastasis of human lung cancer cell lines and in a mouse model. We also measured the effect of doxycycline on the transcription of epithelial-mesenchymal transition (EMT) markers, and used immunohistochemistry to determine whether EMT reversal was associated with doxycycline inhibition. Doxycycline dose-dependently inhibited proliferation, migration, and invasion of NCI-H446 human small cell lung cancer cells. It also suppressed tumor growth from NCI-H446 and A549 lung cancer cell xenografts without altering body weight, inhibited Lewis lung carcinoma cell migration, and prolonged survival. The activities of the transcription factors Twist1/2, SNAI1/2, AP1, NF-κB, and Stat3 were suppressed by doxycycline, which reversed EMT and inhibited signal transduction, thereby suppressing tumor growth and metastasis. Our data demonstrate functional targeting of transcription factors by doxycycline to reverse EMT and suppress tumor proliferation and metastasis. Thus, doxycycline selectively targets malignant tumors and reduces its metastatic potential with less cytotoxicity in lung cancer patients.

  8. WNT5A inhibits metastasis and alters splicing of Cd44 in breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Wen Jiang

    Full Text Available Wnt5a is a non-canonical signaling Wnt. Low expression of WNT5A is correlated with poor prognosis in breast cancer patients. The highly invasive breast cancer cell lines, MDA-MB-231 and 4T1, express very low levels of WNT5A. To determine if enhanced expression of WNT5A would affect metastatic behavior, we generated WNT5A expressing cells from the 4T1 and MDA-MB-231 parental cell lines. WNT5A expressing cells demonstrated cobblestone morphology and reduced in vitro migration relative to controls. Cell growth was not altered. Metastasis to the lung via tail vein injection was reduced in the 4T1-WNT5A expressing cells relative to 4T1-vector controls. To determine the mechanism of WNT5A action on metastasis, we performed microarray and whole-transcriptome sequence analysis (RNA-seq to compare gene expression in 4T1-WNT5A and 4T1-vector cells. Analysis indicated highly significant alterations in expression of genes associated with cellular movement. Down-regulation of a subset of these genes, Mmp13, Nos2, Il1a, Cxcl2, and Lamb3, in WNT5A expressing cells was verified by semi-quantitative RT-PCR. Significant differences in transcript splicing were also detected in cell movement associated genes including Cd44. Cd44 is an adhesion molecule with a complex genome structure. Variable exon usage is associated with metastatic phenotype. Alternative spicing of Cd44 in WNT5A expressing cells was confirmed using RT-PCR. We conclude that WNT5A inhibits metastasis through down-regulation of multiple cell movement pathways by regulating transcript levels and splicing of key genes like Cd44.

  9. DC electric fields direct breast cancer cell migration, induce EGFR polarization, and increase the intracellular level of calcium ions.

    Science.gov (United States)

    Wu, Dan; Ma, Xiuli; Lin, Francis

    2013-01-01

    Migration of cancer cells leads to invasion of primary tumors to distant organs (i.e., metastasis). Growing number of studies have demonstrated the migration of various cancer cell types directed by applied direct current electric fields (dcEF), i.e., electrotaxis, and suggested its potential implications in metastasis. MDA-MB-231 cell, a human metastatic breast cancer cell line, has been shown to migrate toward the anode of dcEF. Further characterizations of MDA-MB-231 cell electrotaxis and investigation of its underlying signaling mechanisms will lead to a better understanding of electrically guided cancer cell migration and metastasis. Therefore, we quantitatively characterized MDA-MB-231 cell electrotaxis and a few associated signaling events. Using a microfluidic device that can create well-controlled dcEF, we showed the anode-directing migration of MDA-MB-231 cells. In addition, surface staining of epidermal growth factor receptor (EGFR) and confocal microscopy showed the dcEF-induced anodal EGFR polarization in MDA-MB-231 cells. Furthermore, we showed an increase of intracellular calcium ions in MDA-MB-231 cells upon dcEF stimulation. Altogether, our study provided quantitative measurements of electrotactic migration of MDA-MB-231 cells, and demonstrated the electric field-mediated EGFR and calcium signaling events, suggesting their involvement in breast cancer cell electrotaxis.

  10. Computational modelling of cell chain migration reveals mechanisms that sustain follow-the-leader behaviour.

    Science.gov (United States)

    Wynn, Michelle L; Kulesa, Paul M; Schnell, Santiago

    2012-07-07

    Follow-the-leader chain migration is a striking cell migratory behaviour observed during vertebrate development, adult neurogenesis and cancer metastasis. Although cell-cell contact and extracellular matrix (ECM) cues have been proposed to promote this phenomenon, mechanisms that underlie chain migration persistence remain unclear. Here, we developed a quantitative agent-based modelling framework to test mechanistic hypotheses of chain migration persistence. We defined chain migration and its persistence based on evidence from the highly migratory neural crest model system, where cells within a chain extend and retract filopodia in short-lived cell contacts and move together as a collective. In our agent-based simulations, we began with a set of agents arranged as a chain and systematically probed the influence of model parameters to identify factors critical to the maintenance of the chain migration pattern. We discovered that chain migration persistence requires a high degree of directional bias in both lead and follower cells towards the target. Chain migration persistence was also promoted when lead cells maintained cell contact with followers, but not vice-versa. Finally, providing a path of least resistance in the ECM was not sufficient alone to drive chain persistence. Our results indicate that chain migration persistence depends on the interplay of directional cell movement and biased cell-cell contact.

  11. ERP44 inhibits human lung cancer cell migration mainly via IP3R2.

    Science.gov (United States)

    Huang, Xue; Jin, Meng; Chen, Ying-Xiao; Wang, Jun; Zhai, Kui; Chang, Yan; Yuan, Qi; Yao, Kai-Tai; Ji, Guangju

    2016-06-01

    Cancer cell migration is involved in tumour metastasis. However, the relationship between calcium signalling and cancer migration is not well elucidated. In this study, we used the human lung adenocarcinoma A549 cell line to examine the role of endoplasmic reticulum protein 44 (ERP44), which has been reported to regulate calcium release inside of the endoplasmic reticulum (ER), in cell migration. We found that the inositol 1,4,5-trisphosphate receptors (IP3Rs/ITPRs) inhibitor 2-APB significantly inhibited A549 cell migration by inhibiting cell polarization and pseudopodium protrusion, which suggests that Ca2+ is necessary for A549 cell migration. Similarly, the overexpression of ERP44 reduced intracellular Ca2+ release via IP3Rs, altered cell morphology and significantly inhibited the migration of A549 cells. These phenomena were primarily dependent on IP3R2 because wound healing in A549 cells with IP3R2 rather than IP3R1 or IP3R3 siRNA was markedly inhibited. Moreover, the overexpression of ERP44 did not affect the migration of the human neuroblastoma cell line SH-SY5Y, which mainly expresses IP3R1. Based on the above observations, we conclude that ERP44 regulates A549 cell migration mainly via an IP3R2-dependent pathway.

  12. Overexpression of DDR2 contributes to cell invasion and migration in head and neck squamous cell carcinoma.

    Science.gov (United States)

    Xu, Jinke; Lu, Wei; Zhang, Senlin; Zhu, Chuchao; Ren, Tingting; Zhu, Tong; Zhao, Hu; Liu, Yanpu; Su, Jin

    2014-05-01

    Background Discoidin domain receptor 2 (DDR2) is a unique receptor tyrosine kinase (RTK) that is activated by fibrillar collagens. Although DDR2 contributes to the metastasis of some tumors, its role in head and neck squamous cell carcinoma (HNSCC) remains unknown. The aim of this study was to investigate the expression level, clinical and pathological significance, and biologic function of DDR2 in HNSCC. Methods Real-time quantitative PCR, western blot, and immunohistochemical staining were employed to assess the expression levels of DDR2 in HNSCC specimens. Adenovirus-mediated overexpression of DDR2 was used to evaluate its consequences on cell proliferation, invasion, migration, and the process of hypoxia-induced epithelial-mesenchymal transition (EMT). Then nude mouse xenograft and tail vein metastasis models were utilized to validate the in vitro results. Results DDR2 was highly expressed in high grade HNSCC tissues and lowly expressed in low grade HNSCC tissues, but absent or rarely expressed in cancer-associated normal tissues. Both the frequency and expression intensity of DDR2 were significantly associated with tumor pathologic stage and lymph node metastasis. In vitro, DDR2 overexpression in HNSCC cells failed to alter cell proliferation but markedly accelerates cell invasion and migration as well as hypoxia-induced EMT. In vivo, elevated expression of DDR2 speeds up the metastasis of HNSCC cells to the lung. Conclusion DDR2 plays an important role in HNSCC metastasis, and might be a promising target for future therapies in this type of cancer.

  13. iTRAQ analysis of colorectal cancer cell lines suggests Drebrin (DBN1) is overexpressed during liver metastasis.

    Science.gov (United States)

    Lin, Qifeng; Tan, Hwee Tong; Lim, Teck Kwang; Khoo, Avery; Lim, Kiat Hon; Chung, Maxey C M

    2014-06-01

    Colorectal cancer is currently the third in cancer incidence worldwide and the fourth most common cause of cancer deaths. Mortality in colorectal cancer is often ascribed to liver metastasis. In an effort to elucidate the proteins involved in colorectal cancer liver metastasis, we compared the proteome profiles of the human colon adenocarcinoma cell line HCT-116 with its metastatic derivative E1, using the iTRAQ labelling technology, coupled to 2D-LC and MALDI-TOF/TOF MS. A total of 547 proteins were identified, of which 31 of them were differentially expressed in the E1 cell line. Among these proteins, the differential expressions of translationally controlled tumour protein 1, A-kinase anchor protein 12 and Drebrin (DBN1) were validated using Western blot. In particular, DBN1, a protein not previously known to be involved in colorectal cancer metastasis, was found to be overexpressed in E1 as compared to HCT-116 cells. The overexpression of DBN1 was further validated using immunohistochemistry on colorectal cancer tissue sections with matched lymph node and liver metastasis tissues. DBN1 is currently believed to be involved in actin cytoskeleton reorganisation and suppresses actin filament cross-linking and bundling. Since actin reorganisation is an important process for tumour cell migration and invasion, DBN1 may have an important role during colorectal cancer metastasis.

  14. Establishment of an animal model of spontaneous cervical lymph node metastasis of laryngeal squamous cell carcinoma and obtaining laryngocarcinoma cells with high metastatic potential.

    Science.gov (United States)

    Chen, L W; Wang, J L; Zhang, L Y; Yang, S M; Li, C S; Yu, N; Zhao W, J D; Zhao, L D; Li, K; Liu, M B; Zhai, S Q

    2013-01-01

    To establish an animal model of spontaneous cervical lymph node metastasis of laryngeal squamous cell carcinoma and obtain laryngocarcinoma cells with high metastatic potential, laryngeal squamous cell carcinoma cell line HEP-2 in logarithmic phase were inoculated under the lingual margin mucosa of nude mice. HEP-2 cells metastasized to the cervical lymph nodes were isolated, cultured, and re-inoculated under the lingual margin mucosa of nude mice twice. The tumor formation in the tongue and in the cervical lymph nodes was confirmed by pathological examination. Carcinoma cells' ability of invasion and migration was detected by transwell assay. Human specific Alu sequences were detected by PCR, which indicated that the tumor cells originated from human laryngeal squamous cell carcinoma cell line HEP-2. Finally, an animal model of spontaneous lymph node metastasis of laryngeal squamous cell carcinoma was successfully established. Laryngeal squamous cell carcinoma cells with high metastatic potential to lymph nodes were obtained through repeated inoculations. .

  15. Cellular and molecular processes in ovarian cancer metastasis. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis.

    Science.gov (United States)

    Yeung, Tsz-Lun; Leung, Cecilia S; Yip, Kay-Pong; Au Yeung, Chi Lam; Wong, Stephen T C; Mok, Samuel C

    2015-10-01

    Ovarian cancer is the most lethal gynecological malignancy. It is usually diagnosed at a late stage, with a 5-yr survival rate of metastasis. Although metastasis plays a crucial role in promoting ovarian tumor progression and decreasing patient survival rates, the underlying mechanisms of ovarian cancer spread have yet to be thoroughly explored. For many years, researchers have believed that ovarian cancer metastasizes via a passive mechanism by which ovarian cancer cells are shed from the primary tumor and carried by the physiological movement of peritoneal fluid to the peritoneum and omentum. However, the recent discovery of hematogenous metastasis of ovarian cancer to the omentum via circulating tumor cells instigated rethinking of the mode of ovarian cancer metastasis and the importance of the "seed-and-soil" hypothesis for ovarian cancer metastasis. In this review we discuss the possible mechanisms by which ovarian cancer cells metastasize from the primary tumor to the omentum, the cross-talk signaling events between ovarian cancer cells and various stromal cells that play crucial roles in ovarian cancer metastasis, and the possible clinical implications of these findings in the management of this deadly, highly metastatic disease.

  16. Nifedipine promotes the proliferation and migration of breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Dong-Qing Guo

    Full Text Available Nifedipine is widely used as a calcium channel blocker (CCB to treat angina and hypertension,but it is controversial with respect the risk of stimulation of cancers. In this study, we demonstrated that nifedipine promoted the proliferation and migration of breast cancer cells both invivo and invitro. However, verapamil, another calcium channel blocker, didn't exert the similar effects. Nifedipine and high concentration KCl failed to alter the [Ca2+]i in MDA-MB-231 cells, suggesting that such nifedipine effect was not related with calcium channel. Moreover, nifedipine decreased miRNA-524-5p, resulting in the up-regulation of brain protein I3 (BRI3. Erk pathway was consequently activated and led to the proliferation and migration of breast cancer cells. Silencing BRI3 reversed the promoting effect of nifedipine on the breast cancer. In a summary, nifedipine stimulated the proliferation and migration of breast cancer cells via the axis of miRNA-524-5p-BRI3-Erk pathway independently of its calcium channel-blocking activity. Our findings highlight that nifedipine but not verapamil is conducive for breast cancer growth and metastasis, urging that the caution should be taken in clinic to prescribe nifedipine to women who suffering both hypertension and breast cancer, and hypertension with a tendency in breast cancers.

  17. Let-7b-mediated suppression of basigin expression and metastasis in mouse melanoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Tzu-Yen [Department of Animal Science, National Chung Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan (China); Chang, Chia-Che [Institute of Biomedical Sciences, National Chung Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan (China); Graduate Institute of Basic Medical Science, China Medical University, 91 Hsueh Shih Road, Taichung 40402, Taiwan (China); Lin, Chun-Ting [Department of Animal Science, National Chung Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan (China); Lai, Cong-Hao [Institute of Biomedical Sciences, National Chung Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan (China); Department of Life Sciences, National Chung Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan (China); Peng, Shao-Yu; Ko, Yi-Ju [Department of Animal Science, National Chung Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan (China); Tang, Pin-Chi, E-mail: pctang@dragon.nchu.edu.tw [Department of Animal Science, National Chung Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan (China)

    2011-02-15

    Basigin (Bsg), also called extracellular matrix metalloproteinase inducer (EMMPRIN), is highly expressed on the surface of tumor cells and stimulates adjacent fibroblasts or tumor cells to produce matrix metalloproteinases (mmps). It has been shown that Bsg plays an important role in growth, development, cell differentiation, and tumor progression. MicroRNAs (miRNAs) are a class of short endogenous non-protein coding RNAs of 20-25 nucleotides (nt) that function as post-transcriptional regulators of gene expression by base-pairing to their target mRNAs and thereby mediate cleavage of target mRNAs or translational repression. In this study, let-7b, one of the let-7 family members, was investigated for its effect on the growth and invasiveness of the mouse melanoma cell line B16-F10. We have shown that let-7b can suppress the expression of Bsg in B16-F10 cells and also provided evidence that this suppression could result in the indirect suppression of mmp-9. The ability of B16-F10 cells transfected with let-7b to invade or migrate was significantly reduced. In addition, let-7b transfected B16-F10 cells displayed an inhibition of both cellular proliferation and colony formation. Furthermore, it was shown that the overexpression of let-7b in B16-F10 cells could reduce lung metastasis. Taken together, the present study identifies let-7b as a tumor suppressor that represses cancer cell proliferation and migration as well as tumor metastasis in mouse melanoma cells.

  18. Nuclear Membrane-Targeted Gold Nanoparticles Inhibit Cancer Cell Migration and Invasion.

    Science.gov (United States)

    Ali, Moustafa R K; Wu, Yue; Ghosh, Deepraj; Do, Brian H; Chen, Kuangcai; Dawson, Michelle R; Fang, Ning; Sulchek, Todd A; El-Sayed, Mostafa A

    2017-03-27

    Most cancer patients die from metastasis. Recent studies have shown that gold nanoparticles (AuNPs) can slow down the migration/invasion speed of cancer cells and suppress metastasis. Since nuclear stiffness of the cell largely decreases cell migration, our hypothesis is that targeting AuNPs to the cell nucleus region could enhance nuclear stiffness, and therefore inhibit cell migration and invasion. Our results showed that upon nuclear targeting of AuNPs, the ovarian cancer cell motilities decrease significantly, compared with nontargeted AuNPs. Furthermore, using atomic force microscopy, we observed an enhanced cell nuclear stiffness. In order to understand the mechanism of cancer cell migration/invasion inhibition, the exact locations of the targeted AuNPs were clearly imaged using a high-resolution three-dimensional imaging microscope, which showed that the AuNPs were trapped at the nuclear membrane. In addition, we observed a greatly increased expression level of lamin A/C protein, which is located in the inner nuclear membrane and functions as a structural component of the nuclear lamina to enhance nuclear stiffness. We propose that the AuNPs that are trapped at the nuclear membrane both (1) add to the mechanical stiffness of the nucleus and (2) stimulate the overexpression of lamin A/C located around the nuclear membrane, thus increasing nuclear stiffness and slowing cancer cell migration and invasion.

  19. Novel interactions between erythroblast macrophage protein and cell migration.

    Science.gov (United States)

    Javan, Gulnaz T; Can, Ismail; Yeboah, Fred; Lee, Youngil; Soni, Shivani

    2016-09-01

    Erythroblast macrophage protein is a novel protein known to mediate attachment of erythroid cells to macrophages to form erythroblastic islands in bone marrow during erythropoiesis. Emp-null macrophages are small with round morphologies, and lack cytoplasmic projections which imply immature structure. The role of Emp in macrophage development and function is not fully elucidated. Macrophages perform varied functions (e.g. homeostasis, erythropoiesis), and are implicated in numerous pathophysiological conditions such as cellular malignancy. The objective of the current study is to investigate the interaction of Emp with cytoskeletal- and cell migration-associated proteins involved in macrophage functions. A short hairpin RNA lentiviral system was use to down-regulate the expression of Emp in macrophage cells. A cell migration assay revealed that the relocation of macrophages was significantly inhibited when Emp expression was decreased. To further analyze changes in gene expression related to cell motility, PCR array was performed by down-regulating Emp expression. The results indicated that expression of mitogen-activated protein kinase 1 and thymoma viral proto-oncogene 1 were significantly higher when Emp was down-regulated. The results implicate Emp in abnormal cell motility, thus, warrants to assess its role in cancer where tumor cell motility is required for invasion and metastasis.

  20. Metastatic transitional cell carcinoma presenting with skin metastasis.

    Science.gov (United States)

    Açıkgöz, Onur; Ölçücüoğlu, Erkan; Kasap, Yusuf; Yığman, Metin; Güneş, Zeki Ender; Gazel, Eymen

    2015-01-01

    Transitional cell carcinomas (TCC) of upper urinary system account for 5% of all TCCs. The incidence of such metastases ranges from 0.18% to 2%. Experimental studies reported a general unsatisfactory survival time following skin metastasis. We report in this paper a case of metastatic urinary system TCC, which had become evident with a skin lesion in the right hypogastric region. A 60-year-old female patient with a history of being operated upon due to renal pelvic TCC was admitted to our outpatient clinic with complaints of red skin lesion in the near vicinity of the operational incision scar for 3 months. Her medical history revealed nothing but nephroureterectomy operation on the upper urinary system; moreover, it was learned that she had been ignoring what was recommended to her for routine controls. Thoraco-abdominal computed tomographic (CT) examination performed on the basis of aforementioned findings depicted a mass lesion of 24*20 mm dimension with high contrast uptake detected within the subcutaneous fat tissue in the right abdominal wall. The skin lesion depicted in CT was surgically excised. The pathological examination of the excised material was reported to be compatible with TCC. The patient was referred due to abdominal lesion to medical oncology after the operation. Followed up under chemotherapy protocol, the patient died 3 months after the metastasectomy operation. Skin metastasis of upper urinary system TCCs, especially renal pelvic TCCs, are quite rare conditions. Among the likely skin sites of metastasis for genitourinary system TCCs are head, face, extremities, suprapubic region and abdomen. Taking into consideration the low survival rates, the importance of early diagnosis of recurrences and/or distant metastases should be better appreciated. These patients die soon after the skin metastasis even with the administration of aggressive therapy. Similarly, our patient died 90 days after the diagnosis of skin metastasis despite the oncologic

  1. Cardiac metastasis from a renal cell carcinoma

    OpenAIRE

    AlGhamdi, Abdulaziz; Tam, James

    2006-01-01

    A 59-year-old man developed an episode of syncope while he was driving. This resulted in a motor vehicle accident, and the patient sustained an open fracture of the left femur. Biopsy of the left femur fracture showed a metastastic renal cell carcinoma, and echocardiography revealed a right ventricular mass without contiguous vena caval or right atrial involvement. This is one of the few reported cases of renal cell carcinoma associated with syncope as an initial symptom.

  2. An alternative model of cancer cell growth and metastasis.

    Science.gov (United States)

    Vaidya, Jayant S

    2007-04-01

    I propose an alternative model of cancer in which metastasis need not all arise out of spread from the "original" tumour. The model assumes that cancer cells arise from stem cells that best grow in the organ of their differentiation. When the internal milieu allows it they also grow at other sites as well, thus complementing the conventional (spreading) metastatic process. Several phenomena in the natural history of cancer, especially breast cancer, that challenge the conventional model, fit well after inclusion of the new model. These are (a) a very modest benefit of screening (b) frequent sparing of lungs from haematogenous metastasis (c) presence of occult cancers in autopsy studies (d) only a modest effect of local treatment (e) relative ineffectiveness of high-dose chemotherapy (f) constant time between surgery and peak of hazard of relapse irrespective of stage of the tumour. All these phenomena are much easier to explain when one rejects the dogma that all metastasis arise only from the primary tumour. This paper is aimed only to suggest an alternative perspective of natural history of solid tumours--to stimulate research on the complex internal milieu that allows cancer cells to develop in new light.

  3. Rho GTPases in collective cell migration

    NARCIS (Netherlands)

    Zegers, M.M.; Friedl, P.

    2014-01-01

    The family of Rho GTPases are intracellular signal transducers that link cell surface signals to multiple intracellular responses. They are best known for their role in regulating actin dynamics required for cell migration, but in addition control cell-cell adhesion, polarization, vesicle traffickin

  4. Mesenchymal Stromal Cell Dependent Regression of Pulmonary Metastasis from Ewing's

    Directory of Open Access Journals (Sweden)

    Andrea Anita Hayes-Jordan

    2014-05-01

    Full Text Available Introduction: Ewing’s sarcoma (ES is the second most common bone tumor in children. Survival has not improved over the last decade and once pulmonary metastatic disease is present, survival is dismal. Mesenchymal stromal cell (MSC therapy has shown potential benefit for Kaposi's sarcoma; however, the role of progenitor cell therapies for cancer remains controversial. MSC treatment of ES or pulmonary metastatic disease has not been demonstrated. We have developed an orthotopic xenograft model of ES in which animals develop spontaneous pulmonary metastases. Within this model, we demonstrate the use of MSCs to target ES lung metastasis. Materials and MethodsHuman ES cells were transfected with luciferase and injected into the rib of nude mice. Development of pulmonary metastases was confirmed by imaging. After flow cytometry based characterization, MSC’s were injected into the tail vein of nude mice with established local ES tumor or pulmonary metastasis. Mice were treated with intravenous MSCs weekly followed by bioluminescent imaging.ResultsThe intravenous injection of MSCs in an ES model decreases the volume of pulmonary metastatic lesions; however, no effect on primary chest wall tumor size is observed. Thus verifying the MSC preferential homing to the lung. MSCs are found to ‘home to’ the pulmonary parenchyma and remain engrafted up to 5 days after delivery. DiscussionMSC treatment of ES slows growth of pulmonary metastasis. MSC’s have more affinity for pulmonary metastasis and can effect a greater decrease in tumor growth in the lungs compared to the primary tumor site

  5. Entropy measures of collective cell migration

    Science.gov (United States)

    Whitby, Ariadne; Parrinello, Simona; Faisal, Aldo

    2015-03-01

    Collective cell migration is a critical process during tissue formation and repair. To this end there is a need to develop tools to quantitatively measure the dynamics of collective cell migration obtained from microscopy data. Drawing on statistical physics we use entropy of velocity fields derived from dense optic flow to quantitatively measure collective migration. Using peripheral nerve repair after injury as experimental system, we study how Schwann cells, guided by fibroblasts, migrate in cord-like structures across the cut, paving a highway for neurons. This process of emergence of organised behaviour is key for successful repair, yet the emergence of leader cells and transition from a random to ordered state is not understood. We find fibroblasts induce correlated directionality in migrating Schwann cells as measured by a decrease in the entropy of motion vector. We show our method is robust with respect to image resolution in time and space, giving a principled assessment of how various molecular mechanisms affect macroscopic features of collective cell migration. Finally, the generality of our method allows us to process both simulated cell movement and microscopic data, enabling principled fitting and comparison of in silico to in vitro. ICCS, Imperial College London & MRC Clinical Sciences Centre.

  6. Nobiletin inhibits human osteosarcoma cells metastasis by blocking ERK and JNK-mediated MMPs expression

    Science.gov (United States)

    Cheng, Hsin-Lin; Hsieh, Ming-Ju; Yang, Jia-Sin; Lin, Chiao-Wen; Lue, Ko-Haung; Lu, Ko-Hsiu; Yang, Shun-Fa

    2016-01-01

    Nobiletin, a polymethoxyflavone, has a few pharmacological activities, including anti-inflammation and anti-cancer effects. However, its effect on human osteosarcoma progression remains uninvestigated. Therefore, we examined the effectiveness of nobiletin against cellular metastasis of human osteosarcoma and the underlying mechanisms. Nobiletin, up to 100 μM without cytotoxicity, significantly decreased motility, migration and invasion as well as enzymatic activities, protein levels and mRNA expressions of matrix metalloproteinase (MMP)-2 and MMP-9 in U2OS and HOS cells. In addition to inhibition of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), the inhibitory effect of nobiletin on the DNA-binding activity of the transcription factor nuclear factor-kappa B (NF-κB), cAMP response element-binding protein (CREB), and specificity protein 1 (SP-1) in U2OS and HOS cells. Co-treatment with ERK and JNK inhibitors and nobiletin further reduced U2OS cells migration and invasion. These results indicated that nobiletin inhibits human osteosarcoma U2OS and HOS cells motility, migration and invasion by down-regulating MMP-2 and MMP-9 expressions via ERK and JNK pathways and through the inactivation of downstream NF-κB, CREB, and SP-1. Nobiletin has the potential to serve as an anti-metastatic agent for treating osteosarcoma. PMID:27144433

  7. Urethral metastasis of lung carcinoma with germinative cell features

    Directory of Open Access Journals (Sweden)

    Tefilli Marcos V.

    2003-01-01

    Full Text Available INTRODUCTION: We present the case of a patient with urethral metastasis of a lung carcinoma with germinative cell features. CASE REPORT: A White, 57-year old man underwent urologic assessment due to gross hematuria. Patient was being treated with chemotherapy and radiotherapy during the past 3 months due to primary carcinoma of the lung with brain metastasis. Urethrocistoscopy and nuclear magnetic resonance imaging revealed a stenosing mass invading the bulbomembranous urethra. No other tumor was found. Biopsy specimens, obtained from the lung, brain and urethra tumors, revealed the same neoplasia, with definitive diagnosis being undifferentiated giant cell carcinoma of the lung with germinative features. Considering his clinical condition and poor prognosis, a decision was made to treat the patient only clinically. Clinical conditions deteriorated and the patient evolved to death within 3 months. COMMENTS: As far as we were able to access, urethral metastasis from lung carcinoma had never been described in the indexed literature. Due to the extremely limited experience with these tumors, there is not a defined treatment and the prognosis remains quite poor.

  8. Sarcomatoid Renal Cell Carcinoma Metastasis to the Penis.

    Science.gov (United States)

    Liou, Victor D; Darwish, Oussama M; Henry, Mary M; Jun, Ik C; Siddiqui, Sameer A

    2015-01-01

    Secondary cancers of the penis are extremely uncommon with less than 300 cases reported in the past 100 years. These cancers are most frequently a result of an aggressive or poorly managed primary prostate or bladder cancer and rarely a metastasis from a primary kidney tumor. Currently, there is no published literature which describes the spread of sarcomatoid renal cell carcinoma (SRCC) to the penis. In this report, we present a 55-year-old-man who presented with a large right-sided SRCC which metastasized to the base of his penis within 1 month of symptom onset. We also discuss the possible route of metastasis based on primary tumor size and location within the retroperitoneum.

  9. Sarcomatoid Renal Cell Carcinoma Metastasis to the Penis

    Directory of Open Access Journals (Sweden)

    Victor D. Liou

    2015-01-01

    Full Text Available Secondary cancers of the penis are extremely uncommon with less than 300 cases reported in the past 100 years. These cancers are most frequently a result of an aggressive or poorly managed primary prostate or bladder cancer and rarely a metastasis from a primary kidney tumor. Currently, there is no published literature which describes the spread of sarcomatoid renal cell carcinoma (SRCC to the penis. In this report, we present a 55-year-old-man who presented with a large right-sided SRCC which metastasized to the base of his penis within 1 month of symptom onset. We also discuss the possible route of metastasis based on primary tumor size and location within the retroperitoneum.

  10. Down-Regulation of NDUFB9 Promotes Breast Cancer Cell Proliferation, Metastasis by Mediating Mitochondrial Metabolism.

    Directory of Open Access Journals (Sweden)

    Liang-Dong Li

    Full Text Available Despite advances in basic and clinical research, metastasis remains the leading cause of death in breast cancer patients. Genetic abnormalities in mitochondria, including mutations affecting complex I and oxidative phosphorylation, are found in breast cancers and might facilitate metastasis. Genes encoding complex I components have significant breast cancer prognostic value. In this study, we used quantitative proteomic analyses to compare a highly metastatic cancer cell line and a parental breast cancer cell line; and observed that NDUFB9, an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, was down-regulated in highly metastatic breast cancer cells. Furthermore, we demonstrated that loss of NDUFB9 promotes MDA-MB-231 cells proliferation, migration, and invasion because of elevated levels of mtROS, disturbance of the NAD+/NADH balance, and depletion of mtDNA. We also showed that, the Akt/mTOR/p70S6K signaling pathway and EMT might be involved in this mechanism. Thus, our findings contribute novel data to support the hypothesis that misregulation of mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells, suggesting that complex I deficiency is a potential and important biomarker for further basic research or clinical application.

  11. WLS inhibits melanoma cell proliferation through the β-catenin signalling pathway and induces spontaneous metastasis.

    Science.gov (United States)

    Yang, Pei-Tzu; Anastas, Jamie N; Toroni, Rachel A; Shinohara, Michi M; Goodson, Jamie M; Bosserhoff, Anja K; Chien, Andy J; Moon, Randall T

    2012-12-01

    Elevated levels of nuclear β-catenin are associated with higher rates of survival in patients with melanoma, raising questions as to how ß-catenin is regulated in this context. In the present study, we investigated the formal possibility that the secretion of WNT ligands that stabilize ß-catenin may be regulated in melanoma and thus contributes to differences in ß-catenin levels. We find that WLS, a conserved transmembrane protein necessary for WNT secretion, is decreased in both melanoma cell lines and in patient tumours relative to skin and to benign nevi. Unexpectedly, reducing endogenous WLS with shRNAs in human melanoma cell lines promotes spontaneous lung metastasis in xenografts in mice and promotes cell proliferation in vitro. Conversely, overexpression of WLS inhibits cell proliferation in vitro. Activating β-catenin downstream of WNT secretion blocks the increased cell migration and proliferation observed in the presence of WLS shRNAs, while inhibiting WNT signalling rescues the growth defects induced by excess WLS. These data suggest that WLS functions as a negative regulator of melanoma proliferation and spontaneous metastasis by activating WNT/β-catenin signalling.

  12. Lipid raft association restricts CD44-ezrin interaction and promotion of breast cancer cell migration.

    LENUS (Irish Health Repository)

    Donatello, Simona

    2012-12-01

    Cancer cell migration is an early event in metastasis, the main cause of breast cancer-related deaths. Cholesterol-enriched membrane domains called lipid rafts influence the function of many molecules, including the raft-associated protein CD44. We describe a novel mechanism whereby rafts regulate interactions between CD44 and its binding partner ezrin in migrating breast cancer cells. Specifically, in nonmigrating cells, CD44 and ezrin localized to different membranous compartments: CD44 predominantly in rafts, and ezrin in nonraft compartments. After the induction of migration (either nonspecific or CD44-driven), CD44 affiliation with lipid rafts was decreased. This was accompanied by increased coprecipitation of CD44 and active (threonine-phosphorylated) ezrin-radixin-moesin (ERM) proteins in nonraft compartments and increased colocalization of CD44 with the nonraft protein, transferrin receptor. Pharmacological raft disruption using methyl-β-cyclodextrin also increased CD44-ezrin coprecipitation and colocalization, further suggesting that CD44 interacts with ezrin outside rafts during migration. Conversely, promoting CD44 retention inside lipid rafts by pharmacological inhibition of depalmitoylation virtually abolished CD44-ezrin interactions. However, transient single or double knockdown of flotillin-1 or caveolin-1 was not sufficient to increase cell migration over a short time course, suggesting complex crosstalk mechanisms. We propose a new model for CD44-dependent breast cancer cell migration, where CD44 must relocalize outside lipid rafts to drive cell migration. This could have implications for rafts as pharmacological targets to down-regulate cancer cell migration.

  13. GPR171 expression enhances proliferation and metastasis of lung cancer cells

    Science.gov (United States)

    Dho, So Hee; Lee, Kwang-Pyo; Jeong, Dongjun; Kim, Chang-Jin; Chung, Kyung-Sook; Kim, Ji Young; Park, Bum-Chan; Park, Sung Sup; Kim, Seon-Young; Kwon, Ki-Sun

    2016-01-01

    G protein-coupled receptors (GPCRs) are among the most significant therapeutic targets and some of them promote the growth and metastasis of cancer. Here, we show that an increase in the levels of GPR171 is crucial for lung cancer tumor progression in vitro and in vivo. Immunostaining of clinical samples indicated that GPR171 was overexpressed in 46.8% of lung carcinoma tissues. Depletion of GPR171 with an anti-GPR171 antibody decreased proliferation of lung carcinoma cells and attenuated tumor progression in a mouse xenograft model. Knockdown of GPR171 also inhibited migration and invasion of the lung cancer cell lines. Notably, inhibition of GPR171 synergistically enhanced the tumoricidal activity of an epidermal growth factor receptor (EGFR) inhibitor in lung cancer cells. These results indicate that GPR171 blockade is a promising antineoplastic strategy and provide a preclinical rationale for combined inhibition of GPR171 and EGFR. PMID:26760963

  14. FH535 inhibited migration and growth of breast cancer cells.

    Science.gov (United States)

    Iida, Joji; Dorchak, Jesse; Lehman, John R; Clancy, Rebecca; Luo, Chunqing; Chen, Yaqin; Somiari, Stella; Ellsworth, Rachel E; Hu, Hai; Mural, Richard J; Shriver, Craig D

    2012-01-01

    There is substantial evidence indicating that the WNT signaling pathway is activated in various cancer cell types including breast cancer. Previous studies reported that FH535, a small molecule inhibitor of the WNT signaling pathway, decreased growth of cancer cells but not normal fibroblasts, suggesting this pathway plays a role in tumor progression and metastasis. In this study, we tested FH535 as a potential inhibitor for malignant phenotypes of breast cancer cells including migration, invasion, and growth. FH535 significantly inhibited growth, migration, and invasion of triple negative (TN) breast cancer cell lines (MDA-MB231 and HCC38) in vitro. We demonstrate that FH535 was a potent growth inhibitor for TN breast cancer cell lines (HCC38 and MDA-MB-231) but not for other, non-TN breast cancer cell lines (MCF-7, T47D or SK-Br3) when cultured in three dimensional (3D) type I collagen gels. Western blotting analyses suggest that treatment of MDA-MB-231 cells with FH535 markedly inhibited the expression of NEDD9 but not activations of FAK, Src, or downstream targets such as p38 and Erk1/2. We demonstrated that NEDD9 was specifically associated with CSPG4 but not with β1 integrin or CD44 in MDA-MB-231 cells. Analyses of gene expression profiles in breast cancer tissues suggest that CSPG4 expression is higher in Basal-type breast cancers, many of which are TN, than any other subtypes. These results suggest not only a mechanism for migration and invasion involving the canonical WNT-signaling pathways but also novel strategies for treating patients who develop TN breast cancer.

  15. FH535 inhibited migration and growth of breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Joji Iida

    Full Text Available There is substantial evidence indicating that the WNT signaling pathway is activated in various cancer cell types including breast cancer. Previous studies reported that FH535, a small molecule inhibitor of the WNT signaling pathway, decreased growth of cancer cells but not normal fibroblasts, suggesting this pathway plays a role in tumor progression and metastasis. In this study, we tested FH535 as a potential inhibitor for malignant phenotypes of breast cancer cells including migration, invasion, and growth. FH535 significantly inhibited growth, migration, and invasion of triple negative (TN breast cancer cell lines (MDA-MB231 and HCC38 in vitro. We demonstrate that FH535 was a potent growth inhibitor for TN breast cancer cell lines (HCC38 and MDA-MB-231 but not for other, non-TN breast cancer cell lines (MCF-7, T47D or SK-Br3 when cultured in three dimensional (3D type I collagen gels. Western blotting analyses suggest that treatment of MDA-MB-231 cells with FH535 markedly inhibited the expression of NEDD9 but not activations of FAK, Src, or downstream targets such as p38 and Erk1/2. We demonstrated that NEDD9 was specifically associated with CSPG4 but not with β1 integrin or CD44 in MDA-MB-231 cells. Analyses of gene expression profiles in breast cancer tissues suggest that CSPG4 expression is higher in Basal-type breast cancers, many of which are TN, than any other subtypes. These results suggest not only a mechanism for migration and invasion involving the canonical WNT-signaling pathways but also novel strategies for treating patients who develop TN breast cancer.

  16. Silencing of CD44 gene expression in human 143-B osteosarcoma cells promotes metastasis of intratibial tumors in SCID mice.

    Directory of Open Access Journals (Sweden)

    Ana Gvozdenovic

    Full Text Available Osteosarcoma (OS is the most frequent primary malignant bone cancer in children and adolescents with a high propensity for lung metastasis. Therefore, it is of great importance to identify molecular markers leading to increased metastatic potential in order to devise more effective therapeutic strategies that suppress metastasis, the major cause of death in OS. CD44, the principal receptor for the extracellular matrix component hyaluronan (HA, is frequently found overexpressed in tumor cells and has been implicated in metastatic spread in various cancer types. Here, we investigated the effects of stable shRNA-mediated silencing of CD44 gene products on in vitro and in vivo metastatic properties of the highly metastatic human 143-B OS cell line. In vitro, CD44 knockdown resulted in a 73% decrease in the adhesion to HA, a 57% decrease in the migration rate in a trans-filter migration assay, and a 28% decrease in the cells' capacity for anchorage-independent growth in soft agar compared to the control cells, implicating that CD44 expression contributes to the metastatic activity of 143-B cells. However, making use of an orthotopic xenograft OS mouse model, we demonstrated that reduced CD44 expression facilitated primary tumor growth and formation of pulmonary metastases. The enhanced malignant phenotype was associated with decreased adhesion to HA and reduced expression of the tumor suppressor merlin in vivo. In conclusion, our study identified CD44 as a metastasis suppressor in this particular experimental OS model.

  17. ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion.

    Science.gov (United States)

    Chen, Wei-Ta; Ebelt, Nancy D; Stracker, Travis H; Xhemalce, Blerta; Van Den Berg, Carla L; Miller, Kyle M

    2015-06-01

    Ataxia-telangiectasia mutated (ATM) protein kinase regulates the DNA damage response (DDR) and is associated with cancer suppression. Here we report a cancer-promoting role for ATM. ATM depletion in metastatic cancer cells reduced cell migration and invasion. Transcription analyses identified a gene network, including the chemokine IL-8, regulated by ATM. IL-8 expression required ATM and was regulated by oxidative stress. IL-8 was validated as an ATM target by its ability to rescue cell migration and invasion defects in ATM-depleted cells. Finally, ATM-depletion in human breast cancer cells reduced lung tumors in a mouse xenograft model and clinical data validated IL-8 in lung metastasis. These findings provide insights into how ATM activation by oxidative stress regulates IL-8 to sustain cell migration and invasion in cancer cells to promote metastatic potential. Thus, in addition to well-established roles in tumor suppression, these findings identify a role for ATM in tumor progression.

  18. Inflammation Mediated Metastasis: Immune Induced Epithelial-To-Mesenchymal Transition in Inflammatory Breast Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Evan N Cohen

    Full Text Available Inflammatory breast cancer (IBC is the most insidious form of locally advanced breast cancer; about a third of patients have distant metastasis at initial staging. Emerging evidence suggests that host factors in the tumor microenvironment may interact with underlying IBC cells to make them aggressive. It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT in these cells. We hypothesized that soluble factors secreted by activated immune cells can induce an EMT in IBC and thus promote metastasis. In a pilot study of 16 breast cancer patients, TNF-α production by peripheral blood T cells was correlated with the detection of circulating tumor cells expressing EMT markers. In a variety of IBC model cell lines, soluble factors from activated T cells induced expression of EMT-related genes, including FN1, VIM, TGM2, ZEB1. Interestingly, although IBC cells exhibited increased invasion and migration following exposure to immune factors, the expression of E-cadherin (CDH1, a cell adhesion molecule, increased uniquely in IBC cell lines but not in non-IBC cell lines. A combination of TNF-α, IL-6, and TGF-β was able to recapitulate EMT induction in IBC, and conditioned media preloaded with neutralizing antibodies against these factors exhibited decreased EMT. These data suggest that release of cytokines by activated immune cells may contribute to the aggressiveness of IBC and highlight these factors as potential target mediators of immune-IBC interaction.

  19. miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Jia; Liu, Xiuheng, E-mail: l_xiuheng@163.com; Wang, Min

    2015-09-04

    Microarray data analyses were performed to search for metastasis-associated oncogenes in prostate cancer (PCa). RNF31 mRNA expressions in tumor tissues and benign prostate tissues were evaluated. The RNF31 protein expression levels were also analyzed by western blot and immunohistochemistry. Luciferase reporter assays were used to identify miRNAs that can regulate RNF31. The effect of RNF31 on PCa progression was studied in vitro and in vivo. We found that RNF31 was significantly increased in PCa and its expression level was highly correlated with seminal vesicle invasion, clinical stage, prostate specific antigen (PSA) level, Gleason score, and BCR. Silence of RNF31 suppressed PCa cell proliferation and metastasis in vitro and in vivo. miR-503 can directly regulate RNF31. Enforced expression of miR-503 inhibited the expression of RNF31 significantly and the restoration of RNF31 expression reversed the inhibitory effects of miR-503 on PCa cell proliferation and metastasis. These findings collectively indicated an oncogene role of RNF31 in PCa progression which can be regulated by miR-503, suggesting that RNF31 could serve as a potential prognostic biomarker and therapeutic target for PCa. - Highlights: • RNF31 is a potential metastasis associated gene and is associated with prostate cancer progression. • Silence of RNF31 inhibits PCa cell colony formation, migration and invasion. • RNF31 as a direct target of miR-503. • miR-503 can regulate cell proliferation, invasion and migration by targeting RNF31. • RNF31 plays an important role in PCa growth and metastasis in vivo.

  20. Tamoxifen inhibits tumor cell invasion and metastasis in mouse melanoma through suppression of PKC/MEK/ERK and PKC/PI3K/Akt pathways

    Energy Technology Data Exchange (ETDEWEB)

    Matsuoka, Hiroshi [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502 (Japan); Department of Pharmacy, Nara Hospital, Kinki University School of Medicine, 1248-1 Ikoma, Nara 630-0293 (Japan); Tsubaki, Masanobu [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502 (Japan); Yamazoe, Yuzuru [Department of Pharmacy, Kinki University Hospital, Osakasayama, Osaka 589-8511 (Japan); Ogaki, Mitsuhiko [Department of Pharmacy, Higahiosaka City General Hospital, Higashi-osaka, Osaka 578-8588 (Japan); Satou, Takao; Itoh, Tatsuki [Department of Pathology, Kinki University School of Medicine, Osakasayama, Osaka 589-8511 (Japan); Kusunoki, Takashi [Department of Otolaryngology, Juntendo University School of Medicine, Tokyo (Japan); Nishida, Shozo, E-mail: nishida@phar.kindai.ac.jp [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502 (Japan)

    2009-07-15

    In melanoma, several signaling pathways are constitutively activated. Among these, the protein kinase C (PKC) signaling pathways are activated through multiple signal transduction molecules and appear to play major roles in melanoma progression. Recently, it has been reported that tamoxifen, an anti-estrogen reagent, inhibits PKC signaling in estrogen-negative and estrogen-independent cancer cell lines. Thus, we investigated whether tamoxifen inhibited tumor cell invasion and metastasis in mouse melanoma cell line B16BL6. Tamoxifen significantly inhibited lung metastasis, cell migration, and invasion at concentrations that did not show anti-proliferative effects on B16BL6 cells. Tamoxifen also inhibited the mRNA expressions and protein activities of matrix metalloproteinases (MMPs). Furthermore, tamoxifen suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt through the inhibition of PKC{alpha} and PKC{delta} phosphorylation. However, other signal transduction factor, such as p38 mitogen-activated protein kinase (p38MAPK) was unaffected. The results indicate that tamoxifen suppresses the PKC/mitogen-activated protein kinase kinase (MEK)/ERK and PKC/phosphatidylinositol-3 kinase (PI3K)/Akt pathways, thereby inhibiting B16BL6 cell migration, invasion, and metastasis. Moreover, tamoxifen markedly inhibited not only developing but also clinically evident metastasis. These findings suggest that tamoxifen has potential clinical applications for the treatment of tumor cell metastasis.

  1. Upregulation of metastasis-associated gene 2 promotes cell proliferation and invasion in nasopharyngeal carcinoma

    Directory of Open Access Journals (Sweden)

    Wu MH

    2016-03-01

    Full Text Available Minhua Wu,1,2,* Xiaoxia Ye,2,* Xubin Deng,3,* Yanxia Wu,4 Xiaofang Li,4 Lin Zhang11Department of Histology and Embryology, Southern Medical University, Guangzhou, 2Department of Histology and Embryology, Guangdong Medical University, Zhanjiang, 3Affiliated Cancer Hospital of Guangzhou Medical University, Cancer Center of Guangzhou Medical University, Guangzhou, 4Pathological Diagnosis and Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, People’s Republic of China*These authors contributed equally to this workAims: Metastasis-associated gene 2 (MTA2 is reported to play an important role in tumor progression, but little is known about the role of MTA2 in nasopharyngeal carcinoma (NPC. The aim of the study was to explore the expression and function of MTA2 in NPC.Methods: Expression of MTA2 in NPC tissues and cell lines was detected by immunohistochemistry and Western blotting. Relationship between MTA2 expression and clinicopathological features was analyzed. Stable MTA2-overexpressing and MTA2-siliencing NPC cells were established by transfection with plasmids encoding MTA2 cDNA and lentivirus-mediated short hairpin RNA, respectively. Cell viability was determined by Cell Counting Kit-8 and colony formation assay. Cell migration ability was evaluated by wound healing and transwell invasion assay. The impact of MTA2 knockdown on growth and metastasis of CNE2 cells in vivo was determined by nude mouse xenograft models. Expression of several Akt pathway proteins was detected by Western blotting.Results: MTA2 was upregulated in NPC tissues and three NPC cell lines detected (CNE1, CNE2, and HNE1. MTA2 expression was related to clinical stage and lymph node metastasis of patients with NPC. MTA2 upregulation promoted proliferation and invasion of CNE1 cells, while MTA2 depletion had opposite effects on CNE2 cells. Moreover, MTA2 depletion suppressed growth and metastasis of CNE2 cells in vivo. MTA2 overexpression

  2. Visualizing T cell migration in-situ

    Directory of Open Access Journals (Sweden)

    Alexandre P Benechet

    2014-07-01

    Full Text Available Mounting a protective immune response is critically dependent on the orchestrated movement of cells within lymphoid tissues. The structure of secondary lymphoid organs regulates immune responses by promoting optimal cell-cell and cell-extracellular matrix interactions. Naïve T cells are initially activated by antigen presenting cells in secondary lymphoid organs. Following priming, effector T cells migrate to the site of infection to exert their functions. Majority of the effector cells die while a small population of antigen specific T cells persist as memory cells in distinct anatomical locations. The persistence and location of memory cells in lymphoid and non-lymphoid tissues is critical to protect the host from re-infection. The localization of memory T cells is carefully regulated by several factors including the highly organized secondary lymphoid structure, the cellular expression of chemokine receptors and compartmentalized secretion of their cognate ligands. This balance between the anatomy and the ordered expression of cell surface and soluble proteins regulates the subtle choreography of T cell migration. In recent years, our understanding of cellular dynamics of T cells has been advanced by the development of new imaging techniques allowing in-situ visualization of T cell responses. Here we review the past and more recent studies that have utilized sophisticated imaging technologies to investigate the migration dynamics of naive, effector and memory T cells.

  3. The Role of MicroRNAs in Breast Cancer Migration, Invasion and Metastasis

    Directory of Open Access Journals (Sweden)

    Joy Tang

    2012-10-01

    Full Text Available MicroRNAs (miRNAs are a major class of small, noncoding RNA molecules that regulate gene expression by targeting mRNAs to trigger either translational repression or mRNA degradation. They have recently been more widely investigated due to their potential role as targets for cancer therapy. Many miRNAs have been implicated in several human cancers, including breast cancer. miRNAs are known to regulate cell cycle and development, and thus may serve as useful targets for exploration in anticancer therapeutics. The link between altered miRNA signatures and breast cancer development and metastasis can be observed either through the loss of tumor suppressor miRNAs, such as let-7s, miR-30a/31/34a/125s/200s/203/205/206/342 or the overexpression of oncogenic miRNAs, such as miR-10b/21/135a/155/221/222/224/373/520c in breast cancer cells. Some of these miRNAs have also been validated in tumor specimens of breast cancer patients, underscoring their potential roles in diagnostics, as well as targets for novel therapeutics for breast cancer. In this review article, we will provide an overview and update of our current understanding of the mode of action of several of these well characterized miRNAs in breast cancer models. Therefore, better understanding of the gene networks orchestrated by these miRNAs may help exploit the full potential of miRNAs in regards to cancer diagnosis, treatment, and therapeutics.

  4. R-Ras regulates migration through an interaction with filamin A in melanoma cells.

    Directory of Open Access Journals (Sweden)

    Joanna E Gawecka

    Full Text Available BACKGROUND: Changes in cell adhesion and migration in the tumor microenvironment are key in the initiation and progression of metastasis. R-Ras is one of several small GTPases that regulate cell adhesion and migration on the extracellular matrix, however the mechanism has not been completely elucidated. Using a yeast two-hybrid approach we sought to identify novel R-Ras binding proteins that might mediate its effects on integrins. METHODS AND FINDINGS: We identified Filamin A (FLNa as a candidate interacting protein. FLNa is an actin-binding scaffold protein that also binds to integrin beta1, beta2 and beta7 tails and is associated with diverse cell processes including cell migration. Indeed, M2 melanoma cells require FLNa for motility. We further show that R-Ras and FLNa interact in co-immunoprecipitations and pull-down assays. Deletion of FLNa repeat 3 (FLNaDelta3 abrogated this interaction. In M2 melanoma cells active R-Ras co-localized with FLNa but did not co-localize with FLNa lacking repeat 3. Thus, activated R-Ras binds repeat 3 of FLNa. The functional consequence of this interaction was that active R-Ras and FLNa coordinately increased cell migration. In contrast, co-expression of R-Ras and FLNaDelta3 had a significantly reduced effect on migration. While there was enhancement of integrin activation and fibronectin matrix assembly, cell adhesion was not altered. Finally, siRNA knockdown of endogenous R-Ras impaired FLNa-dependent fibronectin matrix assembly. CONCLUSIONS: These data support a model in which R-Ras functionally associates with FLNa and thereby regulates integrin-dependent migration. Thus in melanoma cells R-Ras and FLNa may cooperatively promote metastasis by enhancing cell migration.

  5. Solitary spinal metastasis of Hürthle cell thyroid carcinoma.

    Science.gov (United States)

    Sciubba, Daniel M; Petteys, Rory J; Kang, Steven; Than, Khoi D; Gokaslan, Ziya L; Gallia, Gary L; Wolinsky, Jean-Paul

    2010-06-01

    Hürthle cell carcinoma is a rare variant of differentiated thyroid cancer that occasionally forms distant metastases. However, even in the presence of metastases, patients with Hürthle cell carcinoma have a relatively good prognosis. There are few reports of Hürthle cell carcinoma metastases to the vertebral column, and none describing aggressive resection of spinal metastases. Here, we report a 68-year-old woman with a solitary metastasis of Hürthle cell carcinoma to the T1 vertebral body causing severe kyphotic deformity, myelopathy, and pain. The patient was treated with aggressive excisional decompression of the spinal cord and T1 vertebral body resection from an entirely posterior approach. Reconstruction and stabilization of the anterior spine was accomplished with a transforaminal lumbar interbody fusion allograft spacer and posterior instrumentation. We discuss aspects of the diagnosis, management, patient selection, and surgical treatment of metastatic Hürthle cell carcinoma in reference to the literature.

  6. Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE

    Science.gov (United States)

    Carmona, Guillaume; Perera, Upamali; Gillett, Cheryl; Naba, Alexandra; Law, Ah-Lai; Sharma, Ved P.; Wang, Jian; Wyckoff, Jeffrey; Balsamo, Michele; Mosis, Fuad; De Piano, Mario; Monypenny, James; Woodman, Natalie; McConnell, Russell E.; Mouneimne, Ghassan; Van Hemelrijck, Mieke; Cao, Yihai; Condeelis, John; Hynes, Richard O.; Gertler, Frank B.; Krause, Matthias

    2016-01-01

    Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlates with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation, and matrix degradation were impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not Ena/VASP is required for random 2D cell migration. We identify a phosphorylation-dependent mechanism that regulates selective recruitment of these effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, while Src-dependent phosphorylation enhances binding to Scar/WAVE but not Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of EGF gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activities at the plasma membrane to promote 3D invasion and metastasis. PMID:26996666

  7. Licoricidin, an Active Compound in the Hexane/Ethanol Extract of Glycyrrhiza uralensis, Inhibits Lung Metastasis of 4T1 Murine Mammary Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    So Young Park

    2016-06-01

    Full Text Available Licorice extracts containing glycyrrhizin exhibit anti-carcinogenic properties. Because glycyrrhizin induces severe hypokalemia and hypertension, we prepared a hexane/ethanol extract of Glycyrrhiza uralensis (HEGU that lacks glycyrrhizin, and showed that HEGU induces apoptosis and G1 cell cycle arrest and inhibits migration of DU145 human prostate cancer cells. Our previous in vitro studies identified two active components in HEGU: isoangustone A, which induces apoptosis and G1 cycle arrest, and licoricidin, which inhibits metastasis. This study examined whether HEGU and licoricidin inhibit metastasis using the 4T1 mammary cancer model. Both HEGU and licoricidin treatment reduced pulmonary metastasis and the expression of CD45, CD31, HIF-1α, iNOS, COX-2, and VEGF-A in tumor tissues. Additionally, a decrease in protein expression of VEGF-R2, VEGF-C, VEGF-R3, and LYVE-1 was noted in tumor tissues of licoricidin-treated mice. Furthermore, the blood concentrations of MMP-9, ICAM-1, VCAM-1, and VEGF-A were decreased in HEGU-treated mice. In vitro 4T1 cell culture results showed that both HEGU and licoricidin inhibited cell migration, MMP-9 secretion, and VCAM expression. The present study demonstrates that the licoricidin in HEGU inhibits lung metastasis of 4T1 mammary carcinoma cells, which may be mediated via inhibition of cancer cell migration, tumor angiogenesis, and lymphangiogenesis.

  8. Sarcomatoid Renal Cell Carcinoma Metastasis to the Penis

    OpenAIRE

    Liou, Victor D.; Darwish, Oussama M.; Henry, Mary M.; Jun, Ik C.; Sameer A. Siddiqui

    2015-01-01

    Secondary cancers of the penis are extremely uncommon with less than 300 cases reported in the past 100 years. These cancers are most frequently a result of an aggressive or poorly managed primary prostate or bladder cancer and rarely a metastasis from a primary kidney tumor. Currently, there is no published literature which describes the spread of sarcomatoid renal cell carcinoma (SRCC) to the penis. In this report, we present a 55-year-old-man who presented with a large right-sided SRCC wh...

  9. Cell migration or cytokinesis and proliferation? – Revisiting the “go or grow” hypothesis in cancer cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Garay, Tamás; Juhász, Éva; Molnár, Eszter [2nd Department of Pathology, Semmelweis University, Budapest (Hungary); Eisenbauer, Maria [Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna (Austria); Czirók, András [Department of Biological Physics, Eötvös University, Budapest (Hungary); Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS (United States); Dekan, Barbara; László, Viktória; Hoda, Mir Alireza [Department of Thoracic Surgery, Medical University of Vienna, Vienna (Austria); Döme, Balázs [Department of Thoracic Surgery, Medical University of Vienna, Vienna (Austria); National Korányi Institute of TB and Pulmonology, Budapest (Hungary); Tímár, József [2nd Department of Pathology, Semmelweis University, Budapest (Hungary); MTA-SE Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest (Hungary); Klepetko, Walter [Department of Thoracic Surgery, Medical University of Vienna, Vienna (Austria); Berger, Walter [Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna (Austria); Hegedűs, Balázs, E-mail: balazs.hegedus@meduniwien.ac.at [Department of Thoracic Surgery, Medical University of Vienna, Vienna (Austria); MTA-SE Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest (Hungary)

    2013-12-10

    The mortality of patients with solid tumors is mostly due to metastasis that relies on the interplay between migration and proliferation. The “go or grow” hypothesis postulates that migration and proliferation spatiotemporally excludes each other. We evaluated this hypothesis on 35 cell lines (12 mesothelioma, 13 melanoma and 10 lung cancer) on both the individual cell and population levels. Following three-day-long videomicroscopy, migration, proliferation and cytokinesis-length were quantified. We found a significantly higher migration in mesothelioma cells compared to melanoma and lung cancer while tumor types did not differ in mean proliferation or duration of cytokinesis. Strikingly, we found in melanoma and lung cancer a significant positive correlation between mean proliferation and migration. Furthermore, non-dividing melanoma and lung cancer cells displayed slower migration. In contrast, in mesothelioma there were no such correlations. Interestingly, negative correlation was found between cytokinesis-length and migration in melanoma. FAK activation was higher in melanoma cells with high motility. We demonstrate that the cancer cells studied do not defer proliferation for migration. Of note, tumor cells from various organ systems may differently regulate migration and proliferation. Furthermore, our data is in line with the observation of pathologists that highly proliferative tumors are often highly invasive. - Highlights: • We investigated the “go or grow” hypothesis in human cancer cells in vitro. • Proliferation and migration positively correlate in melanoma and lung cancer cells. • Duration of cytokinesis and migration shows inverse correlation. • Increased FAK activation is present in highly motile melanoma cells.

  10. Study of cell migration in microfabricated channels.

    Science.gov (United States)

    Vargas, Pablo; Terriac, Emmanuel; Lennon-Duménil, Ana-Maria; Piel, Matthieu

    2014-02-21

    The method described here allows the study of cell migration under confinement in one dimension. It is based on the use of microfabricated channels, which impose a polarized phenotype to cells by physical constraints. Once inside channels, cells have only two possibilities: move forward or backward. This simplified migration in which directionality is restricted facilitates the automatic tracking of cells and the extraction of quantitative parameters to describe cell movement. These parameters include cell velocity, changes in direction, and pauses during motion. Microchannels are also compatible with the use of fluorescent markers and are therefore suitable to study localization of intracellular organelles and structures during cell migration at high resolution. Finally, the surface of the channels can be functionalized with different substrates, allowing the control of the adhesive properties of the channels or the study of haptotaxis. In summary, the system here described is intended to analyze the migration of large cell numbers in conditions in which both the geometry and the biochemical nature of the environment are controlled, facilitating the normalization and reproducibility of independent experiments.

  11. Tumor microenvironment regulates metastasis and metastasis genes of mouse MMTV-PymT mammary cancer cells in vivo.

    Science.gov (United States)

    Werbeck, J L; Thudi, N K; Martin, C K; Premanandan, C; Yu, L; Ostrowksi, M C; Rosol, T J

    2014-07-01

    Metastasis is the primary cause of death in breast cancer patients, yet there are challenges to modeling this process in vivo. The goal of this study was to analyze the effects of injection site on tumor growth and metastasis and gene expression of breast cancer cells in vivo using the MMTV-PymT breast cancer model (Met-1 cells). Met-1 cells were injected into 5 sites (subcutaneous, mammary fat pad, tail vein, intracardiac, and intratibial), and tumors and metastases were monitored using bioluminescent imaging and confirmed with gross necropsy and histopathology. Met-1 tumors were analyzed based on morphology and changes in gene expression in each tissue microenvironment. There were 6 permissible sites of Met-1 tumor growth (mammary gland, subcutis, lung, adrenal gland, ovary, bone). Met-1 cells grew faster in the subcutis compared to mammary fat pad tumors (highest Ki-67 index). Morphologic differences were evident in each tumor microenvironment. Finally, 7 genes were differentially expressed in the Met-1 tumors in the 6 sites of growth or metastasis. This investigation demonstrates that breast cancer progression and metastasis are regulated by not only the tumor cells but also the experimental model and unique molecular signals from the tumor microenvironment.

  12. MiR-378 Promotes the Migration of Liver Cancer Cells by Down-Regulating Fus Expression

    Directory of Open Access Journals (Sweden)

    Jichun Ma

    2014-12-01

    Full Text Available Background: miR-378 regulates osteoblast differentiation and participates in tumor cell self-renewal and chemo-resistance. However, the function of miR-378 in liver cancer cell migration has not been reported to date. Methods: miR-378 expression was examined using real-time quantitative PCR. HepG2 cell migration and liver cell invasion were examined using wound-healing and cell invasion assays. Additionally, HepG2 cell metastasis was analyzed in nude mice. Results: miR-378 over-expression enhances HepG2 cell proliferation, migration and liver cell invasion. Typical metastatic lesions were found in the livers of mice injected with miR-378-transfected cells, and high levels of the CMV promoter were detected in the nodules, indicating that miR-378 promoted the metastasis of the tumor cells to the liver. We also demonstrated that miR-378 down-regulated Fus expression. Conclusions: Our results suggested that miR-378 enhanced cell migration and metastasis by down-regulating Fus expression.

  13. TRPM7 Is Required for Breast Tumor Cell Metastasis.

    NARCIS (Netherlands)

    Middelbeek, J.A.J.; Kuipers, A.J.; Henneman, L.; Visser, D.; Eidhof, I.; Horssen, R. van; Wieringa, B.; Canisius, S.V.M.; Zwart, W.; Wessels, L.F.; Sweep, F.C.; Bult, P.; Span, P.N.; Leeuwen, F.N. van; Jalink, K.

    2012-01-01

    TRPM7 encodes a Ca(2+)-permeable nonselective cation channel with kinase activity. TRPM7 has been implicated in control of cell adhesion and migration, but whether TRPM7 activity contributes to cancer progression has not been established. Here we report that high levels of TRPM7 expression independe

  14. Concentric Gel System to Study the Biophysical Role of Matrix Microenvironment on 3D Cell Migration

    Science.gov (United States)

    Kurniawan, Nicholas Agung; Chaudhuri, Parthiv Kant; Lim, Chwee Teck

    2015-01-01

    The ability of cells to migrate is crucial in a wide variety of cell functions throughout life from embryonic development and wound healing to tumor and cancer metastasis. Despite intense research efforts, the basic biochemical and biophysical principles of cell migration are still not fully understood, especially in the physiologically relevant three-dimensional (3D) microenvironments. Here, we describe an in vitro assay designed to allow quantitative examination of 3D cell migration behaviors. The method exploits the cell’s mechanosensing ability and propensity to migrate into previously unoccupied extracellular matrix (ECM). We use the invasion of highly invasive breast cancer cells, MDA-MB-231, in collagen gels as a model system. The spread of cell population and the migration dynamics of individual cells over weeks of culture can be monitored using live-cell imaging and analyzed to extract spatiotemporally-resolved data. Furthermore, the method is easily adaptable for diverse extracellular matrices, thus offering a simple yet powerful way to investigate the role of biophysical factors in the microenvironment on cell migration. PMID:25867104

  15. Constitutive activation of BMP signalling abrogates experimental metastasis of OVCA429 cells via reduced cell adhesion

    Directory of Open Access Journals (Sweden)

    Shepherd Trevor G

    2010-02-01

    Full Text Available Abstract Background Activation of bone morphogenetic protein (BMP4 signalling in human ovarian cancer cells induces a number of phenotypic changes in vitro, including altered cell morphology, adhesion, motility and invasion, relative to normal human ovarian surface epithelial cells. From these in vitro analyses, we had hypothesized that active BMP signalling promotes the metastatic potential of ovarian cancer. Methods To test this directly, we engineered OVCA429 human ovarian cancer cells possessing doxycycline-inducible expression of a constitutively-active mutant BMP receptor, ALK3QD, and administered these cells to immunocompromised mice. Further characterization was performed in vitro to address the role of activated BMP signalling on the EOC phenotype, with particular emphasis on epithelial-mesenchymal transition (EMT and cell adhesion. Results Unexpectedly, doxycycline-induced ALK3QD expression in OVCA429 cells reduced tumour implantation on peritoneal surfaces and ascites formation when xenografted into immunocompromised mice by intraperitoneal injection. To determine the potential mechanisms controlling this in vivo observation, we followed with several cell culture experiments. Doxycycline-induced ALK3QD expression enhanced the refractile, spindle-shaped morphology of cultured OVCA429 cells eliciting an EMT-like response. Using in vitro wound healing assays, we observed that ALK3QD-expressing cells migrated with long, cytoplasmic projections extending into the wound space. The phenotypic alterations of ALK3QD-expressing cells correlated with changes in specific gene expression patterns of EMT, including increased Snail and Slug and reduced E-cadherin mRNA expression. In addition, ALK3QD signalling reduced β1- and β3-integrin expression, critical molecules involved in ovarian cancer cell adhesion. The combination of reduced E-cadherin and β-integrin expression correlates directly with the reduced EOC cell cohesion in spheroids and

  16. CHRNA7 inhibits cell invasion and metastasis of LoVo human colorectal cancer cells through PI3K/Akt signaling.

    Science.gov (United States)

    Xiang, Tao; Yu, Feng; Fei, Rushan; Qian, Jing; Chen, Wenbin

    2016-02-01

    The α7 neuronal nicotinic receptor gene (CHRNA7) is widely expressed in both the brain and periphery whereas its encoding protein of α7 neuronal acetylcholine receptor (α7nAChR) belongs to the nicotinic acetylcholine receptor family. Considerable evidence suggests that α7nAChR plays an important role in chronic inflammatory and neuropathic pain signaling and thus has been proposed as a potential target for treating cognitive deficits in patients with schizophrenia, attention deficit hyperactivity disorder (ADHD) and Alzheimer's disease. The aim of the present study was to determine the role of endogenous α7nAChR signaling in human colorectal cancer growth and metastasis. pLVX‑CHRNA7 encoding the full length of CHRNA7 was constructed and transfected into LoVo human colorectal cancer cells. Cell proliferation was measured by Cell Counting Kit‑8 (CCK‑8), and cell migration and invasion were detected by Transwell chamber assays. Expression and activity of metastasis‑related metalloproteinases (MMPs) were analyzed by western blotting and gelatin zymography, respectively. Activation of metastasis-related signaling molecules was detected by western blotting. LY294002 was used to specifically block the phosphatidylinositol 3‑kinase/v‑akt murine thymoma viral oncogene homologue (PI3K/Akt) pathway. We showed that concomitantly with an increase in α7nAChR expression after transfection, LoVo cells presented reduced abilities for migration and invasion, which was accompanied by reduced expression levels of MMP‑1 and MMP‑9 as well as activation of the PI3K/Akt signaling pathway. The application of LY294002 restored the migration and invasion abilities of the LoVo cells bearing CHRNA7. Collectively, we conclude that overexpression of CHRNA7 negatively controls colorectal cancer LoVo cell invasion and metastasis via PI3K/Akt pathway activation and may serve as either a diagnostic marker or a therapeutic target for colorectal cancer metastasis.

  17. Interleukin-32α induces migration of human melanoma cells through downregulation of E-cadherin.

    Science.gov (United States)

    Lee, Joohyun; Kim, Kyung Eun; Cheon, Soyoung; Song, Ju Han; Houh, Younkyung; Kim, Tae Sung; Gil, Minchan; Lee, Kyung Jin; Kim, Seonghan; Kim, Daejin; Hur, Dae Young; Yang, Yoolhee; Bang, Sa Ik; Park, Hyun Jeong; Cho, Daeho

    2016-10-04

    Interleukin (IL)-32α, the shortest isoform of proinflammatory cytokine IL-32, is associated with various inflammatory diseases and cancers. However, its involvement in human melanoma is not understood. To determine the effect of IL-32α in melanoma, IL-32α levels were examined in human melanoma cell lines that exhibit different migratory abilities. IL-32α levels were higher in human melanoma cell lines with more migratory ability. An IL-32α-overexpressing G361 human melanoma cell line was generated to investigate the effect of IL-32α on melanoma migration. IL-32α-overexpressing G361 cells (G361-IL-32α) exhibit an increased migratory ability compared to vector control cells (G361-vector). To identify factors involved in IL-32α-induced migration, we compared expression of E-cadherin in G361-vector and G361-IL-32α cells. We observed decreased levels of E-cadherin in G361-IL-32α cells, resulting in F-actin polymerization. To further investigate signaling pathways related to IL-32α-induced migration, we treated G361-vector and G361-IL-32α cells with PD98059, a selective MEK inhibitor. Inhibition of Erk1/2 by PD98059 restored E-cadherin expression and decreased IL-32α-induced migration. In addition, cell invasiveness of G361-IL-32α cells was tested using an in vivo lung metastasis model. As results, lung metastasis was significantly increased by IL-32α overexpression. Taken together, these data indicate that IL-32α induced human melanoma migration via Erk1/2 activation, which repressed E-cadherin expression. Our findings suggest that IL-32α is a novel regulator of migration in melanoma.

  18. TM4SF1 Promotes Proliferation, Invasion, and Metastasis in Human Liver Cancer Cells

    Science.gov (United States)

    Huang, Yu-Kun; Fan, Xue-Gong; Qiu, Fu

    2016-01-01

    Transmembrane 4 superfamily member 1 (TM4SF1) is a member of tetraspanin family, which mediates signal transduction events regulating cell development, activation, growth and motility. Our previous studies showed that TM4SF1 is highly expressed in liver cancer. HepG2 cells were transfected with TM4SFl siRNA and TM4SF1-expressing plasmids and their biological functions were analyzed in vitro and in vivo. HepG2 cells overexpressing TM4SF1 showed reduced apoptosis and increased cell migration in vitro and enhanced tumor growth and metastasis in vivo, whereas siRNA-mediated silencing of TM4SF1 had the opposite effect. TM4SF1 exerts its effect by regulating a few apoptosis- and migration-related genes including caspase-3, caspase-9, MMP-2, MMP-9 and VEGF. These results indicate that TM4SF1 is associated with liver tumor growth and progression, suggesting that TM4SF1 may be a potential target for treatment of liver cancer in future. PMID:27153056

  19. Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth

    OpenAIRE

    Gonzalez, Maria E.; Martin, Emily E.; Talha Anwar; Caroline Arellano-Garcia; Natasha Medhora; Arjun Lama; Yu-Chih Chen; Kevin S. Tanager; Euisik Yoon; Kidwell, Kelley M.; Chunxi Ge; Franceschi, Renny T.; Celina G. Kleer

    2017-01-01

    Increased collagen deposition by breast cancer (BC)-associated mesenchymal stem/multipotent stromal cells (MSC) promotes metastasis, but the mechanisms are unknown. Here, we report that the collagen receptor discoidin domain receptor 2 (DDR2) is essential for stromal-BC communication. In human BC metastasis, DDR2 is concordantly upregulated in metastatic cancer and multipotent mesenchymal stromal cells. In MSCs isolated from human BC metastasis, DDR2 maintains a fibroblastic phenotype with co...

  20. Roles of Chemokine Receptor 4(CXCR4)and Chemokine Ligand 12(CXCL12)in Metastasis of Hepatocellular Carcinoma Cells

    Institute of Scientific and Technical Information of China (English)

    Hui Liu; Zeya Pan; Aijun Li; Siyuan Fu; Yin Lei; Hangyong Sun; Mengchao Wu; Weiping Zhou

    2008-01-01

    Chemokines are involved in human hepatocellular carcinoma (HCC) carcinogenesis.However,the exact mechanism of chemokines in HCC carcinogenesis remains unknown.Here we investigated the roles of chemokine receptor 4(CXCR4) and chemokine ligand 12(CXCL12)in the metastasis of HCC.We found that the expression levels of CXCR4 mRNA in HCC tissues,MHCC97 cells,and HUVEC cells were 2.52±1.13,2.34±1.16 and 1.63±1.26,respectively and that the CXCR4 protein levels were 1.38±0.13,1.96±0.32 and 1.86±0.21,respectively.In contrast,CXCR4 was not detected in normal hepatic tissues.In 78 HCC patients,we also found that the concentration of CXCL12 in cancerous ascitic fluid was 783-8,364 Pg/ml and that CXCL12 mRNA level in HCC metastasis portal lymph nodes was 1.21±0.87 but undetectable in normal hepatic tissues.Finally we discovered that recombinant human CXCL12 could induce MHCC97 cells and HUVEC cells to migrate with chemotactic indexes(CI)of 3.9±1.1 and 4.1±1.6,respectively.Cancerous ascitic fluid could also induce the migration of MHCC97 cells with a CI of 1.9±0.8.Thus,our data suggest that CXCR4 and CXCL12 may play an important role in the metastasis of HCC by promoting the migration of tumor cells.

  1. Siva1 suppresses epithelial-mesenchymal transition and metastasis of tumor cells by inhibiting stathmin and stabilizing microtubules.

    Science.gov (United States)

    Li, Nan; Jiang, Peng; Du, Wenjing; Wu, Zhengsheng; Li, Cong; Qiao, Mengran; Yang, Xiaolu; Wu, Mian

    2011-08-02

    Epithelial-mesenchymal transition (EMT) enables epithelial cells to acquire motility and invasiveness that are characteristic of mesenchymal cells. It plays an important role in development and tumor cell metastasis. However, the mechanisms of EMT and their dysfunction in cancer cells are still not well understood. Here we report that Siva1 interacts with stathmin, a microtubule destabilizer. Siva1 inhibits stathmin's activity directly as well as indirectly through Ca(2+)/calmodulin-dependent protein kinase II-mediated phosphorylation of stathmin at Ser16. Via the inhibition of stathmin, Siva1 enhances the formation of microtubules and impedes focal adhesion assembly, cell migration, and EMT. Low levels of Siva1 and Ser16-phosphorylated stathmin correlate with high metastatic states of human breast cancer cells. In mouse models, knockdown of Siva1 promotes cancer dissemination, whereas overexpression of Siva1 inhibits it. These results suggest that microtubule dynamics are critical for EMT. Furthermore, they reveal an important role for Siva1 in suppressing cell migration and EMT and indicate that down-regulation of Siva1 may contribute to tumor cell metastasis.

  2. Cutaneous Metastasis of Large Cell Lung Cancer: A Case Report

    Directory of Open Access Journals (Sweden)

    Ižsmail Gedik

    2016-05-01

    Full Text Available Lung cancer has the highest incidence among all cancer types in the world. Skin is an uncommon organ that lung cancers metastasize and the incidence of cutaneous metastasis has been reported between 1-12%. In this report, we would like to present the case of a 67 year old male patient who admitted to our hospital with the complaint of multiple swollen masses on the different parts of his skin and has a homogenous mass with the width of 3 cm on chest x ray. The nodule at the intersection of the right 6th intercostal space and the mid-axillary line and with the dimensions of 1.5x1 cm was excised under local anesthesia and the specimen was sent to the pathology laboratory for histopathological examination. The diagnosis of %u201Clarge cell neuroendocrine carcinoma%u201D was made histopathologically. The patient was diagnosed as the distant metastasis of the large cell lung cancer, considered inoperable and referred to oncology clinics.

  3. Engineered Models of Confined Cell Migration

    Science.gov (United States)

    Paul, Colin D.; Hung, Wei-Chien; Wirtz, Denis; Konstantopoulos, Konstantinos

    2017-01-01

    Cells in the body are physically confined by neighboring cells, tissues, and the extracellular matrix. Although physical confinement modulates intracellular signaling and the underlying mechanisms of cell migration, it is difficult to study in vivo. Furthermore, traditional two-dimensional cell migration assays do not recapitulate the complex topographies found in the body. Therefore, a number of experimental in vitro models that confine and impose forces on cells in well-defined microenvironments have been engineered. We describe the design and use of microfluidic microchannel devices, grooved substrates, micropatterned lines, vertical confinement devices, patterned hydrogels, and micropipette aspiration assays for studying cell responses to confinement. Use of these devices has enabled the delineation of changes in cytoskeletal reorganization, cell–substrate adhesions, intracellular signaling, nuclear shape, and gene expression that result from physical confinement. These assays and the physiologically relevant signaling pathways that have been elucidated are beginning to have a translational and clinical impact. PMID:27420571

  4. Regulation of cancer cell migration and invasion by sphingosine-1-phosphate

    Institute of Scientific and Technical Information of China (English)

    James; R; Van; Brocklyn

    2010-01-01

    Sphingosine-1-phosphate (S1P) is a bioactive sphingo-lipid that has been implicated in regulation of a number of cancer cell malignant behaviors, including cell proliferation, survival, chemotherapeutic resistance and angiogenesis. However, the effects of S1P on cancer cell migration, invasion and metastasis, are perhaps its most complex, due to the fact that, depending upon the S1P receptors that mediate its responses and the crosstalk with other signaling pathways, S1P can either positively or negatively regulate invasion. This review summarizes the effects of S1P on cancer cell invasion and the mechanisms by which it affects this important aspect of cancer cell behavior.

  5. Integrin β6 serves as an immunohistochemical marker for lymph node metastasis and promotes cell invasiveness in cholangiocarcinoma

    Science.gov (United States)

    Li, Zequn; Biswas, Siddhartha; Liang, Benjia; Zou, Xueqing; Shan, Liqun; Li, Yang; Fang, Ruliang; Niu, Jun

    2016-01-01

    Cholangiocarcinoma is a devastating malignancy that is notoriously difficult to diagnose and is associated with a high mortality. Despite extensive efforts to improve the diagnosis and treatment of this neoplasm, limited progress has been made. Integrin β6 is a subtype of integrin that is expressed exclusively on the surfaces of epithelial cells and is associated with a variety of tumors. In the present study, we investigated the expression and roles of integrin β6 in cholangiocarcinoma. β6 upregulation in cholangiocarcinoma was correlated with lymph node metastasis and distant metastasis. Moreover, integrin β6 was identified as a biomarker for the diagnosis of cholangiocarcinoma and an indicator of lymph node metastasis. Integrin β6 significantly promoted the proliferation, migration and invasion of cholangiocarcinoma cells. Furthermore, integrin β6 increased Rac1-GTPase, resulting in the upregulation of metalloproteinase-9 (MMP9) and F-actin polymerization. Taken together, our results indicate that integrin β6 promotes tumor invasiveness in a Rac1-dependent manner and is a potential biomarker for tumor metastasis. Integrin β6 may help to improve the diagnostic accuracy, and targeting β6 may be a novel strategy for the treatment of cholangiocarcinoma. PMID:27440504

  6. Plasticity of cell migration: a multiscale tuning model.

    NARCIS (Netherlands)

    Friedl, P.H.A.; Wolf, K. van der

    2010-01-01

    Cell migration underlies tissue formation, maintenance, and regeneration as well as pathological conditions such as cancer invasion. Structural and molecular determinants of both tissue environment and cell behavior define whether cells migrate individually (through amoeboid or mesenchymal modes) or

  7. Metadherin mediates lipopolysaccharide-induced migration and invasion of breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Yuhan Zhao

    Full Text Available BACKGROUND: Breast cancer is the most prevalent cancer in women worldwide and metastatic breast cancer has very poor prognosis. Inflammation has been implicated in migration and metastasis of breast cancer, although the exact molecular mechanism remains elusive. PRINCIPAL FINDINGS: We show that the pro-inflammatory endotoxin Lipopolysaccharide (LPS upregulates the expression of Metadherin (MTDH, a recently identified oncogene, in a number of breast cancer lines. Stable knockdown of MTDH by shRNA in human breast MDA-MB-231 cells abolishes LPS-induced cell migration and invasion as determined by several in vitro assays. In addition, knockdown of MTDH diminishes Nuclear Factor-kappa B (NF-κB activation by LPS and inhibited LPS-induced IL-8 and MMP-9 production. CONCLUSIONS: These results strongly suggest that MTDH is a pivotal molecule in inflammation-mediated tumor metastasis. Since NF-κB, IL-8 and MMP-9 play roles in LPS-induced invasion or metastasis, the mechanism of MTDH-promoted invasion and metastasis may be through the activation of NF-κB, IL-8 and MMP-9, also suggesting a role of MTDH in regulating both inflammatory responses and inflammation-associated tumor invasion. These findings indicate that MTDH is involved in inflammation-induced tumor progression, and support that MTDH targeting therapy may hold promising prospects in treating breast cancer.

  8. Migration of cells in a social context

    DEFF Research Database (Denmark)

    Vedel, Søren; Tay, Savas; Johnston, Darius M;

    2013-01-01

    In multicellular organisms and complex ecosystems, cells migrate in a social context. Whereas this is essential for the basic processes of life, the influence of neighboring cells on the individual remains poorly understood. Previous work on isolated cells has observed a stereotypical migratory...... based on the experimentally identified "cellular traffic rules" and basic physics that revealed that these emergent behaviors are caused by the interplay of single-cell properties and intercellular interactions, the latter being dominated by a pseudopod formation bias mediated by secreted chemicals...... and pseudopod collapse following collisions. The model demonstrates how aspects of complex biology can be explained by simple rules of physics and constitutes a rapid test bed for future studies of collective migration of individual cells....

  9. Bursts of activity in collective cell migration

    CERN Document Server

    Chepizhko, Oleksandr; Mastrapasqua, Eleonora; Nourazar, Mehdi; Ascagni, Miriam; Sugni, Michela; Fascio, Umberto; Leggio, Livio; Malinverno, Chiara; Scita, Giorgio; Santucci, Stephane; Alava, Mikko J; Zapperi, Stefano; La Porta, Caterina A M

    2016-01-01

    Dense monolayers of living cells display intriguing relaxation dynamics, reminiscent of soft and glassy materials close to the jamming transition, and migrate collectively when space is available, as in wound healing or in cancer invasion. Here we show that collective cell migration occurs in bursts that are similar to those recorded in the propagation of cracks, fluid fronts in porous media and ferromagnetic domain walls. In analogy with these systems, the distribution of activity bursts displays scaling laws that are universal in different cell types and for cells moving on different substrates. The main features of the invasion dynamics are quantitatively captured by a model of interacting active particles moving in a disordered landscape. Our results illustrate that collective motion of living cells is analogous to the corresponding dynamics in driven, but inanimate, systems.

  10. Recombinant disintegrin domain of ADAM15 inhibits the proliferation and migration of Bel-7402 cells

    Energy Technology Data Exchange (ETDEWEB)

    Hou, Y. [Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd., Wuxi, Jiangsu 214122 (China); Chu, M. [Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Medicine, Jiangnan University, 1800 Lihu Rd., Wuxi, Jiangsu 214122 (China); Du, F.F.; Lei, J.Y.; Chen, Y.; Zhu, R.Y.; Gong, X.H.; Ma, X. [Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd., Wuxi, Jiangsu 214122 (China); Jin, J., E-mail: jinjian31@126.com [Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Rd., Wuxi, Jiangsu 214122 (China)

    2013-06-14

    Highlights: •rhddADAM15 inhibited the proliferation and migration of Bel-7402 cells. •rhddADAM15 inhibited growth and metastasis of Bel-7402 cells in zebrafish xenograft. •rhddADAM15 induced apoptosis in Bel-7402 cells and somatic cells of zebrafish. •Cell-cycle in Bel-7402 cells showed a partial G{sub 2}/S arrest. •Activity of caspases 8, 9 and 3 was increased in rhddADAM15-treated Bel-7402 cells. -- Abstract: ADAM15 (A Disintegrin And Metalloproteinase 15), a transmembrane protein containing seven domains, interacts with some integrins via its disintegrin domain and overexpresses in many solid tumors. In this study, the effect of the recombinant human disintegrin domain (rhddADAM15) on the proliferation and migration of Bel-7402 cells was evaluated in vitro and in vivo in zebrafish xenografts. rhddADAM15 (4 μM) severely inhibited the proliferation and migration of Bel-7402 cells, inducing a partial G{sub 2}/S arrest and morphological nucleus changes of apoptosis. Moreover, the activity of caspases 8, 9 and 3 in Bel-7402 cells was increased. In addition, the zebrafish was used as a model for apoptosis-induction and tumor-xenograft. rhddADAM15 (1 pM) inhibited the growth and metastasis of Bel-7402 cell xenografts in zebrafish and a lower concentration (0.1 pM) induced severe apoptosis in the somatic cells of zebrafish. In conclusion, our data identified rhddADAM15 as a potent inhibitor of tumor growth and metastasis, making it a promising tool for use in anticancer treatment.

  11. Androgen-induced cell migration: role of androgen receptor/filamin A association.

    Directory of Open Access Journals (Sweden)

    Gabriella Castoria

    Full Text Available BACKGROUND: Androgen receptor (AR controls male morphogenesis, gametogenesis and prostate growth as well as development of prostate cancer. These findings support a role for AR in cell migration and invasiveness. However, the molecular mechanism involved in AR-mediated cell migration still remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: Mouse embryo NIH3T3 fibroblasts and highly metastatic human fibrosarcoma HT1080 cells harbor low levels of transcriptionally incompetent AR. We now report that, through extra nuclear action, AR triggers migration of both cell types upon stimulation with physiological concentrations of the androgen R1881. We analyzed the initial events leading to androgen-induced cell migration and observed that challenging NIH3T3 cells with 10 nM R1881 rapidly induces interaction of AR with filamin A (FlnA at cytoskeleton. AR/FlnA complex recruits integrin beta 1, thus activating its dependent cascade. Silencing of AR, FlnA and integrin beta 1 shows that this ternary complex controls focal adhesion kinase (FAK, paxillin and Rac, thereby driving cell migration. FAK-null fibroblasts migrate poorly and Rac inhibition by EHT impairs motility of androgen-treated NIH3T3 cells. Interestingly, FAK and Rac activation by androgens are independent of each other. Findings in human fibrosarcoma HT1080 cells strengthen the role of Rac in androgen signaling. The Rac inhibitor significantly impairs androgen-induced migration in these cells. A mutant AR, deleted of the sequence interacting with FlnA, fails to mediate FAK activation and paxillin tyrosine phosphorylation in androgen-stimulated cells, further reinforcing the role of AR/FlnA interaction in androgen-mediated motility. CONCLUSIONS/SIGNIFICANCE: The present report, for the first time, indicates that the extra nuclear AR/FlnA/integrin beta 1 complex is the key by which androgen activates signaling leading to cell migration. Assembly of this ternary complex may control organ development

  12. Cell migration is regulated by AGE-RAGE interaction in human oral cancer cells in vitro.

    Directory of Open Access Journals (Sweden)

    Shun-Yao Ko

    Full Text Available Advanced glycation end products (AGEs are produced in an irreversible non-enzymatic reaction of carbohydrates and proteins. Patients with diabetes mellitus (DM are known to have elevated AGE levels, which is viewed as a risk factor of diabetes-related complications. In a clinical setting, it has been shown that patients with oral cancer in conjunction with DM have a higher likelihood of cancer metastasis and lower cancer survival rates. AGE-RAGE (a receptor of AGEs is also correlated with metastasis and angiogenesis. Recent studies have suggested that the malignancy of cancer may be enhanced by glyceraldehyde-derived AGEs; however, the underlying mechanism remains unclear. This study examined the apparently close correlation between AGE-RAGE and the malignancy of SAS oral cancer cell line. In this study, AGEs increased ERK phosphorylation, enhanced cell migration, and promoted the expression of RAGE, MMP2, and MMP9. Using PD98059, RAGE antibody, and RAGE RNAi to block RAGE pathway resulted in the inhibition of ERK phosphorylation. Cell migration, MMP2 and MMP9 expression were also reduced by this treatment. Our findings demonstrate the importance of AGE-RAGE with regard to the malignancy of oral cancer, and help to explain the poor prognosis of DM subjects with oral cancer.

  13. Cardiac metastasis from renal cell carcinoma successfully treated with pazopanib: impact of TKIs' antiangiogenic activity.

    Science.gov (United States)

    Schinzari, Giovanni; Monterisi, Santa; Signorelli, Diego; Cona, Silvia; Cassano, Alessandra; Danza, Francesco; Barone, Carlo

    2014-01-01

    Cardiac metastasis from renal cell carcinoma, especially without neoplastic thrombosis of the vena cava, is extremely rare. The prognosis of patients with metastatic renal cell carcinoma has been radically influenced by the introduction of tyrosine kinase inhibitors, but very few reports in the literature have described their activity in heart metastasis. We report the case of a woman with a left ventricle metastasis from kidney cancer without renal vein involvement, who was treated with pazopanib. The patient achieved a prolonged partial response, with clear signs of metastasis devascularization and a favorable toxicity profile.

  14. Metastin has potential as a suitable biomarker and novel effective therapy for cancer metastasis (Review)

    OpenAIRE

    SHOJI, SUNAO; TANG, XIAN YANG; SATO, HARUHIRO; Usui, Yukio; UCHIDA, TOYOAKI; Terachi, Toshiro

    2010-01-01

    Cancer metastasis is a leading cause of death in cancer patients and is a multistep process involving complex interactions between tumor and host cells. To metastasize, tumor cells must invade or migrate from the primary tumor and be transported to close or distant secondary sites. A tumor cell should successfully accomplish each step of the pathway or metastasis may not develop. KiSS-1 is a human metastasis suppressor gene that inhibits metastasis of human melanomas and breast carcinomas wit...

  15. Invasion and metastasis in pancreatic cancer.

    Science.gov (United States)

    Keleg, Shereen; Büchler, Peter; Ludwig, Roman; Büchler, Markus W; Friess, Helmut

    2003-01-22

    Pancreatic cancer remains a challenging disease with an overall cumulative 5-year survival rate below 1%. The process of cancer initiation, progression and metastasis is still not understood well. Invasion and tumor metastasis are closely related and both occur within a tumour-host microecology, where stroma and tumour cells exchange enzymes and cytokines that modify the local extracellular matrix, stimulate cell migration, and promote cell proliferation and tumor cell survival. During the last decade considerable progress has been made in understanding genetic alterations of genes involved in local and systemic tumor growth. The most important changes occur in genes which regulate cell cycle progression, extracellular matrix homeostasis and cell migration. Furthermore, there is growing evidence that epigenetic factors including angiogenesis and lymphangiogenesis may participate in the formation of tumor metastasis. In this review we highlight the most important genetic alterations involved in tumor invasion and metastasis and further outline the role of tumor angiogenesis and lymphangiogenesis in systemic tumor dissemination.

  16. Metformin: An Emerging New Therapeutic Option for Targeting Cancer Stem Cells and Metastasis

    Directory of Open Access Journals (Sweden)

    Ramandeep Rattan

    2012-01-01

    Full Text Available Metastasis is an intricate process by which a small number of cancer cells from the primary tumor site undergo numerous alterations, which enables them to form secondary tumors at another and often multiple sites in the host. Transition of a cancer cell from epithelial to mesenchymal phenotype is thought to be the first step in the progression of metastasis. Recently, the recognition of cancer stem cells has added to the perplexity in understanding metastasis, as studies suggest cancer stem cells to be the originators of metastasis. All current and investigative drugs have been unable to prevent or reverse metastasis, as a result of which most metastatic cancers are incurable. A potential drug that can be considered is metformin, an oral hypoglycemic drug. In this review we discuss the potential of metformin in targeting both epithelial to mesenchymal transition and cancer stem cells in combating cancer metastases.

  17. Angiogenin enhances cell migration by regulating stress fiber assembly and focal adhesion dynamics.

    Directory of Open Access Journals (Sweden)

    Saisai Wei

    Full Text Available Angiogenin (ANG acts on both vascular endothelial cells and cancer cells, but the underlying mechanism remains elusive. In this study, we carried out a co-immunoprecipitation assay in HeLa cells and identified 14 potential ANG-interacting proteins. Among these proteins, β-actin, α-actinin 4, and non-muscle myosin heavy chain 9 are stress fiber components and involved in cytoskeleton organization and movement, which prompted us to investigate the mechanism of action of ANG in cell migration. Upon confirmation of the interactions between ANG and the three proteins, further studies revealed that ANG co-localized with β-actin and α-actinin 4 at the leading edge of migrating cells. Down-regulation of ANG resulted in fewer but thicker stress fibers with less dynamics, which was associated with the enlargements of focal adhesions. The focal adhesion kinase activity and cell migration capacity were significantly decreased in ANG-deficient cells. Taken together, our data demonstrated that the existence of ANG in the cytoplasm optimizes stress fiber assembly and focal adhesion formation to accommodate cell migration. The finding that ANG promoted cancer cell migration might provide new clues for tumor metastasis research.

  18. Cell membrane fluid-mosaic structure and cancer metastasis.

    Science.gov (United States)

    Nicolson, Garth L

    2015-04-01

    Cancer cells are surrounded by a fluid-mosaic membrane that provides a highly dynamic structural barrier with the microenvironment, communication filter and transport, receptor and enzyme platform. This structure forms because of the physical properties of its constituents, which can move laterally and selectively within the membrane plane and associate with similar or different constituents, forming specific, functional domains. Over the years, data have accumulated on the amounts, structures, and mobilities of membrane constituents after transformation and during progression and metastasis. More recent information has shown the importance of specialized membrane domains, such as lipid rafts, protein-lipid complexes, receptor complexes, invadopodia, and other cellular structures in the malignant process. In describing the macrostructure and dynamics of plasma membranes, membrane-associated cytoskeletal structures and extracellular matrix are also important, constraining the motion of membrane components and acting as traction points for cell motility. These associations may be altered in malignant cells, and probably also in surrounding normal cells, promoting invasion and metastatic colonization. In addition, components can be released from cells as secretory molecules, enzymes, receptors, large macromolecular complexes, membrane vesicles, and exosomes that can modify the microenvironment, provide specific cross-talk, and facilitate invasion, survival, and growth of malignant cells.

  19. TAZ Mediates Lysophosphatidic Acid-Induced Migration and Proliferation of Epithelial Ovarian Cancer Cells

    Directory of Open Access Journals (Sweden)

    Geun Ok Jeong

    2013-07-01

    Full Text Available Background: Transcriptional co-activator with PDZ-binding motif (TAZ, a downstream effector of the Hippo pathway, has been reported to regulate organ size, tissue homeostasis, and tumorigenesis by acting as a transcriptional co-activator. Lysophosphatidic acid (LPA is a bioactive lipid implicated in tumorigenesis and metastasis of ovarian cancer through activation of G protein-coupled receptors. However, the involvement of TAZ in LPA-induced tumorigenesis of ovarian cancer has not been elucidated. Methods: In order to demonstrate the role of TAZ in LPA-stimulated tumorigenesis, the effects of LPA on TAZ expression and cell migration were determined by Western blotting and chemotaxis analyses in R182 human epithelial ovarian cancer cells. Results and Conclusion: Treatment of R182 cells with the LPA receptor inhibitor Ki16425 blocked LPA-induced cell migration. In addition, transfection of R182 cells with small interfering RNA specific for LPA receptor 1 resulted in abrogation of LPA-stimulated cell migration. LPA induced phosphorylation of ERK and p38 MAP kinase in R182 cells and pretreatment of cells with the MEK-ERK pathway inhibitor U0126, but not the p38 MAPK inhibitor SB202190, resulted in abrogation of LPA-induced cell migration. Pretreatment of R182 cells with U0126 attenuated LPA-induced mRNA levels of TAZ and its transcriptional target genes, such as CTGF and CYR61, without affecting phosphorylation level of YAP. These results suggest that MEK-ERK pathway plays a key role in LPA-induced cell migration and mRNA expression of TAZ in R182 cells, without affecting stability of TAZ protein. In addition, small interfering RNA-mediated silencing of TAZ expression attenuated LPA-stimulated migration of R182 cells. These results suggest that TAZ plays a key role in LPA-stimulated migration of epithelial ovarian cancer cells.

  20. Inhibition of invasion and metastasis of MHCC97H cells by expression of snake venom cystatin through reduction of proteinases activity and epithelial-mesenchymal transition.

    Science.gov (United States)

    Tang, Nanhong; Xie, Qun; Wang, Xiaoqian; Li, Xiujin; Chen, Yanlin; Lin, Xu; Lin, Jianyin

    2011-05-01

    Snake venom cystatin (sv-cystatin) is a member of the cystatin family of cysteine protease inhibitors. To further evaluate the possibility of sv-cystatin in cancer therapy, this study examined the effects of sv-cystatin on the invasion and metastasis of liver cancer cells (MHCC97H) in vitro and in vivo as well as the underlying mechanism. sv-cystatin cDNA was transfected into MHCC97H cells and the anti-invasion and antimetastasis effects of sv-cystatin were determined using migration and matrigel invasion assays and a lung-metastasis mice model. The results suggest that sv-cyst clone (sv-cystatin expression in MHCC97H cells) delayed the invasion and metastasis in vitro and in vivo compared to the parental, mock and si-sv-cyst clone cells (inhibited sv-cystatin expression by siRNA). The decreased activities of cathepsin B, MMP-2 and MMP-9 and EMT change index including higher E-cadherin, lower N-cadherin and decreased Twist activity were observed in the sv-cyst clone, which contributes to the change in invasion and metastasis ability of MHCC97H cells. This study provides evidence that expression of the sv-cystatin gene in MHCC97H cells inhibits tumor cell invasion and metastasis through the reduction of the proteinases activity and Epithelial-Mesenchymal Transition (EMT), which might contribute to the anticancer research of the sv-cystatin protein.

  1. Oxidative stress enhances Axl-mediated cell migration through an Akt1/Rac1-dependent mechanism.

    Science.gov (United States)

    Huang, Jhy-Shrian; Cho, Chun-Yu; Hong, Chih-Chen; Yan, Ming-De; Hsieh, Mao-Chih; Lay, Jong-Ding; Lai, Gi-Ming; Cheng, Ann-Lii; Chuang, Shuang-En

    2013-12-01

    Persistent oxidative stress is common in cancer cells because of abnormal generation of reactive oxygen species (ROS) and has been associated with malignant phenotypes, such as chemotherapy resistance and metastasis. Both overexpression of Axl and abnormal ROS elevation have been linked to cell transformation and increased cell migration. However, the relationship between Axl and ROS in malignant cell migration has not been previously evaluated. Using an in vitro human lung cancer model, we examined the redox state of lung adenocarcinoma cell lines of low metastatic (CL1-0) and high metastatic (CL1-5) potentials. Here we report that Axl activation elicits ROS accumulation through the oxidase-coupled small GTPase Rac1. We also observed that oxidative stress could activate Axl phosphorylation to synergistically enhance cell migration. Further, Axl signaling activated by H2O2 treatment results in enhancement of cell migration via a PI3K/Akt-dependent pathway. The kinase activity of Axl is required for the Axl-mediated cell migration and prolongs the half-life of phospho-Akt under oxidative stress. Finally, downregulation of Akt1, but not Akt2, by RNAi in Axl-overexpressing cells inhibits the amount of activated Rac1 and the ability to migrate induced by H2O2 treatment. Together, these results show that a novel Axl-signaling cascade induced by H2O2 treatment triggers cell migration through the PI3K/Akt1/Rac1 pathway. Elucidation of redox regulation in Axl-related malignant migration may provide new molecular insights into the mechanisms underlying tumor progression.

  2. Esophageal Squamous Cell Carcinoma With Pancreatic Metastasis: A Case Report

    Directory of Open Access Journals (Sweden)

    Abbas Alibakhshi

    2011-11-01

    Full Text Available Malignant tumors of pancreas are usually primary neoplasms and pancreatic metastases are rare findings. We are reporting a case of squamous cell carcinoma (SCC of the esophagus with pancreatic metastasis. A 59-year old woman was admitted with chief complaint of abdominal pain and mass. She was a known case of esophageal SCC since 4 years before when she had undergone transthoracic esophagectomy and cervical esophago-gastrostomy. In order to evaluate recent abdominal mass, CT scan was done which revealed septated cystic lesion in the body and the tail of the pancreas. Palliative resection of the tumor was performed and its histological study showed SCC compatible with her previously diagnosed esophageal cancer.

  3. Melanoma cells produce multiple laminin isoforms and strongly migrate on α5 laminin(s) via several integrin receptors.

    Science.gov (United States)

    Oikawa, Yuko; Hansson, Johan; Sasaki, Takako; Rousselle, Patricia; Domogatskaya, Anna; Rodin, Sergey; Tryggvason, Karl; Patarroyo, Manuel

    2011-05-01

    Melanoma cells express and interact with laminins (LMs) and other basement membrane components during invasion and metastasis. In the present study we have investigated the production and migration-promoting activity of laminin isoforms in melanoma. Immunohistochemistry of melanoma specimens and immunoprecipitation/western blotting of melanoma cell lines indicated expression of laminin-111/121, laminin-211, laminin-411/421, and laminin-511/521. Laminin-332 was not detected. In functional assays, laminin-111, laminin-332, and laminin-511, but not laminin-211 and laminin-411, strongly promoted haptotactic cell migration either constitutively or following stimulation with insulin-like growth factors. Both placenta and recombinant laminin-511 preparations were highly active, and the isolated recombinant IVa domain of LMα5 also promoted cell migration. Function-blocking antibodies in cell migration assays revealed α6β1 integrin as the major receptor for laminin-111, and both α3β1 and α6β1 integrins for laminin-332 and laminin-511. In contrast, isolated LMα5 IVa domain-promoted melanoma cell migration was largely mediated via αVβ3 integrin and inhibited by RGD peptides. Given the ubiquitous expression of α5 laminins in melanoma cells and in melanoma-target tissues/anatomical structures, as well as the strong migration-promoting activity of these laminin isoforms, the α5 laminins emerge as putative primary extracellular matrix mediators of melanoma invasion and metastasis via α3β1 and other integrin receptors.

  4. Monocarboxylate transporter 4 facilitates cell proliferation and migration and is associated with poor prognosis in oral squamous cell carcinoma patients.

    Directory of Open Access Journals (Sweden)

    Jiang Zhu

    Full Text Available Monocarboxylate transporter 4 (MCT4 is a cell membrane transporter of lactate. Recent studies have shown that MCT4 is over-expressed in various cancers; however, its role in cancer maintenance and aggressiveness has not been fully demonstrated. This study investigated the role of MCT4 in oral squamous cell carcinoma (OSCC, and found that it is highly expressed in OSCC patients by using immunohistochemistry. Moreover, this over-expression of MCT4 was closely associated with tumor size, TNM classification, lymphatic metastasis, distant metastasis and tumor recurrence, and also poor prognosis. To further study mechanisms of MCT4 in vitro, we used small-interfering RNA to silence its expression in OSCC cell lines. The results showed that knock-down of MCT4 decreased cell proliferation, migration, and invasion. The inhibition of proliferation was associated with down-regulation of p-AKT and p-ERK1/2, while decreased cell migration and invasion may be caused by down-regulation of integrin β4-SRC-FAK and MEK-ERK signaling. Together, these findings provide new insight into the critical role of MCT4 in cell proliferation and metastasis in OSCC.

  5. MicroRNA-663 inhibits the proliferation, migration and invasion of glioblastoma cells via targeting TGF-β1.

    Science.gov (United States)

    Li, Qizhuang; Cheng, Quan; Chen, Zigui; Peng, Renjun; Chen, Rui; Ma, Zhiming; Wan, Xin; Liu, Jincan; Meng, Ming; Peng, Zhigang; Jiang, Bing

    2016-02-01

    Cell migration and invasion are key processes involved during tumor metastasis. Recently, microRNAs (miRs) have been demonstrated to play important roles in the regulation of cancer metastasis. However, the underlying mechanisms remain unknown. Here, we aimed to investigate the exact role of miR-663 in the metastasis of glioblastoma as well as the underlying mechanisms. By performing quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis, we demonstrated that miR-663 was significantly downregulated in glioblastoma tissues (n=25), when compared to that in normal brain tissues (n=15). In addition, its expression levels were also reduced in human glioblastoma cell lines, A172 and U87. Furthermore, restoration of miR-663 expression led to a significant decrease in the cell proliferation, migration and invasion of human glioblastoma A172 and U87 cells. We further identified TGF-β1 as a direct target of miR-663, and found that the expression of TGF-β1 was negatively mediated by miR-663 at the post-transcriptional level in glioblastoma cells. Moreover, overexpression of TGF-β1 significantly reversed the inhibitory effects of miR-663 upregulation on the proliferation, migration and invasion in A172 and U87 cells. In addition, our data suggest that MMP2 and E-cadherin, a key factor in epithelial-mesenchymal transition (EMT), are involved in the miR-633/TGF-β1-mediated metastasis of glioblastoma. In summary, miR-663 plays an inhibitory role in the regulation of proliferation, migration and invasion of glioblastoma cells, partly at least, via direct mediation of TGF-β1 as well as downstream MMP2 and E-cadherin. Therefore, we suggest that miR-663 is a potential candidate for the prevention of glioblastoma metastasis.

  6. Alternative splicing isoform of T cell factor 4K suppresses the proliferation and metastasis of non-small cell lung cancer cells.

    Science.gov (United States)

    Fan, Y C; Min, L; Chen, H; Liu, Y L

    2015-10-30

    The Wnt pathway has been implicated in the initiation, progression, and metastasis of lung cancer. T cell factor 4, a member of TCF/LEF family, acts as a transcriptional factor for Wnt pathways in lung cancer. Increasing amounts of evidence have shown that TCF-4 has multiple alternative splicing isoforms with transactivation or transrepression activity toward the Wnt pathway. Here, we found the presence of multiple TCF-4 isoforms in lung cancer cell lines and in normal bronchial epithelial cells. TCF-4K isoform expression was significantly decreased in lung cancer cells compared with normal bronchial epithelial cells and was identified as a transcriptional suppressor of the Wnt pathway in non-small cell lung carcinoma (NSCLC). Overexpression of TCF-4K significantly inhibited the proliferation and migration of NSCLC cells. Collectively, our data indicate that TCF-4K functions as a tumor suppressor in NSCLC by down-regulating the Wnt pathway.

  7. Modeled microgravity suppressed invasion and migration of human glioblastoma U87 cells through downregulating store-operated calcium entry

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Zi-xuan [Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi' an, 710032 (China); Rao, Wei [Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi' an, 710032 (China); Wang, Huan [Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, Xi' an, 710032 (China); Wang, Nan-ding [Department of Cardiology, Xi' an Traditional Chinese Medicine Hospital, Xi' an, 710032 (China); Si, Jing-Wen; Zhao, Jiao; Li, Jun-chang [Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi' an, 710032 (China); Wang, Zong-ren, E-mail: zongren@fmmu.edu.cn [Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi' an, 710032 (China)

    2015-02-13

    Glioblastoma is the most common brain tumor and is characterized with robust invasion and migration potential resulting in poor prognosis. Previous investigations have demonstrated that modeled microgravity (MMG) could decline the cell proliferation and attenuate the metastasis potential in several cell lines. In this study, we studied the effects of MMG on the invasion and migration potentials of glioblastoma in human glioblastoma U87 cells. We found that MMG stimulation significantly attenuated the invasion and migration potentials, decreased thapsigargin (TG) induced store-operated calcium entry (SOCE) and downregulated the expression of Orai1 in U87 cells. Inhibition of SOCE by 2-APB or stromal interaction molecule 1 (STIM1) downregulation both mimicked the effects of MMG on the invasion and migration potentials in U87 cells. Furthermore, upregulation of Orai1 significantly weakened the effects of MMG on the invasion and migration potentials in U87 cells. Therefore, these findings indicated that MMG stimulation inhibited the invasion and migration potentials of U87 cells by downregulating the expression of Orai1 and sequentially decreasing the SOCE, suggesting that MMG might be a new potential therapeutic strategy in glioblastoma treatment in the future. - Highlights: • Modeled microgravity (MMG) suppressed migration and invasion in U87 cells. • MMG downregulated the SOCE and the expression of Orai1. • SOCE inhibition mimicked the effects of MMG on migration and invasion potentials. • Restoration of SOCE diminished the effects of MMG on migration and invasion.

  8. Chemokine CXCL16 Expression Suppresses Migration and Invasiveness and Induces Apoptosis in Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yeying Fang

    2014-01-01

    Full Text Available Background. Increasing evidence argues that soluble CXCL16 promotes proliferation, migration, and invasion of cancer cells in vitro. However, the role of transmembrane or cellular CXCL16 in cancer remains relatively unknown. In this study, we determine the function of cellular CXCL16 as tumor suppressor in breast cancer cells. Methods. Expression of cellular CXCL16 in breast cancer cell lines was determined at both RNA and protein levels. In vitro and in vivo studies that overexpressed or downregulated CXCL16 were conducted in breast cancer cells. Results. We report differential expression of cellular CXCL16 in breast cancer cell lines that was negatively correlated with cell invasiveness and migration. Overexpression of CXCL16 in MDA-MB-231 cells led to a decrease in cell invasion and migration and induced apoptosis of the cells; downregulation of CXCL16 in MCF-7 cells increased cell migration and invasiveness. Consistent with the in vitro data, CXCL16 overexpression inhibited tumorigenesis in vivo. Conclusions. Cellular CXCL16 suppresses invasion and metastasis of breast cancer cells in vitro and inhibits tumorigenesis in vivo. Targeting of cellular CXCL16 expression is a potential therapeutic strategy for breast cancer.

  9. The Exposure of Breast Cancer Cells to Fulvestrant and Tamoxifen Modulates Cell Migration Differently

    Directory of Open Access Journals (Sweden)

    Dionysia Lymperatou

    2013-01-01

    Full Text Available There is no doubt that there are increased benefits of hormonal therapy to breast cancer patients; however, current evidence suggests that estrogen receptor (ER blockage using antiestrogens is associated with a small induction of invasiveness in vitro. The mechanism by which epithelial tumor cells escape from the primary tumor and colonize to a distant site is not entirely understood. This study investigates the effect of two selective antagonists of the ER, Fulvestrant (Fulv and Tamoxifen (Tam, on the invasive ability of breast cancer cells. We found that 17β-estradiol (E2 demonstrated a protective role regarding cell migration and invasion. Fulv did not alter this effect while Tam stimulated active cell migration according to an increase in Snail and a decrease in E-cadherin protein expression. Furthermore, both tested agents increased expression of matrix metalloproteinases (MMPs and enhanced invasive potential of breast cancer cells. These changes were in line with focal adhesion kinase (FAK rearrangement. Our data indicate that the anti-estrogens counteracted the protective role of E2 concerning migration and invasion since their effect was not limited to antiproliferative events. Although Fulv caused a less aggressive result compared to Tam, the benefits of hormonal therapy concerning invasion and metastasis yet remain to be investigated.

  10. Primary Cilia, Signaling Networks and Cell Migration

    DEFF Research Database (Denmark)

    Veland, Iben Rønn

    Primary cilia are microtubule-based, sensory organelles that emerge from the centrosomal mother centriole to project from the surface of most quiescent cells in the human body. Ciliary entry is a tightly controlled process, involving diffusion barriers and gating complexes that maintain a unique...... this controls directional cell migration as a physiological response. The ciliary pocket is a membrane invagination with elevated activity of clathrin-dependent endocytosis (CDE). In paper I, we show that the primary cilium regulates TGF-β signaling and the ciliary pocket is a compartment for CDE...... on formation of the primary cilium and CDE at the pocket region. The ciliary protein Inversin functions as a molecular switch between canonical and non-canonical Wnt signaling. In paper II, we show that Inversin and the primary cilium control Wnt signaling and are required for polarization and cell migration...

  11. Matrine suppresses invasion and metastasis of NCI-H1299 cells by enhancing microRNA-133a expression.

    Science.gov (United States)

    Liao, Hehe; Zhao, Xixi; Qu, Jinkun; Zhang, Jia; Cai, Hui

    2015-01-01

    Matrine has been proved to inhibit proliferation and induce apoptosis of human lung cancer cells. However, less studies involved in evaluating the effects and mechanism of matrine in cell migration and invasion of lung cancer. This study was aim to investigate the involvement of miR-133a in matrine's anti-invasion and anti-metastasis in lung cancer. MTT assay was used to assess the inhibition of proliferation effects of matrine in NCI-H1299 cells. Migration and invasion abilities of NCI-H1299 cells were investigated by Transwell assays. Expression of miR-133a was detected by real-time PCR. Anti-miR technique was applied to inhibit miR-133a in matrine treated HCI-H1299 cells. Real-time PCR and Western blotting were performed to evaluate the activation of EGFR/Akt/MMP-9 pathway. As results, matrine treatment significantly inhibited proliferation, migration and invasion of NCI-H1299 cells in a concentration-dependent manner, accompanied by significantly elevation of miR-133a expression. However, matrine failed to inhibit the metastatic ability when cells transfected with anti-miR-133a. Matrine treatment also suppressed activation of EGFR/Akt/MMP-9 pathway. The inhibitory effects of matrine on activation of EGFR pathway were also reversed by anti-miR-133a transfection in NCI-H1299 cells. In conclusion, matrine inhibited the invasion and metastasis of lung cancer cell by elevating expression of miR-133a which further suppressed activation of EGFR/Akt/MMP-9 pathway.

  12. Ezrin promotes invasion and migration of the MG63 osteosarcoma cell

    Institute of Scientific and Technical Information of China (English)

    Zhang Jian; Zuo Jianhong; Lei Mingsheng; Wu Song; Zang Xiaofang; Zhang Chaoyue

    2014-01-01

    Background Evidence shows that ezrin plays an important role in the development of some human malignancies.But the mechanism by which ezrin may affect tumor cell invasion and metastasis remains unclear.Methods In this study,the expression of ezrin was verified in osteosarcoma (OS) cells and tissues by comparison with normal bone cells and tissues using Western blotting.OS-MG63 were transfected with pcDNA3.1-ezrin or pGenesil-1/ shRNA-ezrin and the stably transfected cells were selected with G418 to yield the ezrin cell line.The OS-MG63 tumor cells were delivered by tail vein to female BALB/c to develop pulmonary metastasis model in vivo.Ezrin was identified as a direct target of miR-183 via a luciferase reporter carrying the 3'-untranslated region of ezrin.Migration assays and invasion assays were done with the transwells.Signaling pathway was studied by Western blotting and/or inhibitor.Results Ectopic overexpression of ezrin in OS cell line MG63 promoted tumor cell invasion and migration.Consistent with this,knockdown of ezrin inhibited tumor cell invasion and migration.Similar results were obtained in the experimental metastasis model in vivo.We identified ezrin as a direct target of miR-183.What is more,ectopic expression of ezrin could induce the expression of N-cadherin and enhance the activity of extracellular signal-regulated kinase (ERK) signaling.Conclusion Collectively,these results suggest that ezrin as a direct target of miR-183 promotes the aggressiveness of OS via increased N-cadherin and activating ERK signaling.

  13. FOXO3a promotes gastric cancer cell migration and invasion through the induction of cathepsin L

    Science.gov (United States)

    Zhang, Wen; Yuan, Wei; Zhao, Naiqing; Li, Qian; Cui, Yuehong; Wang, Yan; Li, Wei; Sun, Yihong; Liu, Tianshu

    2016-01-01

    Forkhead box O3A (FOXO3a) is an important transcription factor involved in various human cancers. However, the role of FOXO3a in regulating the invasion and metastasis of gastric cancer cells has not been clarified. Here, we report that FOXO3a overexpression promoted migration and invasion of gastric cancer cells by upregulating cathepsin L. FOXO3a knockdown suppressed migration and invasion and also downregulated cathepsin L expression in gastric cancer cells. Silencing cathepsin L in these cells suppressed FOXO3a overexpression-induced cell migration and invasion. Mechanistic studies revealed that FOXO3a increased cathepsin L promoter activation, and cathepsin L overexpression repressed E-cadherin expression, causing gastric cancer cells to undergo epithelial-mesenchymal transition (EMT). Our data reveal a previously unexplored function of FOXO3a in gastric cancer invasion by regulating proteins involved in extracellular matrix (ECM) degradation and EMT. We suggest that FOXO3a may be of prognostic value and a potential therapeutic target in blocking tumor metastasis. PMID:27127880

  14. Mitochondrial Ca{sup 2+} uniporter is critical for store-operated Ca{sup 2+} entry-dependent breast cancer cell migration

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Shihao [Department of Occupational Health and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong (China); Guangzhou No.12 Hospital, Guangzhou (China); Wang, Xubu [Department of Occupational Health and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong (China); Shen, Qiang [Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX (United States); Yang, Xinyi; Yu, Changhui; Cai, Chunqing [Department of Occupational Health and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong (China); Cai, Guoshuai [Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX (United States); Meng, Xiaojing, E-mail: xiaojingmeng@smu.edu.cn [Department of Occupational Health and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong (China); Zou, Fei, E-mail: zoufei616@163.com [Department of Occupational Health and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong (China)

    2015-02-27

    Metastasis of cancer cells is a complicated multistep process requiring extensive and continuous cytosolic calcium modulation. Mitochondrial Ca{sup 2+} uniporter (MCU), a regulator of mitochondrial Ca{sup 2+} uptake, has been implicated in energy metabolism and various cellular signaling processes. However, whether MCU contributes to cancer cell migration has not been established. Here we examined the expression of MCU mRNA in the Oncomine database and found that MCU is correlated to metastasis and invasive breast cancer. MCU inhibition by ruthenium red (RuR) or MCU silencing by siRNA abolished serum-induced migration in MDA-MB-231 breast cancer cells and reduced serum- or thapsigargin (TG)-induced store-operated Ca2+ entry (SOCE). Serum-induced migrations in MDA-MB-231 cells were blocked by SOCE inhibitors. Our results demonstrate that MCU plays a critical role in breast cancer cell migration by regulating SOCE. - Highlights: • MCU is correlated to metastasis and invasive breast cancer. • MCU inhibition abolished serum-induced migration in MDA-MB-231 breast cancer cells and reduced serum- or TG-induced SOCE. • Serum-induced migrations in MDA-MB-231 cells were blocked by SOCE inhibitors. • MCU plays a critical role in MDA-MB-231 cell migration by regulating SOCE.

  15. Leader cells regulate collective cell migration via Rac activation in the downstream signaling of integrin β1 and PI3K.

    Science.gov (United States)

    Yamaguchi, Naoya; Mizutani, Takeomi; Kawabata, Kazushige; Haga, Hisashi

    2015-01-07

    Collective cell migration plays a crucial role in several biological processes, such as embryonic development, wound healing, and cancer metastasis. Here, we focused on collectively migrating Madin-Darby Canine Kidney (MDCK) epithelial cells that follow a leader cell on a collagen gel to clarify the mechanism of collective cell migration. First, we removed a leader cell from the migrating collective with a micromanipulator. This then caused disruption of the cohesive migration of cells that followed in movement, called "follower" cells, which showed the importance of leader cells. Next, we observed localization of active Rac, integrin β1, and PI3K. These molecules were clearly localized in the leading edge of leader cells, but not in follower cells. Live cell imaging using active Rac and active PI3K indicators was performed to elucidate the relationship between Rac, integrin β1, and PI3K. Finally, we demonstrated that the inhibition of these molecules resulted in the disruption of collective migration. Our findings not only demonstrated the significance of a leader cell in collective cell migration, but also showed that Rac, integrin β1, and PI3K are upregulated in leader cells and drive collective cell migration.

  16. Acidic extracellular pH promotes prostate cancer bone metastasis by enhancing PC-3 stem cell characteristics, cell invasiveness and VEGF-induced vasculogenesis of BM-EPCs.

    Science.gov (United States)

    Huang, Sheng; Tang, Yubo; Peng, Xinsheng; Cai, Xingdong; Wa, Qingde; Ren, Dong; Li, Qiji; Luo, Jiaquan; Li, Liangping; Zou, Xuenong; Huang, Shuai

    2016-10-01

    Bone metastasis is a main cause of cancer-related mortality in patients with advanced prostate cancer. Emerging evidence suggests that the acidic extracellular microenvironment plays significant roles in the growth and metastasis of tumors. However, the effects of acidity on bone metastasis of PCa remain undefined. In the present study, PC-3 cells were cultured in acidic medium (AM; pH 6.5) or neutral medium (NM; pH 7.4), aiming to investigate the effects and possible mechanisms of acidic extracellular microenvironment in bone metastasis of PCa. Our results showed that AM can promote spheroid and colony formations, cell viability and expression of stem cell characteristic-related markers in PC-3 cells. Moreover, AM stimulates MMP-9 secretion and promotes invasiveness of PC-3 cells, and these effects can be inhibited by blocking of MMP-9. Furthermore, AM stimulates VEGF secretion of PC-3 and AM conditioned medium (CMAM) promotes vasculogenesis of BM-EPCs by increasing cell viability, migration, tube formation, which involved activating the phosphorylation of VEGFR-2, Akt and P38, when pH of NM conditioned medium (CMNM) was modulated the same as AM conditioned medium (CMAM). Further studies have shown that CMNM induced vasculogenesis of BM-EPCs can be inhibited by the inhibition of VEGFR2 with DMH4. These findings suggest that acidic extracellular microenvironment may have the potential to modulate prostate cancer bone metastasis by enhancing PC-3 stem cell characteristics, cell invasiveness and VEGF-induced vasculogenesis of BM-EPCs. Improved anticancer strategies should be designed to selectively target acidic tumor microenvironment.

  17. TNF-alpha-induced metastasis gene changes in MCF-7 cells

    Institute of Scientific and Technical Information of China (English)

    Xiaofeng Chen; Yongqian Shu; Wei Li; Yongmei Yin

    2008-01-01

    Objective: Studies have shown that TNF- a secreted by tumor cells and macrophages infiltrated into the tumor microenvironment might promote the metastasis of a variety of malignant cancers, including breast cancer. The present study was designed to detect global metastasis-related gene expression changes of MCF-7 cells treated by low dose TNF-a and to further explore the mechanisms by which TNF-a contributes to metastasis. Methods: MCF-7 cells were cultured and treated with low dose TNF-a (20 ng/ml), cDNA array analysis was applied to detect the metastasis related gene expressions. Results: A total of 36 gene expressions were significantly regulated by TNF-a. Functional analysis indicates that the altered genes belong to different functional group. Most of the genes changed may promote the metastasis of MCF-7 cells while the others may inhibit metastasis. The changes observed in gene expression following TNF-a were somewhat time dependent. Conclusion: TNF-a can enhance the invasive ability of MCF-7 cells, partly by regulating a series of metastasis related genes, and these genes may take part in every step of metastasis. Some of the genes deserve further study.

  18. CCR7 regulates cell migration and invasion through MAPKs in metastatic squamous cell carcinoma of head and neck.

    Science.gov (United States)

    Liu, Fa-Yu; Safdar, Jawad; Li, Zhen-Ning; Fang, Qi-Gen; Zhang, Xu; Xu, Zhong-Fei; Sun, Chang-Fu

    2014-12-01

    Migration and invasion of tumor cells are essential prerequisites for the formation of metastasis in malignant diseases. Previously, we have reported that CC chemokine receptor 7 (CCR7) regulates the mobility of squamous cell carcinoma of head and neck (SCCHN) cells through several pathways, such as integrin and cdc42. In this study, we investigated the connection between CCR7 and mitogen-activated protein kinase (MAPK) family members, and their influence on cell invasion and migration in metastatic SCCHN cells. Western blotting, immunostaining and fluorescence microcopy were used to detect the protein expression and distribution of MAPKs, and the Migration assay, Matrigel invasion assay and wound-healing assay to detect the role of MAPKs in CCR7 regulating cell mobility. To analyze the correlation between CCR7 and MAPK activity and clinicopathological factors immunohistochemical staining was emplyed. The results showed stimulation of CCL19 and the activation of CCR7 could induce ERK1/2 and JNK phosphorylation, while it had no efect on p38. After activation, ERK1/2 and JNK promoted E-cadherin low expression and Vimentin high expression. The MAPK pathway not only mediated CCR7 induced cell migration, but also mediated invasion speed. The immunohistochemistry results showed that CCR7 was correlated with the phosphorylation of ERK1/2 and JNK in SCCHN, and these molecules were all associated with lymph node metastasis. Therefore, our study demonstrates that MAPK members (ERK1/2 and JNK) play a key role in CCR7 regulating SCCHN metastasis.

  19. Determinants of leader cells in collective cell migration.

    NARCIS (Netherlands)

    Khalil, A.; Friedl, P.H.A.

    2010-01-01

    Collective migration is a basic mechanism of cell translocation during morphogenesis, wound repair and cancer invasion. Collective movement requires cells to retain cell-cell contacts, exhibit group polarization with defined front-rear asymmetry, and consequently move as one multicellular unit. Depe

  20. The Junctional Adhesion Molecule-B regulates JAM-C-dependent melanoma cell metastasis.

    Science.gov (United States)

    Arcangeli, Marie-Laure; Frontera, Vincent; Bardin, Florence; Thomassin, Jeanne; Chetaille, Bruno; Adams, Susanne; Adams, Ralf H; Aurrand-Lions, Michel

    2012-11-16

    Metastasis is a major clinical issue and results in poor prognosis for most cancers. The Junctional Adhesion Molecule-C (JAM-C) expressed by B16 melanoma and endothelial cells has been involved in metastasis of tumor cells through homophilic JAM-C/JAM-C trans-interactions. Here, we show that JAM-B expressed by endothelial cells contributes to murine B16 melanoma cells metastasis through its interaction with JAM-C on tumor cells. We further show that this adhesion molecular pair mediates melanoma cell adhesion to primary Lung Microvascular Endothelial Cells and that it is functional in vivo as demonstrated by the reduced metastasis of B16 cells in Jam-b deficient mice.

  1. Reciprocal control of cell proliferation and migration

    Directory of Open Access Journals (Sweden)

    De Donatis Alina

    2010-09-01

    Full Text Available Abstract In adult tissue the quiescent state of a single cell is maintained by the steady state conditions of its own microenvironment for what concern both cell-cell as well as cell-ECM interaction and soluble factors concentration. Physiological or pathological conditions can alter this quiescent state through an imbalance of both soluble and insoluble factors that can trigger a cellular phenotypic response. The kind of cellular response depends by many factors but one of the most important is the concentration of soluble cytokines sensed by the target cell. In addition, due to the intrinsic plasticity of many cellular types, every single cell is able, in response to the same stimulus, to rapidly switch phenotype supporting minimal changes of microenviromental cytokines concentration. Wound healing is a typical condition in which epithelial, endothelial as well as mesenchymal cells are firstly subjected to activation of their motility in order to repopulate the damaged region and then they show a strong proliferative response in order to successfully complete the wound repair process. This schema constitute the leitmotif of many other physiological or pathological conditions such as development vasculogenesis/angiogenesis as well as cancer outgrowth and metastasis. Our review focuses on the molecular mechanisms that control the starting and, eventually, the switching of cellular phenotypic outcome in response to changes in the symmetry of the extracellular environment.

  2. On-Chip Quantitative Measurement of Mechanical Stresses During Cell Migration with Emulsion Droplets

    Science.gov (United States)

    Molino, D.; Quignard, S.; Gruget, C.; Pincet, F.; Chen, Y.; Piel, M.; Fattaccioli, J.

    2016-07-01

    The ability of immune cells to migrate within narrow and crowded spaces is a critical feature involved in various physiological processes from immune response to metastasis. Several in-vitro techniques have been developed so far to study the behaviour of migrating cells, the most recent being based on the fabrication of microchannels within which cells move. To address the question of the mechanical stress a cell is able to produce during the encounter of an obstacle while migrating, we developed a hybrid microchip made of parallel PDMS channels in which oil droplets are sparsely distributed and serve as deformable obstacles. We thus show that cells strongly deform droplets while passing them. Then, we show that the microdevice can be used to study the influence of drugs on migration at the population level. Finally, we describe a quantitative analysis method of the droplet deformation that allows measuring in real-time the mechanical stress exerted by a single cell. The method presented herein thus constitutes a powerful analytical tool for cell migration studies under confinement.

  3. On-Chip Quantitative Measurement of Mechanical Stresses During Cell Migration with Emulsion Droplets

    Science.gov (United States)

    Molino, D.; Quignard, S.; Gruget, C.; Pincet, F.; Chen, Y.; Piel, M.; Fattaccioli, J.

    2016-01-01

    The ability of immune cells to migrate within narrow and crowded spaces is a critical feature involved in various physiological processes from immune response to metastasis. Several in-vitro techniques have been developed so far to study the behaviour of migrating cells, the most recent being based on the fabrication of microchannels within which cells move. To address the question of the mechanical stress a cell is able to produce during the encounter of an obstacle while migrating, we developed a hybrid microchip made of parallel PDMS channels in which oil droplets are sparsely distributed and serve as deformable obstacles. We thus show that cells strongly deform droplets while passing them. Then, we show that the microdevice can be used to study the influence of drugs on migration at the population level. Finally, we describe a quantitative analysis method of the droplet deformation that allows measuring in real-time the mechanical stress exerted by a single cell. The method presented herein thus constitutes a powerful analytical tool for cell migration studies under confinement. PMID:27373558

  4. Independent regulation of tumor cell migration by matrix stiffness and confinement

    Science.gov (United States)

    Pathak, Amit; Kumar, Sanjay

    2012-01-01

    Tumor invasion and metastasis are strongly regulated by biophysical interactions between tumor cells and the extracellular matrix (ECM). While the influence of ECM stiffness on cell migration, adhesion, and contractility has been extensively studied in 2D culture, extension of this concept to 3D cultures that more closely resemble tissue has proven challenging, because perturbations that change matrix stiffness often concurrently change cellular confinement. This coupling is particularly problematic given that matrix-imposed steric barriers can regulate invasion speed independent of mechanics. Here we introduce a matrix platform based on microfabrication of channels of defined wall stiffness and geometry that allows independent variation of ECM stiffness and channel width. For a given ECM stiffness, cells confined to narrow channels surprisingly migrate faster than cells in wide channels or on unconstrained 2D surfaces, which we attribute to increased polarization of cell-ECM traction forces. Confinement also enables cells to migrate increasingly rapidly as ECM stiffness rises, in contrast with the biphasic relationship observed on unconfined ECMs. Inhibition of nonmuscle myosin II dissipates this traction polarization and renders the relationship between migration speed and ECM stiffness comparatively insensitive to matrix confinement. We test these hypotheses in silico by devising a multiscale mathematical model that relates cellular force generation to ECM stiffness and geometry, which we show is capable of recapitulating key experimental trends. These studies represent a paradigm for investigating matrix regulation of invasion and demonstrate that matrix confinement alters the relationship between cell migration speed and ECM stiffness. PMID:22689955

  5. Numerical solutions for a model of tissue invasion and migration of tumour cells.

    Science.gov (United States)

    Kolev, M; Zubik-Kowal, B

    2011-01-01

    The goal of this paper is to construct a new algorithm for the numerical simulations of the evolution of tumour invasion and metastasis. By means of mathematical model equations and their numerical solutions we investigate how cancer cells can produce and secrete matrix degradative enzymes, degrade extracellular matrix, and invade due to diffusion and haptotactic migration. For the numerical simulations of the interactions between the tumour cells and the surrounding tissue, we apply numerical approximations, which are spectrally accurate and based on small amounts of grid-points. Our numerical experiments illustrate the metastatic ability of tumour cells.

  6. Expression Profile of Metastasis-associated Genes in Esophageal Squamous Cell Carcinoma

    Institute of Scientific and Technical Information of China (English)

    LI Pei; LING Zhiqiang; YANG Hongyan; HUANG Youtian; ZHAO Mingyao; ZHENG Zhimin; DONG Ziming

    2006-01-01

    The differentially expressed genes between esophageal squamous cell carcinoma (ESCC)with or without lymphatic metastasis were investigated by gene chip, and the lymphatic metastasisassociated genes were screened out. Expression array was used to detect the mRNA from both the primary carcinoma and the corresponding esophageal epithelium in 15 cases of human ESCC. The lymphatic metastasis-associated genes were screened by bioinformatics between ESCC with or without lymphatic metastasis. The results showed that 43 (4.85%) genes significantly differed between the ESCC with and without lymphatic metastasis (P<0.05), of which 18(2.03%)were upregulated and 25 (2.82 %) down-regulated. The up-regulated genes were involved in cell adhesion molecules and cell membrane receptors and the down-regulated genes were mostly cell cycle regulators and intracellular signaling molecules. It was suggested that lymphatic metastasis-associated genes were screened by gene chip, which was helpful to understand the molecular mechanism of ESCC lymphatic metastasis and lymphatic metastasis-associated genes might be used as diagnostic markers and therapeutic targets for lymphatic metastasis.

  7. Optimal chemotaxis in animal cell intermittent migration

    CERN Document Server

    Romanczuk, Pawel

    2015-01-01

    Animal cells can sense chemical gradients without moving, and are faced with the challenge of migrating towards a target despite noisy information on the target position. Here we discuss optimal search strategies for a chaser that moves by switching between two phases of motion ("run" and "tumble"), reorienting itself towards the target during tumble phases, and performing a persistent random walk during run phases. We show that the chaser average run time can be adjusted to minimize the target catching time or the spatial dispersion of the chasers. We obtain analytical results for the catching time and for the spatial dispersion in the limits of small and large ratios of run time to tumble time, and scaling laws for the optimal run times. Our findings have implications for optimal chemotactic strategies in animal cell migration.

  8. Mitochondrial Ca²⁺ uniporter is critical for store-operated Ca²⁺ entry-dependent breast cancer cell migration.

    Science.gov (United States)

    Tang, Shihao; Wang, Xubu; Shen, Qiang; Yang, Xinyi; Yu, Changhui; Cai, Chunqing; Cai, Guoshuai; Meng, Xiaojing; Zou, Fei

    2015-02-27

    Metastasis of cancer cells is a complicated multistep process requiring extensive and continuous cytosolic calcium modulation. Mitochondrial Ca(2+) uniporter (MCU), a regulator of mitochondrial Ca(2+) uptake, has been implicated in energy metabolism and various cellular signaling processes. However, whether MCU contributes to cancer cell migration has not been established. Here we examined the expression of MCU mRNA in the Oncomine database and found that MCU is correlated to metastasis and invasive breast cancer. MCU inhibition by ruthenium red (RuR) or MCU silencing by siRNA abolished serum-induced migration in MDA-MB-231 breast cancer cells and reduced serum- or thapsigargin (TG)-induced store-operated Ca2+ entry (SOCE). Serum-induced migrations in MDA-MB-231 cells were blocked by SOCE inhibitors. Our results demonstrate that MCU plays a critical role in breast cancer cell migration by regulating SOCE.

  9. RNA-Based TWIST1 Inhibition via Dendrimer Complex to Reduce Breast Cancer Cell Metastasis

    Directory of Open Access Journals (Sweden)

    James Finlay

    2015-01-01

    Full Text Available Breast cancer is the leading cause of cancer-related deaths among women in the United States, and survival rates are lower for patients with metastases and/or triple-negative breast cancer (TNBC; ER, PR, and Her2 negative. Understanding the mechanisms of cancer metastasis is therefore crucial to identify new therapeutic targets and develop novel treatments to improve patient outcomes. A potential target is the TWIST1 transcription factor, which is often overexpressed in aggressive breast cancers and is a master regulator of cellular migration through epithelial-mesenchymal transition (EMT. Here, we demonstrate an siRNA-based TWIST1 silencing approach with delivery using a modified poly(amidoamine (PAMAM dendrimer. Our results demonstrate that SUM1315 TNBC cells efficiently take up PAMAM-siRNA complexes, leading to significant knockdown of TWIST1 and EMT-related target genes. Knockdown lasts up to one week after transfection and leads to a reduction in migration and invasion, as determined by wound healing and transwell assays. Furthermore, we demonstrate that PAMAM dendrimers can deliver siRNA to xenograft orthotopic tumors and siRNA remains in the tumor for at least four hours after treatment. These results suggest that further development of dendrimer-based delivery of siRNA for TWIST1 silencing may lead to a valuable adjunctive therapy for patients with TNBC.

  10. TIPE2 inhibits TNF-α-induced hepatocellular carcinoma cell metastasis via Erk1/2 downregulation and NF-κB activation.

    Science.gov (United States)

    Zhang, Yue Hua; Yan, Hong Qiong; Wang, Fang; Wang, Yan Yan; Jiang, Yi Na; Wang, Yi Nan; Gao, Feng Guang

    2015-01-01

    Tumor necrosis factor-α-induced protein 8-like 2 (TNFAIP8L2, TIPE2), which belongs to the TNF-α-induced protein 8 family, is a negative regulator of immune homeostasis. Although pro-inflammatory cytokines such as TNF-α have been reported to be involved in liver carcinoma metastasis, the effect of TIPE2 on hepatocellular carcinoma metastasis remains unknown. We demonstrate that TNF-α clearly augments MMP-13/MMP-3 expression and promotes cell migration in HepG2 cells through activation of the Erk1/2-NF-κB pathways. Interestingly, in addition to human PBLs, macrophages and fibroblasts, liver cancer cells specifically express TNF-α following LPS treatment. Most importantly, TIPE2 overexpression efficiently abrogates the effects of LPS on TNF-α secretion and abolishes the effects of TNF-α on MMP-13/MMP-3 upregulation, cell migration and Erk1/2-NF-κB activation. Taken together, these findings demonstrate that TIPE2 was able to suppress TNF-α-induced hepatocellular carcinoma metastasis by inhibiting Erk1/2 and NF-κB activation, indicating that both TNF-α and TIPE2 might be potential targets for the treatment of HCC metastasis.

  11. SLUG promotes prostate cancer cell migration and invasion via CXCR4/CXCL12 axis

    Directory of Open Access Journals (Sweden)

    Uygur Berna

    2011-11-01

    Full Text Available Abstract Background SLUG is a zinc-finger transcription factor of the Snail/Slug zinc-finger family that plays a role in migration and invasion of tumor cells. Mechanisms by which SLUG promotes migration and invasion in prostate cancers remain elusive. Methods Expression level of CXCR4 and CXCL12 was examined by Western blot, RT-PCR, and qPCR analyses. Forced expression of SLUG was mediated by retroviruses, and SLUG and CXCL12 was downregulated by shRNAs-expressing lentiviruses. Migration and invasion of prostate cancer were measured by scratch-wound assay and invasion assay, respectively. Research We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. Furthermore, ectopic expression of SLUG increased MMP9 expression and activity in PC3, 22RV1, and DU-145 cells, and SLUG knockdown by shRNA downregulated MMP9 expression. We showed that CXCL12 is required for SLUG-mediated MMP9 expression in prostate cancer cells. Moreover, we found that migration and invasion of prostate cancer cells was increased by ectopic expression of SLUG and decreased by SLUG knockdown. Notably, knockdown of CXCL12 by shRNA impaired SLUG-mediated migration and invasion in prostate cancer cells. Lastly, our data suggest that CXCL12 and SLUG regulate migration and invasion of prostate cancer cells independent of cell growth. Conclusion We provide the first compelling evidence that upregulation of autocrine CXCL12 is a major mechanism underlying SLUG-mediated migration and invasion of prostate cancer cells. Our findings suggest that CXCL12 is a therapeutic target for prostate cancer metastasis.

  12. Repositioning "old" drugs for new causes: identifying new inhibitors of prostate cancer cell migration and invasion.

    Science.gov (United States)

    Shah, Esha T; Upadhyaya, Akanksha; Philp, Lisa K; Tang, Tiffany; Skalamera, Dubravka; Gunter, Jennifer; Nelson, Colleen C; Williams, Elizabeth D; Hollier, Brett G

    2016-04-01

    The majority of prostate cancer (PCa) deaths occur due to the metastatic spread of tumor cells to distant organs. Currently, there is a lack of effective therapies once tumor cells have spread outside the prostate. It is therefore imperative to rapidly develop therapeutics to inhibit the metastatic spread of tumor cells. Gain of cell motility and invasive properties is the first step of metastasis and by inhibiting motility one can potentially inhibit metastasis. Using the drug repositioning strategy, we developed a cell-based multi-parameter primary screening assay to identify drugs that inhibit the migratory and invasive properties of metastatic PC-3 PCa cells. Following the completion of the primary screening assay, 33 drugs were identified from an FDA approved drug library that either inhibited migration or were cytotoxic to the PC-3 cells. Based on the data obtained from the subsequent validation studies, mitoxantrone hydrochloride, simvastatin, fluvastatin and vandetanib were identified as strong candidates that can inhibit both the migration and invasion of PC-3 cells without significantly affecting cell viability. By employing the drug repositioning strategy instead of a de novo drug discovery and development strategy, the identified drug candidates have the potential to be rapidly translated into the clinic for the management of men with aggressive forms of PCa.

  13. KAI1/CD82 suppresses hepatocyte growth factor-induced migration of hepatoma cells via upregulation of Sprouty2

    Institute of Scientific and Technical Information of China (English)

    MU ZhenBin; WANG Hua; ZHANG Jing; LI QingFang; WANG LiSheng; GUO XiaoZhong

    2008-01-01

    We conducted a study concerning the suppressive mechanism of KAI1/CD82 on hepatoma cell metas-tasis. Hepatocyte growth factor (HGF) induces the migration of hepatoma cells through activation of cellular sphingosine kinase 1 (SphK1). Adenovirus-mediated gene transfer of KAI1 (Ad-KAI1) down-regulates the SphK1 expression and suppresses the HGF-induced migration of SMMC-7721 human hepatocellcular carcinoma cells. Overexpression of KAI1/CD82 significantly elevates Sprouty2 at the protein level. Ablation of Sprouty2 with RNA interference can block the KAI1/CD82-induced suppres-sion of hepatoma cell migration and downregulation of SphK1 expression. It is demonstrated that KAI1/CD82 suppresses HGF-induced migration of hepatoma cells via upregulation of Sprouty2.

  14. KAI1/CD82 suppresses hepatocyte growth factorinduced migration of hepatoma cells via upregulation of Sprouty2

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    We conducted a study concerning the suppressive mechanism of KAI1/CD82 on hepatoma cell metastasis.Hepatocyte growth factor(HGF)induces the migration of hepatoma cells through activation of cellular sphingosine kinase 1(SphK1).Adenovirus-mediated gene transfer of KAI1(Ad-KAI1)downregulates the SphK1 expression and suppresses the HGF-induced migration of SMMC-7721 human hepatocellcular carcinoma cells.Overexpression of KAI1/CD82 significantly elevates Sprouty2 at the protein level.Ablation of Sprouty2 with RNA interference can block the KAI1/CD82-induced suppression of hepatoma cell migration and downregulation of SphK1 expression.It is demonstrated that KAI1/CD82 suppresses HGF-induced migration of hepatoma cells via upregulation of Sprouty2.

  15. Screening and target identification of bioactive compounds that modulate cell migration and autophagy.

    Science.gov (United States)

    Tashiro, Etsu; Imoto, Masaya

    2016-08-01

    Cell migration is a fundamental step for embryonic development, wound repair, immune responses, and tumor cell invasion and metastasis. It is well known that protrusive structures, namely filopodia and lamellipodia, can be observed at the leading edge of migrating cells. The formation of these structures is necessary for cell migration; however, the molecular mechanisms behind the formation of these structures remain largely unclear. Therefore, bioactive compounds that modulate protrusive structures are extremely powerful tools for studying the mechanisms behind the formation of these structures and subsequent cell migration. Therefore, we have screened for bioactive compounds that inhibit the formation of filopodia, lamellipodia, or cell migration from natural products, and attempted to identify the target molecules of our isolated compounds. Additionally, autophagy is a bulk, non-specific protein degradation system that is involved in the pathogenesis of cancer and neurodegenerative disorders. Recent extensive studies have revealed the molecular mechanisms of autophagy, however, they also remain largely unclear. Thus, we also have screened for bioactive compounds that modulate autophagy, and identified the target molecules. In the present article, we introduce the phenotypic screening system and target identification of four bioactive compounds.

  16. Inhibition of IGF-1-Mediated Cellular Migration and Invasion by Migracin A in Ovarian Clear Cell Carcinoma Cells.

    Directory of Open Access Journals (Sweden)

    Tamami Ukaji

    Full Text Available Previously we isolated migracin A from a Streptomyces culture filtrate as an inhibitor of cancer cell migration. In the present research, we found that migracin A inhibited migration and invasion of ovarian clear cell carcinoma ES-2 cells. In the course of our mechanistic study, migracin A was shown to enhance vasohibin-1 expression in an angiogenesis array. We also confirmed that it increased the mRNA expression of this protein. Moreover, overexpression of vasohibin-1 lowered the migration but not the invasion of ES-2 cells. Then, we looked for another target protein employing a motility array, and found that migracin A lowered the IGF-1 expression. Knockdown of IGF-1 by siRNA decreased the migration and invasion of ES-2 cells. Migracin A also decreased Akt phosphorylation involved in the downstream signaling. Crosstalk analysis indicated that overexpression of vasohibin-1 decreased the IGF-1 expression. On the other hand, it showed no direct anticancer activity in terms of the ES-2 growth in agar. Migracin A inhibited the migration and IGF-1 expression in not only ES-2 but also another ovarian clear cell carcinoma JHOC-5 cells. In addition, it also inhibited capillary tube formation of human umbilical vein endothelial cells. Since its cytotoxicity is very low, migracin A may be a candidate for an anti-metastasis agent not exhibiting prominent toxicity.

  17. Serpins promote cancer cell survival and vascular co-option in brain metastasis.

    Science.gov (United States)

    Valiente, Manuel; Obenauf, Anna C; Jin, Xin; Chen, Qing; Zhang, Xiang H-F; Lee, Derek J; Chaft, Jamie E; Kris, Mark G; Huse, Jason T; Brogi, Edi; Massagué, Joan

    2014-02-27

    Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers.

  18. Aqueous biphasic cancer cell migration assay enables robust, high-throughput screening of anti-cancer compounds.

    Science.gov (United States)

    Lemmo, Stephanie; Nasrollahi, Samila; Tavana, Hossein

    2014-03-01

    Migration of tumor cells is a fundamental event implicated in metastatic progression of cancer. Therapeutic compounds with the ability to inhibit the motility of cancer cells are critical for preventing cancer metastasis. Achieving this goal requires new technologies that enable high-throughput drug screening against migration of cancer cells and expedite drug discovery. We report an easy-to-implement, robotically operated, cell migration microtechnology with the capability of simultaneous screening of multiple compounds. The technology utilizes a fully biocompatible polymeric aqueous two-phase system to pattern a monolayer of cells containing a cell-excluded gap that serves as the migration niche. We adapted this technology to a standard 96-well plate format and parametrically optimized it to generate highly consistent migration niches. The analysis of migration is done automatically using computerized schemes. We use statistical metrics and show the robustness of this assay for drug screening and its sensitivity to identify effects of different drug compounds on migration of cancer cells. This technology can be employed in core centers, research laboratories, and pharmaceutical industries to evaluate the efficacy of compounds against migration of various types of metastatic cancer cells prior to expensive animal tests and thus, streamline anti-migratory drug screening.

  19. Taking Aim at Moving Targets in Computational Cell Migration.

    Science.gov (United States)

    Masuzzo, Paola; Van Troys, Marleen; Ampe, Christophe; Martens, Lennart

    2016-02-01

    Cell migration is central to the development and maintenance of multicellular organisms. Fundamental understanding of cell migration can, for example, direct novel therapeutic strategies to control invasive tumor cells. However, the study of cell migration yields an overabundance of experimental data that require demanding processing and analysis for results extraction. Computational methods and tools have therefore become essential in the quantification and modeling of cell migration data. We review computational approaches for the key tasks in the quantification of in vitro cell migration: image pre-processing, motion estimation and feature extraction. Moreover, we summarize the current state-of-the-art for in silico modeling of cell migration. Finally, we provide a list of available software tools for cell migration to assist researchers in choosing the most appropriate solution for their needs.

  20. Navigator-3, a modulator of cell migration, may act as a suppressor of breast cancer progression

    Science.gov (United States)

    Cohen-Dvashi, Hadas; Ben-Chetrit, Nir; Russell, Roslin; Carvalho, Silvia; Lauriola, Mattia; Nisani, Sophia; Mancini, Maicol; Nataraj, Nishanth; Kedmi, Merav; Roth, Lee; Köstler, Wolfgang; Zeisel, Amit; Yitzhaky, Assif; Zylberg, Jacques; Tarcic, Gabi; Eilam, Raya; Wigelman, Yoav; Will, Rainer; Lavi, Sara; Porat, Ziv; Wiemann, Stefan; Ricardo, Sara; Schmitt, Fernando; Caldas, Carlos; Yarden, Yosef

    2015-01-01

    Dissemination of primary tumor cells depends on migratory and invasive attributes. Here, we identify Navigator-3 (NAV3), a gene frequently mutated or deleted in human tumors, as a regulator of epithelial migration and invasion. Following induction by growth factors, NAV3 localizes to the plus ends of microtubules and enhances their polarized growth. Accordingly, NAV3 depletion trimmed microtubule growth, prolonged growth factor signaling, prevented apoptosis and enhanced random cell migration. Mathematical modeling suggested that NAV3-depleted cells acquire an advantage in terms of the way they explore their environment. In animal models, silencing NAV3 increased metastasis, whereas ectopic expression of the wild-type form, unlike expression of two, relatively unstable oncogenic mutants from human tumors, inhibited metastasis. Congruently, analyses of > 2,500 breast and lung cancer patients associated low NAV3 with shorter survival. We propose that NAV3 inhibits breast cancer progression by regulating microtubule dynamics, biasing directionally persistent rather than random migration, and inhibiting locomotion of initiated cells. PMID:25678558

  1. First Evidence that Ecklonia cava-Derived Dieckol Attenuates MCF-7 Human Breast Carcinoma Cell Migration

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    Eun-Kyung Kim

    2015-03-01

    Full Text Available We investigated the effect of Ecklonia cava (E. cava-derived dieckol on movement behavior and the expression of migration-related genes in MCF-7 human breast cancer cell. Phlorotannins (e.g., dieckol, 6,6′-biecko, and 2,7″-phloroglucinol-6,6′-bieckol were purified from E. cava by using centrifugal partition chromatography. Among the phlorotannins, we found that dieckol inhibited breast cancer cell the most and was selected for further study. Radius™-well was used to assess cell migration, and dieckol (1–100 µM was found to suppress breast cancer cell movement. Metastasis-related gene expressions were evaluated by RT-PCR and Western blot analysis. In addition, dieckol inhibited the expression of migration-related genes such as matrix metalloproteinase (MMP-9 and vascular endothelial growth factor (VEGF. On the other hand, it stimulated the expression of tissue inhibitor of metalloproteinase (TIMP-1 and TIMP-2. These results suggest that dieckol exerts anti-breast cancer activity via the regulation of the expressions of metastasis-related genes, and this is the first report on the anti-breast cancer effect of dieckol.

  2. Downregulation of discoidin domain receptor 2 in A375 human melanoma cells reduces its experimental liver metastasis ability.

    Science.gov (United States)

    Badiola, Iker; Villacé, Patricia; Basaldua, Iratxe; Olaso, Elvira

    2011-10-01

    Discoidin domain receptors (DDR1 and DDR2) are tyrosine kinase receptors for fibrillar collagen implicated in postnatal development, tissue repair, and primary and metastatic cancer progression. While DDR1 has been described in tumor cells, DDR2 has been localized in the tumor stroma, but its presence in the tumor cells remains unknown. The aim of this study was to elucidate the role of DDR2 signaling in tumor cells during hepatic metastasis progression. DDR2 expression and phosphorylation in cultured human A375 melanoma cells was documented by Western blot analysis. A375 cells were stably transfected with a small interfering RNA (siRNA) against DDR2 and two clones were selected: A375R2-70 and A375R2-40, with 70 and 40% of the DDR2 protein expression respectively, compared to mock-transfected cells (A375R2-100). Development of experimental liver metastasis by intrasplenic inoculation of A375R2-70 and A37R2-40 clones was reduced by 60 and 75%, respectively, measured as tumor volume, compared to livers injected with A375R2-100 cells. Accordingly, A375R2-70 and A37R2-40 clones showed reduced in vitro gelatinase activity and JNK phosphorylation, compared to mock transfected cells, with maximal inhibition in A375R2-40. Additionally, A375 melanoma, SK-HEP hepatoma and HT-29 colon carcinoma human cell lines transiently transfected with siRNA against DDR2 also showed reduced proliferation and migration rates compared to mock-transfected ones. In conclusion, DDR2 promotes A375 melanoma metastasis to the liver and the underlying mechanism implicates regulation of metalloproteinase release, cell growth and chemotactic invasion of the host tissue.

  3. Collective cell migration: Implications for wound healing and cancer invasion

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    Li Li

    2013-07-01

    Full Text Available During embryonic morphogenesis, wound repair and cancer invasion, cells often migrate collectively via tight cell-cell junctions, a process named collective migration. During such migration, cells move as coherent groups, large cell sheets, strands or tubes rather than individually. One unexpected finding regarding collective cell migration is that being a "multicellular structure" enables cells to better respond to chemical and physical cues, when compared with isolated cells. This is important because epithelial cells heal wounds via the migration of large sheets of cells with tight intercellular connections. Recent studies have gained some mechanistic insights that will benefit the clinical understanding of wound healing in general. In this review, we will briefly introduce the role of collective cell migration in wound healing, regeneration and cancer invasion and discuss its underlying mechanisms as well as implications for wound healing.

  4. Isolation of Soil Microorganisms Having Antibacterial Activity and Antimigratory Effects on Sphingosylphosphorylcholine-induced Migration of PANC-1 Cells.

    Science.gov (United States)

    Kang, Jun Hee; Park, Mi Kyung; Kim, Hyun Ji; Kim, Yuri; Lee, Chang Hoon

    2011-12-01

    To obtain soil microorganisms producing antimigratory activity which is important in controlling the metastasis of cancer cells, more than three hundreds of soil microbes were isolated from sixteen soil sources including Namsan mountain and designated as DGU1001-10338. At first, their antibiotic activities were examined by paper-disc method. More than 40 soil microbes produced compounds with antibiotic activity. Then, antimigratory activities of selected soil microorganisms were examined in a sphingosylphosphorylcholine-induced migration assay in PANC-1 cells. Six of 42 soil microorganisms having antibacterial activity also had more than 45% inhibitory activity on migration of PANC-1 cells. These results suggested that selected soil microorganisms were a useful starting point to find compounds for controlling metastasis of cancer cells.

  5. Loss of myoferlin redirects breast cancer cell motility towards collective migration.

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    Leonithas I Volakis

    Full Text Available Cell migration plays a central role in the invasion and metastasis of tumors. As cells leave the primary tumor, they undergo an epithelial to mesenchymal transition (EMT and migrate as single cells. Epithelial tumor cells may also migrate in a highly directional manner as a collective group in some settings. We previously discovered that myoferlin (MYOF is overexpressed in breast cancer cells and depletion of MYOF results in a mesenchymal to epithelial transition (MET and reduced invasion through extracellular matrix (ECM. However, the biomechanical mechanisms governing cell motility during MYOF depletion are poorly understood. We first demonstrated that lentivirus-driven shRNA-induced MYOF loss in MDA-MB-231 breast cancer cells (MDA-231(MYOF-KD leads to an epithelial morphology compared to the mesenchymal morphology observed in control (MDA-231(LTVC and wild-type cells. Knockdown of MYOF led to significant reductions in cell migration velocity and MDA-231(MYOF-KD cells migrated directionally and collectively, while MDA-231(LTVC cells exhibited single cell migration. Decreased migration velocity and collective migration were accompanied by significant changes in cell mechanics. MDA-231(MYOF-KD cells exhibited a 2-fold decrease in cell stiffness, a 2-fold increase in cell-substrate adhesion and a 1.5-fold decrease in traction force generation. In vivo studies demonstrated that when immunocompromised mice were implanted with MDA-231(MYOF-KD cells, tumors were smaller and demonstrated lower tumor burden. Moreover, MDA-231(MYOF-KD tumors were highly circularized and did not invade locally into the adventia in contrast to MDA-231(LTVC-injected animals. Thus MYOF loss is associated with a change in tumor formation in xenografts and leads to smaller, less invasive tumors. These data indicate that MYOF, a previously unrecognized protein in cancer, is involved in MDA-MB-231 cell migration and contributes to biomechanical alterations. Our results indicate

  6. Trefoil factor 3 peptide regulates migration via a Twist-dependent pathway in gastric cell.

    Science.gov (United States)

    Zheng, Qianqian; Gao, Jian; Li, Honglin; Guo, Wendong; Mao, Qi; Gao, Enhui; Zhu, Ya-qin

    2013-08-16

    Trefoil factor 3 (TFF3) is a member of the TFF-domain peptide family and essential in regulating cell migration and maintaining mucosal integrity in gastrointestinal tract. However, the role of TFF3 and its downstream regulating mechanisms in cancer cell migration remain unclear. We previously reported that TFF3 prolonged the up-regulation of Twist protein to modulate IL-8 secretion in intestinal epithelial cells. In this study, we investigated the role of Twist protein in TFF3-induced migration of SGC7901 cells. While Twist was activated by TFF3, siRNA-mediated knockdown of Twist abolished TFF3-induced cell migration. Furthermore, the migration related marker CK-8 as well as ZO-1 and MMP-9 was also regulated by TFF3 via a Twist-dependent mechanism. Our study suggests that Twist, as an important potential downstream effector, plays a key role in TFF3-modulated metastasis in gastric cancer and can be a promising therapeutic target against intestinal-type gastric cancer.

  7. Cardiotoxin III suppresses MDA-MB-231 cell metastasis through the inhibition of EGF/EGFR-mediated signaling pathway.

    Science.gov (United States)

    Tsai, Pei-Chien; Hsieh, Chi-Ying; Chiu, Chien-Chih; Wang, Chih-Kuang; Chang, Long-Sen; Lin, Shinne-Ren

    2012-10-01

    Cardiotoxin III (CTX III), a basic polypeptide isolated from Naja naja atra venom, has been shown to exhibit anticancer activity. Epidermal growth factor (EGF) and its receptor, EGFR, play roles in cancer metastasis in various tumors. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CTX III on cell migration. CTX III inhibited the EGF-induced activation of matrix metalloproteinase-9 (MMP-9), and further suppressed cell invasion and migration without obvious cellular cytotoxicity. CTX III suppressed EGF-induced nuclear factor-kappaB (NF-κB) nuclear translocation and also abrogated the EGF-induced phosphorylation of EGFR, phosphatidylinositol 3-kinase (PI3K)/Akt, and extracellular regulated kinase (ERK)1/2. In addition, CTX III similar to wortmannin (a PI3K inhibitor) and U0126 (an up-stream kinase regulating ERK1/2 inhibitor) attenuated cell migration and invasion induced by EGF. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of ERK1/2 and PI3K/Akt, suggesting that ERK1/2 and PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that CTX III inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt, ERK1/2, and NF-κB signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of CTX III as a potent anti-metastatic agent in MDA-MB-231 cells.

  8. HOXA5 inhibits metastasis via regulating cytoskeletal remodelling and associates with prolonged survival in non-small-cell lung carcinoma.

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    Chi-Chung Wang

    Full Text Available Homeobox genes comprise a family of regulatory genes that contain a common homeobox domain and act as transcription factors. Recent studies indicate that homeobox A5 (HOXA5 may serve as a tumour suppressor gene in breast cancers. However, the precise role and the underlying mechanism of HOXA5 in lung cancer remain unclear. Oligonucleotide microarrays and an invasion/metastasis lung adenocarcinoma cell line model were used to determine the correlation between HOXA5 expression and cancer cell invasion ability. We found that ectopic expression of HOXA5 in highly invasive cancer cells suppressed cell migration, invasion, and filopodia formation in vitro and inhibited metastatic potential in vivo. Knockdown of HOXA5 promoted the invasiveness of lung cancer cells. In addition, HOXA5 expression was associated with better clinical outcome in non-small cell lung cancer patients with wild-type EGFR. Furthermore, genome-wide transcriptomic and pathway analyses were performed to identify the potential molecular mechanisms. Our data showed that HOXA5 may bind to the promoters of the cytoskeleton-related genes and downregulate their mRNA and protein expression levels. Our studies provide new insights into how HOXA5 may contribute to the suppression of metastasis in lung cancer via cytoskeleton remodelling regulation. Therefore, targeted induction of HOXA5 may represent a promising approach for non-small-cell lung cancer therapy.

  9. Apigenin Attenuates Melanoma Cell Migration by Inducing Anoikis through Integrin and Focal Adhesion Kinase Inhibition.

    Science.gov (United States)

    Hasnat, Md Abul; Pervin, Mehnaz; Lim, Ji Hong; Lim, Beong Ou

    2015-11-27

    Apigenin, a nonmutagenic flavonoid, has been found to have antitumor properties and is therefore particularly relevant for the development of chemotherapeutic agents for cancers. In this study, time- and dose-dependent cell viability and cytotoxicity were assessed to determine the effects of apigenin on A2058 and A375 melanoma cells. Melanoma cells were pretreated with different concentrations of apigenin and analyzed for morphological changes, anoikis induction, cell migration, and levels of proteins associated with apoptosis. Apigenin reduced integrin protein levels and inhibited the phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK1/2), which induce anoikis in human cutaneous melanoma cells. Apigenin exhibited dose-dependent inhibition of melanoma cell migration, unlike untreated controls. Furthermore, apigenin treatment increased apoptotic factors such as caspase-3 and cleaved poly(ADP-ribose) polymerase in a dose-dependent manner, demonstrating the metastasis of melanoma cells. Our results provide a new insight into the mechanisms by which apigenin prevents melanoma metastasis by sensitizing anoikis induced by the loss of integrin proteins in the FAK/ERK1/2 signaling pathway. These findings elucidate the related mechanisms and suggest the potential of apigenin in developing clinical treatment strategies against malignant melanoma.

  10. Regulator of G protein signaling 20 enhances cancer cell aggregation, migration, invasion and adhesion.

    Science.gov (United States)

    Yang, Lei; Lee, Maggie M K; Leung, Manton M H; Wong, Yung H

    2016-11-01

    Several RGS (regulator of G protein signaling) proteins are known to be upregulated in a variety of tumors but their roles in modulating tumorigenesis remain undefined. Since the expression of RGS20 is elevated in metastatic melanoma and breast tumors, we examined the effects of RGS20 overexpression and knockdown on the cell mobility and adhesive properties of different human cancer cell lines, including cervical cancer HeLa, breast adenocarcinoma MDA-MB-231, and non-small cell lung carcinoma H1299 and A549 cells. Expression of RGS20 enhanced cell aggregation, migration, invasion and adhesion as determined by hanging drop aggregation, wound healing, transwell chamber migration and invasion assays. Conversely, shRNA-mediated knockdown of endogenous RGS20 impaired these responses. In addition, RGS20 elevated the expression of vimentin (a mesenchymal cell marker) but down-regulated the expression of E-cadherin, two indicators commonly associated with metastasis. These results suggest that the expression of RGS20 may promote metastasis of tumor cells.

  11. Role of the Endothelium during Tumor Cell Metastasis: Is the Endothelium a Barrier or a Promoter for Cell Invasion and Metastasis?

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    Claudia Tanja Mierke

    2008-01-01

    Full Text Available The malignancy of cancer disease depends on the ability of the primary tumor to metastasize to distant organs. The process of the metastasis formation has largely been analyzed, but still main pathways regarding the extravasation step at the end of the metastasis formation process are controversially discussed. An agreement has been reached about the importance of the endothelium to promote metastasis formation either by enhancing the growth of the primary tumor or by homing (targeting the tumor cells to blood or lymph vessels. The mechanical properties of the invading tumor cells become the focus of several studies, but the endothelial cell mechanical properties are still elusive. This paper describes the different roles of the endothelium in the process of metastasis formation and focuses on a novel role of the endothelium in promoting tumor cell invasion. It discusses how novel biophysical tools and in vivo animal models help to determine the role of the endothelium in the process of tumor cell invasion. Evidence is provided that cell mechanical properties, for example, contractile force generation of tumor cells, are involved in the process of tumor cell invasion.

  12. T cell migration in rheumatoid arthritis

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    Mario eMellado

    2015-07-01

    Full Text Available Rheumatoid arthritis (RA is an autoimmune disease characterized by chronic inflammation in joints, associated with synovial hyperplasia and with bone and cartilage destruction. Although the primacy of T cell-related events early in the disease continues to be debated, there is strong evidence that autoantigen recognition by specific T cells is crucial to the pathophysiology of rheumatoid synovitis. In addition, T cells are key components of the immune cell infiltrate detected in the joints of RA patients. Initial analysis of the cytokines released into the synovial membrane showed an imbalance, with a predominance of proinflammatory mediators, indicating a deleterious effect of Th1 T cells. There is nonetheless evidence that Th17 cells also play an important role in RA. T cells migrate from the bloodstream to the synovial tissue via their interactions with the endothelial cells that line synovial postcapillary venules. At this stage, selectins, integrins and chemokines have a central role in blood cell invasion of synovial tissue, and therefore in the intensity of the inflammatory response.In this review we will focus on the mechanisms involved in T cell attraction to the joint, the proteins involved in their extravasation from blood vessels, and the signaling pathways activated. Knowledge of these processes will lead to a better understanding of the mechanism by which the systemic immune response causes local joint disorders and will help to provide a molecular basis for therapeutic strategies.

  13. Cell shape dynamics: from waves to migration.

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    Meghan K Driscoll

    Full Text Available We observe and quantify wave-like characteristics of amoeboid migration. Using the amoeba Dictyostelium discoideum, a model system for the study of chemotaxis, we demonstrate that cell shape changes in a wave-like manner. Cells have regions of high boundary curvature that propagate from the leading edge toward the back, usually along alternating sides of the cell. Curvature waves are easily seen in cells that do not adhere to a surface, such as cells that are electrostatically repelled from surfaces or cells that extend over the edge of micro-fabricated cliffs. Without surface contact, curvature waves travel from the leading edge to the back of a cell at -35 µm/min. Non-adherent myosin II null cells do not exhibit these curvature waves. At the leading edge of adherent cells, curvature waves are associated with protrusive activity. Like regions of high curvature, protrusive activity travels along the boundary in a wave-like manner. Upon contact with a surface, the protrusions stop moving relative to the surface, and the boundary shape thus reflects the history of protrusive motion. The wave-like character of protrusions provides a plausible mechanism for the zig-zagging of pseudopods and for the ability of cells both to swim in viscous fluids and to navigate complex three dimensional topography.

  14. Effects of Down-regulation of Integrin-β_1 Expression on Migration and Hepatic Metastasis of Human Colon Carcinoma

    Institute of Scientific and Technical Information of China (English)

    张建立; 高军; 谭晓杰; 王敏; 秦仁义

    2010-01-01

    Organ-specific tumor cell adhesion to extracellular matrix (ECM) components and cell migration into host organs often involve integrin-mediated cellular processes. Direct integrin-mediated cell adhesion to ECM components in the space of Disse appears to be required for the successful liver metastatic formation of colon cancer. In the present study, human colon cancer HT-29 cells were transfected by liposome with integrin-β1 antisense oligodeoxynucleotide (ASODN). The integrin-β1 gene expression in HT-29 cel...

  15. Phosphatase of regenerating liver-3 localizes to cyto-membrane and is required for B16F1 melanoma cell metastasis in vitro and in vivo.

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    Ran Song

    Full Text Available BACKGROUND: Phosphatase of regenerating liver-3 (PRL-3 is a member of the novel phosphatases of regenerating liver family, characterized by one protein tyrosine phosphatase active domain and a C-terminal prenylation (CCVM motif. Though widely proposed to facilitate metastasis in many cancer types, PRL-3's cellular localization and the function of its CCVM motif in metastatic process remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, a series of Myc tagged PRL-3 wild type or mutant plasmids were expressed in B16F1 melanoma cells to investigate the relationship between PRL-3's cellular localization and metastasis. With immuno-fluorescence microcopy and cell adhesion/migration assay in vitro, and an experimental passive metastasis model in vivo, we found that CCVM motif is critical for the localization of PRL-3 on cell plasma membrane and the lung metastasis of melanoma. In particular, Cystine170 is the key site for prenylation in this process. CONCLUSIONS/SIGNIFICANCE: These results suggest that cellular localization of PRL-3 is highly correlated with its function in tumor metastasis, and inhibition of PRL-3 prenylation might be a new approach to cancer therapy.

  16. Melanoma Cell Adhesion and Migration Is Modulated by the Uronyl 2-O Sulfotransferase

    Science.gov (United States)

    Nikolovska, Katerina; Spillmann, Dorothe; Haier, Jörg; Ladányi, Andrea; Stock, Christian; Seidler, Daniela G.

    2017-01-01

    Although the vast majority of melanomas are characterized by a high metastatic potential, if detected early, melanoma can have a good prognostic outcome. However, once metastasised, the prognosis is bleak. We showed previously that uronyl-2-O sulfotransferase (Ust) and 2-O sulfation of chondroitin/dermatan sulfate (CS/DS) are involved in cell migration. To demonstrate an impact of 2-O sulfation in metastasis we knocked-down Ust in mouse melanoma cells. This significantly reduced the amount of Ust protein and enzyme activity. Furthermore, in vitro cell motility and adhesion were significantly reduced correlating with the decrease of cellular Ust protein. Single cell migration of B16VshUst(16) cells showed a decreased cell movement phenotype. The adhesion of B16V cells to fibronectin depended on α5β1 but not αvβ3 integrin. Inhibition of glycosaminoglycan sulfation or blocking fibroblast growth factor receptor (FgfR) reduced α5 integrin in B16V cell lines. Interestingly, FgfR1 expression and activation was reduced in Ust knock-down cells. In vivo, pulmonary metastasis of B16VshUst cells was prevented due to a reduction of α5 integrin. As a proof of concept UST knock-down in human melanoma cells also showed a reduction in ITGa5 and adhesion. This is the first study showing that Ust, and consequently 2-O sulfation of the low affinity receptor for FgfR CS/DS, reduces Itga5 and leads to an impaired adhesion and migration of melanoma cells. PMID:28107390

  17. Desmosome dynamics in migrating epithelial cells requires the actin cytoskeleton

    Science.gov (United States)

    Roberts, Brett J.; Pashaj, Anjeza; Johnson, Keith R.; Wahl, James K.

    2011-01-01

    Re-modeling of epithelial tissues requires that the cells in the tissue rearrange their adhesive contacts in order to allow cells to migrate relative to neighboring cells. Desmosomes are prominent adhesive structures found in a variety of epithelial tissues that are believed to inhibit cell migration and invasion. Mechanisms regulating desmosome assembly and stability in migrating cells are largely unknown. In this study we established a cell culture model to examine the fate of desmosomal components during scratch wound migration. Desmosomes are rapidly assembled between epithelial cells at the lateral edges of migrating cells and structures are transported in a retrograde fashion while the structures become larger and mature. Desmosome assembly and dynamics in this system are dependent on the actin cytoskeleton prior to being associated with the keratin intermediate filament cytoskeleton. These studies extend our understanding of desmosome assembly and provide a system to examine desmosome assembly and dynamics during epithelial cell migration. PMID:21945137

  18. Isolated Late Metastasis of a Renal Cell Cancer Treated by Radical Distal Pancreatectomy

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    J. P. Barras

    1996-01-01

    Full Text Available A 53–year-old man underwent right nephrectomy for a locally advanced renal cell carcinoma with concomitant resection of a solitary metastasis in the right lung. Ten years later, he presented with haematochezia caused by a tumour in the tail of pancreas, invading the transverse colon and the greater curvature of the stomach. The tumour was radically resected, and histological examination revealed a solitary metastasis of the previous renal cell carcinoma. This case illustrates a rare indication for pancreatic resection because of pancreatic metastasis.

  19. Bilateral Choroidal Metastasis from Non-Small Cell Lung Cancer

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    Tariq Namad

    2014-01-01

    Full Text Available Breast and lung cancers are the most common primary neoplasms to manifest with choroidal metastases. The incidence of choroidal metastases from metastatic lung cancer was reported to be 2–6.7%. We report a case of bilateral choroidal metastasis from non-small cell lung cancer. A 59-year-old Caucasian female patient, never a smoker, was diagnosed with stage IV lung adenocarcinoma metastatic to the pleura, bones, and the brain. Her initial scan of the chest showed innumerable soft tissue nodules and mediastinal adenopathy compatible with metastatic disease. Her initial brain MRI showed numerous small enhancing lesions consistent with extensive disease. Unfortunately, during her follow-up visits, she presented with bulge on her left eye. Simultaneously, her follow-up chest scan showed increase in the size of the lung nodules. She continued to have a reasonable performance status at that time, except for mild increase in her dyspnea. The choroidal metastases require a multidisciplinary care and should be among the differential patients with malignancy who present with ocular symptoms.

  20. Nature's rheologists: Lymphatic endothelial cells control migration in response to shear stress

    Science.gov (United States)

    Fuller, Gerald; Dunn, Alex; Surya, Vinay

    2015-03-01

    Endothelial cells (ECs) line the inner surface of blood and lymphatic vessels and are sensitive to fluid flow as part of their physiological function. EC organization, migration and vessel development are profoundly influenced by shear stresses, with important implications in cardiovascular disease and tumor metastasis. How ECs sense fluid flow is a central and unanswered question in cardiovascular biology. We developed a high-throughput live-cell flow chamber that models the gradients in wall shear stress experienced by ECs in vivo. Live-cell imaging allows us to probe cellular responses to flow, most notably EC migration, which has a key role in vessel remodeling. We find that most EC subtypes, including ECs from the venous, arterial, and microvascular systems, migrate in the flow direction. In contrast, human lymphatic microvascular ECs (hLMVECs) migrate against flow and up spatial gradients in wall shear stress. Further experiments reveal that hLMVECs are sensitive to the magnitude, direction, and the local spatial gradients in wall shear stress. Lastly, recent efforts have aimed to link this directional migration to spatial gradients in cell-mediated small molecule emission that may be linked to the gradient in wall shear stress.

  1. Jin Fu Kang Oral Liquid Inhibits Lymphatic Endothelial Cells Formation and Migration

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    Hai-Lang He

    2016-01-01

    Full Text Available Lung cancer is the leading cause of cancer-related deaths worldwide. Jin Fu Kang (JFK, an oral liquid prescription of Chinese herbal drugs, has been clinically available for the treatment of non-small cell lung cancer (NSCLC. Lymphangiogenesis is a primary event in the process of cancer development and metastasis, and the formation and migration of lymphatic endothelial cells (LECs play a key role in the lymphangiogenesis. To assess the activity of stromal cell-derived factor-1 (SDF-1 and the coeffect of SDF-1 and vascular endothelial growth factor-C (VEGF-C on the formation and migration of LECs and clarify the inhibitory effects of JFK on the LECs, the LECs were differentiated from CD34+/VEGFR-3+ endothelial progenitor cells (EPCs, and JFK-containing serums were prepared from rats. SDF-1 and VEGF-C both induced the differentiation of CD34+/VEGFR-3+ EPCs towards LECs and enhanced the LECs migration. Couse of SDF-1 and VEGF-C displayed an additive effect on the LECs formation but not on their migration. JFK inhibited the formation and migration of LECs, and the inhibitory effects were most probably via regulation of the SDF-1/CXCR4 and VEGF-C/VEGFR-3 axes. The current finding suggested that JFK might inhibit NSCLC through antilymphangiogenesis and also provided a potential to discover antilymphangiogenesis agents from natural resources.

  2. [Study on FAK regulation of migration of vascular endothelial cells depending upon focal adhesion proteins].

    Science.gov (United States)

    Gao, Min; Liu, Xiaoheng; Sun, Heng; Ren, Hongyi; Wang, Lijuan; Shen, Yang

    2013-06-01

    Tumor angiogenesis induced by vascular endothelial cells (VECs) migration is a necessary condition for tumor growth and metastasis. The purpose of this study is to investigate the effect of focal adhesion kinase (FAK) inhibitor (50nmol/mL) on the adhesion and migration of endothelial cells(ECs) and the expression of focal adhesion proteins vinculin, talin and paxillin. Scratch wound migration assay was performed to examine the effect of FAK inhibitor with 50nmol/mL on ECs migration at 0, 5, 10, 30, 60 and 120min, respectively. And immunofluorescence analysis was performed to detect the expression of F-actin in ECs treated with FAK inhibitor within 2h. Western blot was carried out to determine the effect of FAK inhibitor on expression of vinculin, talin and paxillin proteins. The results showed that the migration distance and the expression of F-actin in ECs treated with FAK inhibitor decreased significantly compared with that of the controls, and the level of vinculin showed no significant difference with increasing of treated time of FAK inhibitor. However, the talin and paxillin showed an identical decreasing tendency in 5-10min, but slowly going up in 30min and then after subsequently decreasing. The results of this study proved that blocking phosphorylation of FAK could inhibit VECs adhesion and migration by downregulating focal adhesion proteins so that it may inhibit tumor angiogenesis. This may provide a new approach for tumor therapy.

  3. SPAG9 is involved in hepatocarcinoma cell migration and invasion via modulation of ELK1 expression

    Directory of Open Access Journals (Sweden)

    Yan QY

    2016-03-01

    Full Text Available Qiuyue Yan,1,2 Guohua Lou,3 Ying Qian,1 Bo Qin,1 Xiuping Xu,1,2 Yanan Wang,1,2 Yanning Liu,3 Xuejun Dong1 1Shaoxing People’s Hospital, Shaoxing Hospital Zhejiang University, Shaoxing, Zhejiang, 2The Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, 3State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China Background: Sperm-associated antigen 9 (SPAG9 is upregulated in several malignancies and its overexpression is positively correlated with cancer cell malignancies. However, the specific biological roles of SPAG9 in hepatocellular carcinoma (HCC are less understood. Methods: We analyzed SPAG9 and ETS-like gene 1, tyrosine kinase (ELK1 expression in 50 paired HCC specimens and adjacent noncancerous liver specimens using immunohistochemistry. SPAG9 small interfering RNA (siRNA was used to knockdown SPAG9 expression in HCCLM3 and HuH7 cell lines. We used plasmids to upregulate ELK1 expression and siRNA to downregulate ELK1 expression in HuH7 cells. Quantitative real-time polymerase chain reaction and Western blot were used to evaluate the expression of SPAG9 and ELK1 at the mRNA and protein level, respectively. Wound healing, matrigel migration, and invasion analyses were performed to determine the effect of SPAG9 and ELK1 on HCC metastasis. Results: SPAG9 and ELK1 were overexpressed in HCC tissue specimens and their expressions were higher in HCCLM3 and HuH7 cells compared to the low-metastatic HepG2 cells. Overexpression of SPAG9 was positively associated with tumor-node-metastasis staging (P=0.032, metastasis parameters (P=0.018 of HCC patients, and ELK1 expression (r=0.422, P<0.001 in HCC tissue specimens. In addition

  4. Cell surface syndecan-1 contributes to binding and function of macrophage migration inhibitory factor (MIF) on epithelial tumor cells.

    Science.gov (United States)

    Pasqualon, Tobias; Lue, Hongqi; Groening, Sabine; Pruessmeyer, Jessica; Jahr, Holger; Denecke, Bernd; Bernhagen, Jürgen; Ludwig, Andreas

    2016-04-01

    Surface expressed proteoglycans mediate the binding of cytokines and chemokines to the cell surface and promote migration of various tumor cell types including epithelial tumor cells. We here demonstrate that binding of the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) to epithelial lung and breast tumor cell lines A549 and MDA-MB231 is sensitive to enzymatic digestion of heparan sulphate chains and competitive inhibition with heparin. Moreover, MIF interaction with heparin was confirmed by chromatography and a structural comparison indicated a possible heparin binding site. These results suggested that proteoglycans carrying heparan sulphate chains are involved in MIF binding. Using shRNA-mediated gene silencing, we identified syndecan-1 as the predominant proteoglycan required for the interaction with MIF. MIF binding was decreased by induction of proteolytic shedding of syndecan-1, which could be prevented by inhibition of the metalloproteinases involved in this process. Finally, MIF induced the chemotactic migration of A549 cells, wound closure and invasion into matrigel without affecting cell proliferation. These MIF-induced responses were abrogated by heparin or by silencing of syndecan-1. Thus, our study indicates that syndecan-1 on epithelial tumor cells promotes MIF binding and MIF-mediated cell migration. This may represent a relevant mechanism through which MIF enhances tumor cell motility and metastasis.

  5. Tetrahydrocurcumin inhibits HT1080 cell migration and invasion via downregulation of MMPs and uPA

    Institute of Scientific and Technical Information of China (English)

    Supachai YODKEEREE; Spiridione GARBISA; Pomngarm LIMTRAKUL

    2008-01-01

    Aim: Tetrahydrocurcumin (THC) is an active metabolite of curcumin. It has been reported to have similar pharmacological activity to curcumin. The proteases that participate in extracellular matrix (ECM) degradation are involved in cancer cell metastasis. The present study investigates the effect of an ultimate metabolite of curcumin, THC, on the invasion and motility of highly-metastatic HT1080 human fibrosarcoma cells. Methods: The effect of THC on HTI080 cell invasion and migration was determined using Boyden chamber assay. Cell-adhesion assay was used for examining the binding of cells to ECM molecules. Zymography assay was used to analyze the effect of THC on matrix metalloproteinase (MMP)-2, MMP-9, and urokinase plasminogen activator (uPA) secretion from HT1080 cells. Tissue inhibitor of metalloproteinase (TIMP)-2 and membrane-type 1 matrix metalloproteinase (MT1-MMP) proteins levels were analyzed by Western blotting. Results: Treatment with THC reduced HT1080 cell invasion and migration in a dose-dependent manner. THC also decreased the cell adhesion to Matrigel and laminin-coated plates. Analysis by zymography demonstrated that treatment with THC reduced the levels of MMP-2, MMP-9, and uPA. THC also inhibited the levels of MT1-MMP and TIMP-2 proteins detected by Western blot analysis. Conclusion: Our findings revealed that THC reduced HT1080 cell invasion and migration. The inhibition of cancer cell invasion is associated with the downregulation of ECM degradation enzymes and the inhibition of cell adhesion to ECM proteins.

  6. Flow-driven cell migration under external electric fields

    Science.gov (United States)

    Li, Yizeng; Mori, Yoichiro; Sun, Sean X.

    2016-01-01

    Electric fields influence many aspects of cell physiology, including various forms of cell migration. Many cells are sensitive to electric fields, and can migrate toward a cathode or an anode, depending on the cell type. In this paper, we examine an actomyosin-independent mode of cell migration under electrical fields. Our theory considers a one-dimensional cell with water and ionic fluxes at the cell boundary. Water fluxes through the membrane are governed by the osmotic pressure difference across the cell membrane. Fluxes of cations and anions across the cell membrane are determined by the properties of the ion channels as well as the external electric field. Results show that without actin polymerization and myosin contraction, electric fields can also drive cell migration, even when the cell is not polarized. The direction of migration with respect to the electric field direction is influenced by the properties of ion channels, and are cell-type dependent. PMID:26765031

  7. Intracranial metastasis from primary transitional cell carcinoma of female urethra: case report & review of the literature

    Directory of Open Access Journals (Sweden)

    Kim In-Young

    2011-01-01

    Full Text Available Abstract Background Transitional cell carcinoma (TCC of the female urethra is a rare urological malignancy, and intracranial metastasis of this cancer has not yet been reported in the literature. This review is intended to present a case of multiple intracranial metastasis in a female patient with a remote history of primary urethral TCC. Case Presentation A 49-year-old woman, presented with a prolapsed mass in urethral orifice that was diagnosed as primary urethral TCC with distant lung and multiple bone metastases. The patient subsequently underwent chemotherapy under various regimens. A year later, the patient developed headache and vomiting which as was found to be due to multiple intracranial metastasis. The patient underwent surgical resection of the largest lesion located on the cerebellum, and consecutively gamma knife radiosurgery was performed for other small-sized lesions. Pathological examination of the resected mass revealed a metastatic carcinoma from a known urethral TCC. Serial work-up of systemic metastasis revealed concomitant aggravation of lung, spleen, and liver metastasis. The patient died of lung complication 2 months after the diagnosis of brain metastasis. Conclusion To the best of our knowledge, this is the first reported case of cerebral metastasis from primary urethral TCC, with pathological confirmation. As shown in intracranial metastasis of other urinary tract carcinoma, this case occurred in the setting of uncontrolled systemic disease and led to dismal prognosis in spite of aggressive interventional modalities.

  8. Defining Tumor Cell and Immune Cell Behavior in Vivo during Pulmonary Metastasis of Breast Cancer

    Science.gov (United States)

    2015-09-01

    Congress in the Educational Session on Cancer Immunology . I gave a talk entitled “ Harnessing Intravital Microscopy To Understand The Real-Time...AWARD NUMBER: W81XWH-13-1-0009 TITLE: Defining Tumor Cell and Immune Cell Behavior in Vivo during Pulmonary Metastasis of Breast Cancer ...average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data

  9. Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE.

    Science.gov (United States)

    Carmona, G; Perera, U; Gillett, C; Naba, A; Law, A-L; Sharma, V P; Wang, J; Wyckoff, J; Balsamo, M; Mosis, F; De Piano, M; Monypenny, J; Woodman, N; McConnell, R E; Mouneimne, G; Van Hemelrijck, M; Cao, Y; Condeelis, J; Hynes, R O; Gertler, F B; Krause, M

    2016-09-29

    Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlate with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement, we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation and matrix degradation was impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not with Ena/VASP is required for random 2D cell migration. We identified a phosphorylation-dependent mechanism that regulates selective recruitment of these effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, whereas Src-dependent phosphorylation enhances binding to Scar/WAVE but not to Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of epidermal growth factor (EGF) gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activities at the plasma membrane to promote 3D invasion and metastasis.

  10. Cardiotoxin III Inhibits Proliferation and Migration of Oral Cancer Cells through MAPK and MMP Signaling

    Directory of Open Access Journals (Sweden)

    Ching-Yu Yen

    2013-01-01

    Full Text Available Cardiotoxin III (CTXIII, isolated from the snake venom of Formosan cobra Naja naja atra, has previously been found to induce apoptosis in many types of cancer. Early metastasis is typical for the progression of oral cancer. To modulate the cell migration behavior of oral cancer is one of the oral cancer therapies. In this study, the possible modulating effect of CTXIII on oral cancer migration is addressed. In the example of oral squamous carcinoma Ca9-22 cells, the cell viability was decreased by CTXIII treatment in a dose-responsive manner. In wound-healing assay, the cell migration of Ca9-22 cells was attenuated by CTXIII in a dose- and time-responsive manner. After CTXIII treatment, the MMP-2 and MMP-9 protein expressions were downregulated, and the phosphorylation of JNK and p38-MAPK was increased independent of ERK phosphorylation. In conclusion, CTXIII has antiproliferative and -migrating effects on oral cancer cells involving the p38-MAPK and MMP-2/-9 pathways.

  11. Overexpression of forkhead box J2 can decrease the migration of breast cancer cells.

    Science.gov (United States)

    Wang, Yingying; Yang, Shuyun; Ni, Qichao; He, Song; Zhao, Yunhong; Yuan, Qin; Li, Chunmiao; Chen, Hongwei; Zhang, Li; Zou, Lin; Shen, Aiguo; Cheng, Chun

    2012-08-01

    The prognosis of breast cancer patients with metastases is generally poor, so it is essential to elucidate related molecules mechanisms. Forkhead Box J2 (FOXJ2) is a member of Forkhead Box transcription factors, many of which have been reported to participate in tumor migration and invasion. In this study, we showed the expression of FOXJ2 was higher in primary breast cancer tissues without lymph nodes metastases than those with, and there was statistical significance between the expression of FXOJ2 and the clinical factors. Hence, we identified a novel function of metastasis, which was not previously known for FOXJ2. Overexpression of FOXJ2 decreased the motility property of highly migrative MDA-MB-231 cells in vitro by wound healing assays and trans-well migration assays, and it was concurrent with the increased expression of epithelial marker E-cadherin and the decreased expression of mesenchymal marker vimentin by Western blot analysis, reverse transcription PCR analysis, and immunofluorescence analysis. Consistent with these observations, the repression of FOXJ2 in weakly metastatic MCF-7 cells remarkably promoted cellular motility. Our study demonstrates that FOXJ2 can inhibit the metastasis of human breast cancer by regulating the EMT key markers E-cadherin and vimentin.

  12. MicroRNA-125b induces metastasis by targeting STARD13 in MCF-7 and MDA-MB-231 breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Feng Tang

    Full Text Available MicroRNAs (miRNAs are a class of small noncoding RNAs that regulate gene expression by targeting mRNAs to trigger either translation repression or mRNA degradation. miR-125b is down-regulated in human breast cancer cells compared with the normal ones except highly metastatic tumor cells MDA-MB-231. However, few functional studies were designed to investigate metastatic potential of miR-125b. In this study, the effects of miR-125b on metastasis in human breast cancer cells were studied, and the targets of miR-125b were also explored. Transwell migration assay, cell wound healing assay, adhesion assay and nude mice model of metastasis were utilized to investigate the effects of miR-125b on metastasis potential in vitro and in vivo. In addition, it was implied STARD13 (DLC2 was a direct target of miR-125b by Target-Scan analysis, luciferase reporter assay and western blot. Furthermore, activation of STARD13 was identified responsible for metastasis induced by miR-125b through a siRNA targeting STARD13. qRT-PCR, immunofluorescent assay and western blot was used to observe the variation of Vimentin and α-SMA in breast cancer cells. In summary, our study provided new insights into the function of miR-125b during the metastasis of breat cancer cells and also suggested the role of miR-125b in pro-metastasis by targeting STARD13.

  13. MicroRNA-125b induces metastasis by targeting STARD13 in MCF-7 and MDA-MB-231 breast cancer cells.

    Science.gov (United States)

    Tang, Feng; Zhang, Rui; He, Yunmian; Zou, Meijuan; Guo, Le; Xi, Tao

    2012-01-01

    MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression by targeting mRNAs to trigger either translation repression or mRNA degradation. miR-125b is down-regulated in human breast cancer cells compared with the normal ones except highly metastatic tumor cells MDA-MB-231. However, few functional studies were designed to investigate metastatic potential of miR-125b. In this study, the effects of miR-125b on metastasis in human breast cancer cells were studied, and the targets of miR-125b were also explored. Transwell migration assay, cell wound healing assay, adhesion assay and nude mice model of metastasis were utilized to investigate the effects of miR-125b on metastasis potential in vitro and in vivo. In addition, it was implied STARD13 (DLC2) was a direct target of miR-125b by Target-Scan analysis, luciferase reporter assay and western blot. Furthermore, activation of STARD13 was identified responsible for metastasis induced by miR-125b through a siRNA targeting STARD13. qRT-PCR, immunofluorescent assay and western blot was used to observe the variation of Vimentin and α-SMA in breast cancer cells. In summary, our study provided new insights into the function of miR-125b during the metastasis of breat cancer cells and also suggested the role of miR-125b in pro-metastasis by targeting STARD13.

  14. Gas6 induces cancer cell migration and epithelial–mesenchymal transition through upregulation of MAPK and Slug

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Yunhee [Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon (Korea, Republic of); Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Lee, Mira [Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Kim, Semi, E-mail: semikim@kribb.re.kr [Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon (Korea, Republic of); Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of)

    2013-04-26

    Highlights: •We investigated the molecular mechanisms underlying Gas6-mediated cancer cell migration. •Gas6 treatment and subsequent Axl activation induce cell migration and EMT via upregulation of Slug. •Slug expression mediated by Gas6 is mainly through c-Jun and ATF-2 in an ERK1/2 and JNK-dependent manner. •The Gas6/Axl-Slug axis may be exploited as a target for anti-cancer metastasis therapy. -- Abstract: Binding of Gas6 to Axl (Gas6/Axl axis) alters cellular functions, including migration, invasion, proliferation, and survival. However, the molecular mechanisms underlying Gas6-mediated cell migration remain poorly understood. In this study, we found that Gas6 induced the activation of JNK and ERK1/2 signaling in cancer cells expressing Axl, resulting in the phosphorylation of activator protein-1 (AP-1) transcription factors c-Jun and ATF-2, and induction of Slug. Depletion of c-Jun or ATF-2 by siRNA attenuated the Gas6-induced expression of Slug. Slug expression was required for cell migration and E-cadherin reduction/vimentin induction induced by Gas6. These results suggest that Gas6 induced cell migration via Slug upregulation in JNK- and ERK1/2-dependent mechanisms. These data provide an important insight into the molecular mechanisms mediating Gas6-induced cell migration.

  15. Gadd45a inhibits cell migration and invasion by altering the global RNA expression.

    Science.gov (United States)

    Shan, Zhanhai; Li, Guiyuan; Zhan, Qimin; Li, Dan

    2012-09-01

    Gadd45a, the first well-defined p53 downstream gene, can be induced by multiple DNA-damaging agents, which plays important roles in the control of cell cycle checkpoint, DNA repair process and signaling transduction. Our previous findings suggested that Gadd45a maintains cell-cell adhesion and cell contact inhibition. However, little is known about how Gadd45a participates in the suppression of malignancy in human cancer cells. To examine the functions of Gadd45a in cell invasion and metastasis, we performed the adhesion, wound-healing and transwell assays in Gadd45a (+/+) and Gadd45a (-/-) MEF cell lines. We found the adhesion, migration and invasive abilities were much higher in Gadd45a deficient cells. We furthermore applied high-throughput cDNA microarray analysis and bioinformatics analysis to analyze the mechanisms of Gadd45a gene in invasion and metastasis. Compared with the Gadd45a wild type cells, the Gadd45a deficient cells showed a wide range of transcripts alterations. The altered gene pathways were predicted by the MAS software, which indicated focal adhesion,cell communication,ECM-receptor interaction as the three main pathways. Real-time PCR was employed to validate the differentially expressed genes. Interestingly, we figured out that the deregulations of these genes are caused neither by genomic aberrations nor methylation status. These findings provided a novel insight that Gadd45a may involve in tumor progression by regulating related genes expressions.

  16. Downregulation of SOK1 promotes the migration of MCF-7 cells

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xu-Dong, E-mail: xudongchen305@hotmail.com [Key Lab of Molecular Medicine, Ministry of Education, Shanghai Medical College, Fudan University, Shanghai (China); Cho, Chien-Yu [Department of Biochemistry, College of Medicine, National Cheng Kung University, Taiwan (China)

    2011-04-08

    Highlights: {yields} SOK1 is a member of GCK-III subfamily. It is activated by oxidative stress or chemical anoxia. {yields} Barr's group have found that autophosphorylation of SOK1 is triggered by binding to the Golgi matrix protein GM130 and made the cells migration through dimeric adaptor protein 14-3-3. {yields} But what we found is that downregulation of SOK1 promotes cell migration and leads to the upregulation of GM130 and Tyr861 of FAK in MCF-7 cells. -- Abstract: SOK1 is a member of the germinal center kinase (GCK-III) subfamily but little is known about it, particularly with respect to its role in signal transduction pathways relative to tumor metastasis. By stably transfecting SOK1 siRNA into the MCF-7 breast cancer cell line we found that SOK1 promotes the migration of MCF-7 cells, as determined using wound-healing and Boyden chamber assays. However, cell proliferation assays revealed that silencing SOK1 had no effect on cell growth relative to the normal cells. Silencing SOK1 also had an effect on the expression and phosphorylation status of a number of proteins in MCF-7 cells, including FAK and GM130, whereby a decrease in SOK1 led to an increase in the expression of these proteins.

  17. Inhibitory effect of lanthanum chloride on migration and invasion of cervical cancer cells

    Institute of Scientific and Technical Information of China (English)

    CHEN Hongwei; LIU Sisun; MIAO Lifang; YU Lingfang; WANG Yang; GUO Fei

    2013-01-01

    Tumor metastasis remains the main reason for treatment failure and death of patients with cervical cancer.The present study was designed to explore the effects of lanthanum chloride (LaCl3) on the invasion and migration of cervical cancer cells and the underlying mechanisms.The migration and invasion of tumor cells was evaluated by a modified Transwell/Boyden chamber assays.It is well known that MMPs (Matrix metalloprotcinascs) and NF-κB (Nuclear factor-κB) pathway play important roles in migration and invasion of tumor cells,and also the expression of MMPs were regulated by NF-κB signaling.The expression of MMP-1 and MMP-9 was detected by reverse transcription polymerase chain reaction (RT-PCR); Western blot and the NF-κB-DNA-binding activity assay were used to analyze the NF-κB activity.The results indicated that LaCl3 was capable of inhibiting the cell invasion and migration of human cervical cancer Hela cells by decreasing the expression of MMP-1 and MMP-9 via blocking NF-κB pathway.

  18. Selaginellatamariscina attenuates metastasis via Akt pathways in oral cancer cells.

    Directory of Open Access Journals (Sweden)

    Jia-Sin Yang

    Full Text Available BACKGROUND: Crude extracts of Selaginellatamariscina, an oriental medicinal herb, have been evidenced to treat several human diseases. This study investigated the mechanisms by which Selaginellatamariscina inhibits the invasiveness of human oral squamous-cell carcinoma (OSCC HSC-3 cells. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we demonstrate that Selaginellatamariscina attenuated HSC-3 cell migration and invasion in a dose-dependent manner. The anti-metastatic activities of Selaginellatamariscina occurred at least partially because of the down-regulation of matrix metalloproteinases (MMP-2 and MMP-9 gelatinase activity and the down-regulation of protein expression. The expression and function of both MMP-2 and MMP-9 were regulated by Selaginellatamariscina at a transcriptional level, as shown by quantitative real-time PCR and reporter assays. Chromatin immunoprecipitation (ChIP data further indicated that binding of the cAMP response element-binding (CREB protein and activating protein-1 (AP-1 to the MMP-2 promoter diminished at the highest dosage level of Selaginellatamariscina. The DNA-binding activity of specificity protein 1 (SP-1 to the MMP-9 promoter was also suppressed at the same concentration. Selaginellatamariscina did not affect the mitogen-activated protein kinase signaling pathway, but did inhibit the effects of gelatinase by reducing the activation of serine-threonine kinase Akt. CONCLUSIONS: These results demonstrate that Selaginellatamariscina may be a potent adjuvant therapeutic agent in the prevention of oral cancer.

  19. Parathyroid hormone-related protein (PTHrP) is responsible for production of bone metastasis, but not visceral metastasis, by human small cell lung cancer SBC-5 cells in natural killer cell-depleted SCID mice.

    Science.gov (United States)

    Miki, Toyokazu; Yano, Seiji; Hanibuchi, Masaki; Kanematsu, Takanori; Muguruma, Hiroaki; Sone, Saburo

    2004-02-10

    We previously established an osteolytic bone metastasis model with multiorgan dissemination in natural killer (NK) cell-depleted severe combined immunodeficient (SCID) mice using human small cell lung cancer cells (SBC-5), which highly express the parathyroid hormone-related protein (PTHrP). In our present study, we evaluated the role of PTHrP on bone metastasis by SBC-5 cells using anti-PTHrP neutralizing antibody (Ab). Anti-PTHrP Ab did not affect the proliferation or cytokine production of SBC-5 cells in vitro. Repeated intravenous injection with anti-PTHrP Ab inhibited the formation of bone metastasis in a dose-dependent manner, while the same treatment had no significant effect on the metastasis to visceral organs (lung, liver, kidney and lymph node). In addition, treatment with anti-PTHrP Ab improved the elevated serum calcium level, associated with inhibition of osteolytic bone metastasis, suggesting that anti-PTHrP Ab inhibited bone metastasis via suppression of bone resorption probably by neutralizing PTHrP. These findings suggest that PTHrP is essential for bone metastasis, but not visceral metastasis, by small cell lung cancer SBC-5 cells.

  20. Platelet GPIIb supports initial pulmonary retention but inhibits subsequent proliferation of melanoma cells during hematogenic metastasis

    Science.gov (United States)

    Echtler, Katrin; Konrad, Ildiko; Lorenz, Michael; Schneider, Simon; Hofmaier, Sebastian; Plenagl, Florian; Stark, Konstantin; Czermak, Thomas; Tirniceriu, Anca; Eichhorn, Martin; Walch, Axel; Enders, Georg; Massberg, Steffen; Schulz, Christian

    2017-01-01

    Platelets modulate the process of cancer metastasis. However, current knowledge on the direct interaction of platelets and tumor cells is mostly based on findings obtained in vitro. We addressed the role of the platelet fibrinogen receptor glycoprotein IIb (integrin αIIb) for experimental melanoma metastasis in vivo. Highly metastatic B16-D5 melanoma cells were injected intravenously into GPIIb-deficient (GPIIb-/-) or wildtype (WT) mice. Acute accumulation of tumor cells in the pulmonary vasculature was assessed in real-time by confocal videofluorescence microscopy. Arrest of tumor cells was dramatically reduced in GPIIb-/- mice as compared to WT. Importantly, we found that mainly multicellular aggregates accumulated in the pulmonary circulation of WT, instead B16-D5 aggregates were significantly smaller in GPIIb-/- mice. While pulmonary arrest of melanoma was clearly dependent on GPIIb in this early phase of metastasis, we also addressed tumor progression 10 days after injection. Inversely, and unexpectedly, we found that melanoma metastasis was now increased in GPIIb-/- mice. In contrast, GPIIb did not regulate local melanoma proliferation in a subcutaneous tumor model. Our data suggest that the platelet fibrinogen receptor has a differential role in the modulation of hematogenic melanoma metastasis. While platelets clearly support early steps in pulmonary metastasis via GPIIb-dependent formation of platelet-tumor-aggregates, at a later stage its absence is associated with an accelerated development of melanoma metastases. PMID:28253287

  1. miR-103 regulates triple negative breast cancer cells migration and invasion through targeting olfactomedin 4.

    Science.gov (United States)

    Xiong, Bin; Lei, Xuefeng; Zhang, Lei; Fu, Jia

    2017-03-18

    Our previous study showed olfactomedin 4 (OLFM4) suppressed triple-negative breast cancer cells migration, invasion and metastasis-associated protein MMP 9 expression. OLFM4 was identified as a potential target of miR-103 according to microRNA target databases and published studies. The aim of this study is to validate the relationship between miR-103 and OLFM4, and explore the function and clinical significance of miR-103 in triple-negative breast cancer patients. In our results, miR-103 negatively regulated OLFM4 expression by directly targeting its 3'-UTR. OLFM4 was a functional target of miR-103 to regulate triple-negative breast cancer cells migration, invasion and MMP 9 expression. Moreover, miR-103 overexpression was observed in triple-negative breast cancer tissues and cell lines, and associated with lymph node metastasis, distant metastasis and clinical stage. Univariate and multivariate analyses suggested that miR-103 overexpression was a poor independent prognostic factor for triple-negative breast cancer patients. In conclusion, miR-103 acts as an oncogene miRNA to promote triple-negative breast cancer cells migration and invasion through targeting OLFM4.

  2. Metastasis of Renal Cell Carcinoma to the Buccal Mucosa 19 Years after Radical Nephrectomy

    Directory of Open Access Journals (Sweden)

    Hernani Gil-Julio

    2012-01-01

    Full Text Available Renal cell carcinoma (RCC has high metastatic potential, which requires early diagnosis to optimize the chance of cure. Metastasis of RCC to the head and neck region is less common and metastasis to the buccal mucosa is extremely rare. This phenomenon occurs mostly in patients with generalized dissemination, especially with lung metastases. In this article we report a case of buccal mucosa metastasis from RCC in a 65-year-old man who presented 19 years after undergoing a left radical nephrectomy for clear cell RCC. Surgical excision of the buccal lesion was performed without evidence of recurrence or new metastatic lesions after 6 years of followup. To our knowledge, this is the first case of metastasis to the buccal mucosa from a RCC reported in the literature.

  3. Isolated Liver Metastasis in Hürthle Cell Thyroid Cancer Treated with Microwave Ablation

    Directory of Open Access Journals (Sweden)

    Konstantinos Segkos

    2017-01-01

    Full Text Available Hürthle cell thyroid cancer (HCTC is a less common form of differentiated thyroid cancer. It rarely metastasizes to the liver, and when it does, the metastasis is almost never isolated. Here we report a 62-year-old male with widely invasive Hürthle cell thyroid cancer, who underwent total thyroidectomy and received adjuvant treatment with I-131 with posttreatment scan showing no evidence of metastatic disease. His thyroglobulin however continued to rise after that and eventually an isolated liver metastasis was identified. He underwent laparoscopic microwave ablation of the liver metastasis, with dramatic decline in thyroglobulin and no structural disease identified to date. This case highlights the rare occurrence of isolated liver metastasis from HCTC and also illustrates the utility of thermoablation as an alternative to surgical resection in the treatment of small isolated liver metastases from HCTC.

  4. Isolated Liver Metastasis in Hürthle Cell Thyroid Cancer Treated with Microwave Ablation.

    Science.gov (United States)

    Segkos, Konstantinos; Schmidt, Carl; Nabhan, Fadi

    2017-01-01

    Hürthle cell thyroid cancer (HCTC) is a less common form of differentiated thyroid cancer. It rarely metastasizes to the liver, and when it does, the metastasis is almost never isolated. Here we report a 62-year-old male with widely invasive Hürthle cell thyroid cancer, who underwent total thyroidectomy and received adjuvant treatment with I-131 with posttreatment scan showing no evidence of metastatic disease. His thyroglobulin however continued to rise after that and eventually an isolated liver metastasis was identified. He underwent laparoscopic microwave ablation of the liver metastasis, with dramatic decline in thyroglobulin and no structural disease identified to date. This case highlights the rare occurrence of isolated liver metastasis from HCTC and also illustrates the utility of thermoablation as an alternative to surgical resection in the treatment of small isolated liver metastases from HCTC.

  5. Breast cancer cell migration is regulated through junctional adhesion molecule-A-mediated activation of Rap1 GTPase.

    LENUS (Irish Health Repository)

    McSherry, Elaine A

    2011-03-23

    ABSTRACT: INTRODUCTION: The adhesion protein junctional adhesion molecule-A (JAM-A) regulates epithelial cell morphology and migration, and its over-expression has recently been linked with increased risk of metastasis in breast cancer patients. As cell migration is an early requirement for tumor metastasis, we sought to identify the JAM-A signalling events regulating migration in breast cancer cells. METHODS: MCF7 breast cancer cells (which express high endogenous levels of JAM-A) and primary cultures from breast cancer patients were used for this study. JAM-A was knocked down in MCF7 cells using siRNA to determine the consequences for cell adhesion, cell migration and the protein expression of various integrin subunits. As we had previously demonstrated a link between the expression of JAM-A and β1-integrin, we examined activation of the β1-integrin regulator Rap1 GTPase in response to JAM-A knockdown or functional antagonism. To test whether JAM-A, Rap1 and β1-integrin lie in a linear pathway, we tested functional inhibitors of all three proteins separately or together in migration assays. Finally we performed immunoprecipitations in MCF7 cells and primary breast cells to determine the binding partners connecting JAM-A to Rap1 activation. RESULTS: JAM-A knockdown in MCF7 breast cancer cells reduced adhesion to, and migration through, the β1-integrin substrate fibronectin. This was accompanied by reduced protein expression of β1-integrin and its binding partners αV- and α5-integrin. Rap1 activity was reduced in response to JAM-A knockdown or inhibition, and pharmacological inhibition of Rap1 reduced MCF7 cell migration. No additive anti-migratory effect was observed in response to simultaneous inhibition of JAM-A, Rap1 and β1-integrin, suggesting that they lie in a linear migratory pathway. Finally, in an attempt to elucidate the binding partners putatively linking JAM-A to Rap1 activation, we have demonstrated the formation of a complex between JAM-A, AF

  6. Breast cancer cell migration is regulated through junctional adhesion molecule-A-mediated activation of Rap1 GTPase

    LENUS (Irish Health Repository)

    McSherry, Elaine A

    2011-03-23

    Abstract Introduction The adhesion protein junctional adhesion molecule-A (JAM-A) regulates epithelial cell morphology and migration, and its over-expression has recently been linked with increased risk of metastasis in breast cancer patients. As cell migration is an early requirement for tumor metastasis, we sought to identify the JAM-A signalling events regulating migration in breast cancer cells. Methods MCF7 breast cancer cells (which express high endogenous levels of JAM-A) and primary cultures from breast cancer patients were used for this study. JAM-A was knocked down in MCF7 cells using siRNA to determine the consequences for cell adhesion, cell migration and the protein expression of various integrin subunits. As we had previously demonstrated a link between the expression of JAM-A and β1-integrin, we examined activation of the β1-integrin regulator Rap1 GTPase in response to JAM-A knockdown or functional antagonism. To test whether JAM-A, Rap1 and β1-integrin lie in a linear pathway, we tested functional inhibitors of all three proteins separately or together in migration assays. Finally we performed immunoprecipitations in MCF7 cells and primary breast cells to determine the binding partners connecting JAM-A to Rap1 activation. Results JAM-A knockdown in MCF7 breast cancer cells reduced adhesion to, and migration through, the β1-integrin substrate fibronectin. This was accompanied by reduced protein expression of β1-integrin and its binding partners αV- and α5-integrin. Rap1 activity was reduced in response to JAM-A knockdown or inhibition, and pharmacological inhibition of Rap1 reduced MCF7 cell migration. No additive anti-migratory effect was observed in response to simultaneous inhibition of JAM-A, Rap1 and β1-integrin, suggesting that they lie in a linear migratory pathway. Finally, in an attempt to elucidate the binding partners putatively linking JAM-A to Rap1 activation, we have demonstrated the formation of a complex between JAM-A, AF-6

  7. Breast cancer cell migration is regulated through junctional adhesion molecule-A-mediated activation of Rap1 GTPase.

    LENUS (Irish Health Repository)

    McSherry, Elaine A

    2012-02-01

    INTRODUCTION: The adhesion protein junctional adhesion molecule-A (JAM-A) regulates epithelial cell morphology and migration, and its over-expression has recently been linked with increased risk of metastasis in breast cancer patients. As cell migration is an early requirement for tumor metastasis, we sought to identify the JAM-A signalling events regulating migration in breast cancer cells. METHODS: MCF7 breast cancer cells (which express high endogenous levels of JAM-A) and primary cultures from breast cancer patients were used for this study. JAM-A was knocked down in MCF7 cells using siRNA to determine the consequences for cell adhesion, cell migration and the protein expression of various integrin subunits. As we had previously demonstrated a link between the expression of JAM-A and beta1-integrin, we examined activation of the beta1-integrin regulator Rap1 GTPase in response to JAM-A knockdown or functional antagonism. To test whether JAM-A, Rap1 and beta1-integrin lie in a linear pathway, we tested functional inhibitors of all three proteins separately or together in migration assays. Finally we performed immunoprecipitations in MCF7 cells and primary breast cells to determine the binding partners connecting JAM-A to Rap1 activation. RESULTS: JAM-A knockdown in MCF7 breast cancer cells reduced adhesion to, and migration through, the beta1-integrin substrate fibronectin. This was accompanied by reduced protein expression of beta1-integrin and its binding partners alphaV- and alpha5-integrin. Rap1 activity was reduced in response to JAM-A knockdown or inhibition, and pharmacological inhibition of Rap1 reduced MCF7 cell migration. No additive anti-migratory effect was observed in response to simultaneous inhibition of JAM-A, Rap1 and beta1-integrin, suggesting that they lie in a linear migratory pathway. Finally, in an attempt to elucidate the binding partners putatively linking JAM-A to Rap1 activation, we have demonstrated the formation of a complex between

  8. SFMBT2 (Scm-like with four mbt domains 2) negatively regulates cell migration and invasion in prostate cancer cells.

    Science.gov (United States)

    Gwak, Jungsug; Shin, Jee Yoon; Lee, Kwanghyun; Hong, Soon Ki; Oh, Sangtaek; Goh, Sung-Ho; Kim, Won Sun; Ju, Bong Gun

    2016-07-26

    Metastatic prostate cancer is the leading cause of morbidity and mortality in men. In this study, we found that expression level of SFMBT2 is altered during prostate cancer progression and has been associated with the migration and invasion of prostate cancer cells. The expression level of SFMBT2 is high in poorly metastatic prostate cancer cells compared to highly metastatic prostate cancer cells. We also found that SFMBT2 knockdown elevates MMP-2, MMP-3, MMP-9, and MMP-26 expression, leading to increased cell migration and invasion in LNCaP and VCaP cells. SFMBT2 interacts with YY1, RNF2, N-CoR and HDAC1/3, as well as repressive histone marks such as H3K9me2, H4K20me2, and H2AK119Ub which are associated with transcriptional repression. In addition, SFMBT2 knockdown decreased KAI1 gene expression through up-regulation of N-CoR gene expression. Expression of SFMBT2 in prostate cancer was strongly associated with clinicopathological features. Patients having higher Gleason score (≥ 8) had substantially lower SFMBT2 expression than patients with lower Gleason score. Moreover, tail vein or intraprostatic injection of SFMBT2 knockdown LNCaP cells induced metastasis. Taken together, our findings suggest that regulation of SFMBT2 may provide a new therapeutic strategy to control prostate cancer metastasis as well as being a potential biomarker of metastatic prostate cancer.

  9. Phospholipase C gamma 1: Mechanisms of Adhesion and Role in Migration and Metastasis

    Science.gov (United States)

    2009-03-01

    product of Molecular Probes. Mouse and rabbit secondary antibodies used in western blotting were purchased from Licor Biosciences. CycloRGD (RGDfV...Pierce) or Streptavidin IR680 ( Licor inc) and visualized by chemiluminescence or an Oddysey fluorescence imager ( Licor inc). RNA Analysis: Cells were

  10. ANGPTL2 increases bone metastasis of breast cancer cells through enhancing CXCR4 signaling.

    Science.gov (United States)

    Masuda, Tetsuro; Endo, Motoyoshi; Yamamoto, Yutaka; Odagiri, Haruki; Kadomatsu, Tsuyoshi; Nakamura, Takayuki; Tanoue, Hironori; Ito, Hitoshi; Yugami, Masaki; Miyata, Keishi; Morinaga, Jun; Horiguchi, Haruki; Motokawa, Ikuyo; Terada, Kazutoyo; Morioka, Masaki Suimye; Manabe, Ichiro; Iwase, Hirotaka; Mizuta, Hiroshi; Oike, Yuichi

    2015-03-16

    Bone metastasis of breast cancer cells is a major concern, as it causes increased morbidity and mortality in patients. Bone tissue-derived CXCL12 preferentially recruits breast cancer cells expressing CXCR4 to bone metastatic sites. Thus, understanding how CXCR4 expression is regulated in breast cancer cells could suggest approaches to decrease bone metastasis of breast tumor cells. Here, we show that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) increases responsiveness of breast cancer cells to CXCL12 by promoting up-regulation of CXCR4 in those cells. In addition, we used a xenograft mouse model established by intracardiac injection of tumor cells to show that ANGPTL2 knockdown in breast cancer cells attenuates tumor cell responsiveness to CXCL12 by decreasing CXCR4 expression in those cells, thereby decreasing bone metastasis. Finally, we found that ANGPTL2 and CXCR4 expression levels within primary tumor tissues from breast cancer patients are positively correlated. We conclude that tumor cell-derived ANGPTL2 may increase bone metastasis by enhancing breast tumor cell responsiveness to CXCL12 signaling through up-regulation of tumor cell CXCR4 expression. These findings may suggest novel therapeutic approaches to treat metastatic breast cancer.

  11. Effects of Angiopoietin-2-Blocking Antibody on Endothelial Cell–Cell Junctions and Lung Metastasis

    OpenAIRE

    2012-01-01

    Background: Angiopoietin-2 (Ang2), a ligand for endothelial TEK (Tie2) tyrosine kinase receptor, is induced in hypoxic endothelial cells of tumors, where it promotes tumor angiogenesis and growth. However, the effects of Ang2 on tumor lymphangiogenesis and metastasis are poorly characterized. Methods: We addressed the effect of Ang2 on tumor progression and metastasis using systemic Ang2 overexpression in mice carrying tumor xenografts, endothelium-specific overexpression of Ang2 in VEC-t...

  12. Clinical application of whole blood red cell distribution width in lung cancer metastasis

    Institute of Scientific and Technical Information of China (English)

    徐阳飏

    2014-01-01

    Objective To investigate the clinical value of whole blood red cell distribution width(RDW)in discriminating lung cancer metastasis.Methods A retropective analysis was conducted on the patients who were initially diagnosed as primary lung cancer.A total of 525 patients were included for analysis between January 2012 and July2013,stratified by different stages and metastasis scenarios.RDW data was investigated.Kruskal-Wallis H tests

  13. Effects of Inhibiting JAK on Invasion and Metastasis of the Human Breast Cancer Cells through ERK Signaling Transduction Pathway

    Institute of Scientific and Technical Information of China (English)

    Jing Zhao; Hong-fang Chen; Hua-yu Deng

    2009-01-01

    Objective: To explore the effects of Janus activated kinase (JAK) inhibitor AG490 on the phosphorylation of extracellular signal regulated protein kinase (ERK) in human breast cancer cells MDA-MB-231 and the roles of JAK in the invasion and metastasis of the human breast cancer cells through ERK signaling transduction pathways.Methods: MDA-MB-231 cells were treated with 20 (mol/L, 40 (mol/L, 80 (mol/L Janus kinase inhibitor AG490 for 24, 48 and 72 h. Proliferation and adhesion of MDA-MB-231 cells to matrigel were measured with MTT assay. When treated with 40 (mol/L AG490 for 24 h, the expressions of P-ERK and MMP-9 of cells were detected by Western-blot and invasion and metastasis of MDA-MB-231 cells were evaluated with transwell chamber.Results: After being treated with 20 (mol/L, 40 (mol/L, 80 (mol/L AG490 for 24, 48 and 72 h, the proliferation of MDA-MB-231 cells was inhibited in a dose-and time-dependent manner. MDA-MB-231 cells treated with 40 (mol/L AG490 for 30, 60, 90 and 120 min resulted in the increasing adhesion of cells to Matrigel in a time-dependent manner. However, capacity of adhesion in the group treated with AG490 was significantly decreased in comparison with the control group (P<0.01). The expression level of P-ERK and MMP-9 were decreased when treated with AG490. After treatment with 40 (mol/L AG490, in invasion assay, the number of cells in AG490 treated group to migrate to filter coated with Matrigel was reduced compared with control group (P<0.05). Meanwhile, in migration assay, the number of cells in AG490 treated group to migrate to filter was also decreased compared with control group (P<0.05).Conclusion: Our study indicates that JAK kinase could affect the activity of ERK signal transduction pathway through the phosphorylation of ERK. The inhibitory effects of JAK kinase on MMP-9 expression and invasion of breast cancer cells were associated with the down-regulation of the ERK signaling pathway.

  14. Evidence that high-migration drug-surviving MOLT4 leukemia cells exhibit cancer stem cell-like properties.

    Science.gov (United States)

    Huang, Xiaoxing; Xiong, Meng; Jin, Yujie; Deng, Chaohua; Xu, Hui; An, Changqing; Hao, Ling; Yang, Xiangyong; Deng, Xinzhou; Tu, Zhenbo; Li, Xinran; Xiao, Ruijing; Zhang, Qiuping

    2016-07-01

    Leukemia represents a spectrum of hematological malignancies threatening human health. Resistance to treatments and metastasis of leukemia are the main causes of death in patients. Leukemia stem cells (LSCs) are the initiating cells of leukemia as well as the main source of drug resistance, invasion and metastasis. Consequently, eliminating LSCs is a prerequisite to eradicate leukemia. Preliminary studies in our laboratory have shown that chemokines and their related receptors play an important role in the drug resistance and metastasis of leukemic cells. In this study, we obtained high migration drug-surviving (short term) MOLT4 cells (hMDSCs-MOLT4) with treatment of doxorubicin (DOX) after Transwell assay. Then we detected stem cell-associated molecular markers on hMDSCs-MOLT4 cells and the parental MOLT4 cells by FCM, QPCR, western blotting, H&E staining and immunohisto-chemistry experimental techniques in vitro and in vivo. Moreover, we explored its impact on drug resistance and tumor formation. Then we found that compared with the parental MOLT4 cells, the mRNA expression levels of stem cell-related factors Sox2, Oct4, C-myc, Klf4, Nanog, Bmi-1, CXCR4 are increased in hMDSCs-MOLT4 cells, together with the protein expression levels of Sox2, Oct4, Klf4, Nanog, CXCR4 and CD34. Our results indicated that hMDSCs-MOLT4 cells exhibited strong drug resistance and certain cancer stem cell-like characteristics. It is the first indication that the targeting stemness factors such as Sox2, Oct4, Klf4, Nanog and CXCR4 may represent plausible options for eliminating T-ALL stem-like cells. The present findings shed light on the relationship between drug-tolerant leukemic cells and cancer stem cells.

  15. The overexpression of SOX2 affects the migration of human teratocarcinoma cell line NT2/D1

    Directory of Open Access Journals (Sweden)

    DANIJELA DRAKULIC

    2015-03-01

    Full Text Available The altered expression of the SOX2 transcription factor is associated with oncogenic or tumor suppressor functions in human cancers. This factor regulates the migration and invasion of different cancer cells. In this study we investigated the effect of constitutive SOX2 overexpression on the migration and adhesion capacity of embryonal teratocarcinoma NT2/D1 cells derived from a metastasis of a human testicular germ cell tumor. We detected that increased SOX2 expression changed the speed, mode and path of cell migration, but not the adhesion ability of NT2/D1 cells. Additionally, we demonstrated that SOX2 overexpression increased the expression of the tumor suppressor protein p53 and the HDM2 oncogene. Our results contribute to the better understanding of the effect of SOX2 on the behavior of tumor cells originating from a human testicular germ cell tumor. Considering that NT2/D1 cells resemble cancer stem cells in many features, our results could contribute to the elucidation of the role of SOX2 in cancer stem cells behavior and the process of metastasis.

  16. The overexpression of SOX2 affects the migration of human teratocarcinoma cell line NT2/D1.

    Science.gov (United States)

    Drakulic, Danijela; Vicentic, Jelena Marjanovic; Schwirtlich, Marija; Tosic, Jelena; Krstic, Aleksandar; Klajn, Andrijana; Stevanovic, Milena

    2015-03-01

    The altered expression of the SOX2 transcription factor is associated with oncogenic or tumor suppressor functions in human cancers. This factor regulates the migration and invasion of different cancer cells. In this study we investigated the effect of constitutive SOX2 overexpression on the migration and adhesion capacity of embryonal teratocarcinoma NT2/D1 cells derived from a metastasis of a human testicular germ cell tumor. We detected that increased SOX2 expression changed the speed, mode and path of cell migration, but not the adhesion ability of NT2/D1 cells. Additionally, we demonstrated that SOX2 overexpression increased the expression of the tumor suppressor protein p53 and the HDM2 oncogene. Our results contribute to the better understanding of the effect of SOX2 on the behavior of tumor cells originating from a human testicular germ cell tumor. Considering that NT2/D1 cells resemble cancer stem cells in many features, our results could contribute to the elucidation of the role of SOX2 in cancer stem cells behavior and the process of metastasis.

  17. Effects of ovarian cancer G protein coupled receptor 1 on the proliferation, migration, and adhesion of human ovarian cancer cells

    Institute of Scientific and Technical Information of China (English)

    REN Juan; ZHANG Long

    2011-01-01

    Background OGR1 was found as a G-protein coupled receptor (GPCR) and proton sensor. Our previous studies have found that OGR1 has inhibitory effect on the metastasis of prostate cancer. In order to investigate the roles of OGR1 gene in the biological activities of ovarian cancer, we studied the OGR1 effects on ovarian cancer cells, HEY cells.Methods OGR1 gene was transfected into HEY cell, in which endogenous expression is low. OGR1-overxepressed cells and vector-transfected cells were compared in different assays. Western blotting was employed to confirm the high expression level of OGR1. Cell proliferation was determined by MTT assay and cell doubling time assay. Cell migration assay (transwell assay) and cell adhesion assay were performed to determine the migration and adhesion potential of cells. Student's t test was employed for statistical analysis.Results Proliferation of OGR1-overexpressed cells was significantly reduced (P <0.01); cell migration was significantly inhibited in the OGR1-transfected cells (P <0.01); cell adhesion to extracellular matrix including fibronectin, vitronectin,collagen Ⅰ/Ⅳ was significantly increased (P <0.01).Conclusions OGR1 expression in human ovarian cancer cells significantly inhibited the cell proliferation and migration,but significantly enhanced cell adhesion to the extracellular matrix. It indicated that OGR1 may be a tumor suppressor gene for ovarian cancer.

  18. Epidermal growth factor-like domain-containing protein 7 (EGFL7 enhances EGF receptor-AKT signaling, epithelial-mesenchymal transition, and metastasis of gastric cancer cells.

    Directory of Open Access Journals (Sweden)

    Bai-Hua Luo

    Full Text Available Epidermal growth factor-like domain-containing protein 7 (EGFL7 is upregulated in human epithelial tumors and so is a potential biomarker for malignancy. Indeed, previous studies have shown that high EGFL7 expression promotes infiltration and metastasis of gastric carcinoma. The epithelial-mesenchymal transition (EMT initiates the metastatic cascade and endows cancer cells with invasive and migratory capacity; however, it is not known if EGFL7 promotes metastasis by triggering EMT. We found that EGFL7 was overexpressed in multiple human gastric cancer (GC cell lines and that overexpression promoted cell invasion and migration as revealed by scratch wound and transwell migration assays. Conversely, shRNA-mediated EGFL7 knockdown reduced invasion and migration. Furthermore, EGFL7-overexpressing cells grew into larger tumors and were more likely to metastasize to the liver compared to underexpressing CG cells following subcutaneous injection in mice. EGFL7 overexpression protected GC cell lines against anoikis, providing a plausible mechanism for this enhanced metastatic capacity. In excised human gastric tumors, expression of EGFL7 was positively correlated with expression levels of the mesenchymal marker vimentin and the EMT-associated transcription repressor Snail, and negatively correlated with expression of the epithelial cell marker E-cadherin. In GC cell lines, EGFL7 knockdown reversed morphological signs of EMT and decreased both vimentin and Snail expression. In addition, EGFL7 overexpression promoted EGF receptor (EGFR and protein kinase B (AKT phospho-activation, effects markedly suppressed by the EGFR tyrosine kinase inhibitor AG1478. Moreover, AG1478 also reduced the elevated invasive and migratory capacity of GC cell lines overexpressing EGFL7. Collectively, these results strongly suggest that EGFL7 promotes metastasis by activating EMT through an EGFR-AKT-Snail signaling pathway. Disruption of EGFL7-EGFR-AKT-Snail signaling may a

  19. Mammalian CAP (Cyclase-associated protein) in the world of cell migration: Roles in actin filament dynamics and beyond.

    Science.gov (United States)

    Zhou, Guo-Lei; Zhang, Haitao; Field, Jeffrey

    2014-01-01

    Cell migration is essential for a variety of fundamental biological processes such as embryonic development, wound healing, and immune response. Aberrant cell migration also underlies pathological conditions such as cancer metastasis, in which morphological transformation promotes spreading of cancer to new sites. Cell migration is driven by actin dynamics, which is the repeated cycling of monomeric actin (G-actin) into and out of filamentous actin (F-actin). CAP (Cyclase-associated protein, also called Srv2) is a conserved actin-regulatory protein, which is implicated in cell motility and the invasiveness of human cancers. It cooperates with another actin regulatory protein, cofilin, to accelerate actin dynamics. Hence, knockdown of CAP1 slows down actin filament turnover, which in most cells leads to reduced cell motility. However, depletion of CAP1 in HeLa cells, while causing reduction in dynamics, actually led to increased cell motility. The increases in motility are likely through activation of cell adhesion signals through an inside-out signaling. The potential to activate adhesion signaling competes with the negative effect of CAP1 depletion on actin dynamics, which would reduce cell migration. In this commentary, we provide a brief overview of the roles of mammalian CAP1 in cell migration, and highlight a likely mechanism underlying the activation of cell adhesion signaling and elevated motility caused by depletion of CAP1.

  20. Lutein Inhibits the Migration of Retinal Pigment Epithelial Cells via Cytosolic and Mitochondrial Akt Pathways (Lutein Inhibits RPE Cells Migration

    Directory of Open Access Journals (Sweden)

    Ching-Chieh Su

    2014-08-01

    Full Text Available During the course of proliferative vitreoretinopathy (PVR, the retinal pigment epithelium (RPE cells will de-differentiate, proliferate, and migrate onto the surfaces of the sensory retina. Several studies have shown that platelet-derived growth factor (PDGF can induce migration of RPE cells via an Akt-related pathway. In this study, the effect of lutein on PDGF-BB-induced RPE cells migration was examined using transwell migration assays and Western blot analyses. We found that both phosphorylation of Akt and mitochondrial translocation of Akt in RPE cells induced by PDGF-BB stimulation were suppressed by lutein. Furthermore, the increased migration observed in RPE cells with overexpressed mitochondrial Akt could also be suppressed by lutein. Our results demonstrate that lutein can inhibit PDGF-BB induced RPE cells migration through the inhibition of both cytoplasmic and mitochondrial Akt activation.

  1. Melatonin inhibits MMP-9 transactivation and renal cell carcinoma metastasis by suppressing Akt-MAPKs pathway and NF-κB DNA-binding activity.

    Science.gov (United States)

    Lin, Yung-Wei; Lee, Liang-Ming; Lee, Wei-Jiunn; Chu, Chih-Ying; Tan, Peng; Yang, Yi-Chieh; Chen, Wei-Yu; Yang, Shun-Fa; Hsiao, Michael; Chien, Ming-Hsien

    2016-04-01

    Renal cell carcinoma (RCC) is the most lethal of all urological malignancies because of its potent metastasis potential. Melatonin exerts multiple tumor-suppressing activities through antiproliferative, proapoptotic, and anti-angiogenic actions and has been tested in clinical trials. However, the antimetastastic effect of melatonin and its underlying mechanism in RCC are unclear. In this study, we demonstrated that melatonin at the pharmacologic concentration (0.5-2 mm) considerably reduced the migration and invasion of RCC cells (Caki-1 and Achn). Furthermore, we found that melatonin suppressed metastasis of Caki-1 cells in spontaneous and experimental metastasis animal models. Mechanistic investigations revealed that melatonin transcriptionally inhibited MMP-9 by reducing p65- and p52-DNA-binding activities. Moreover, the Akt-mediated JNK1/2 and ERK1/2 signaling pathways were involved in melatonin-regulated MMP-9 transactivation and cell motility. Clinical samples revealed an inverse correlation between melatonin receptor 1A (MTNR1A) and MMP-9 expression in normal kidney and RCC tissues. In addition, a higher survival rate was found in MTNR1A(high) /MMP-9(low) patients than in MTNR1A(low) /MMP-9(high) patients. Overall, our results provide new insights into the role of melatonin-induced molecular regulation in suppressing RCC metastasis and suggest that melatonin has potential therapeutic applications for metastastic RCC.

  2. Differential expression of the RANKL/RANK/OPG system is associated with bone metastasis in human non-small cell lung cancer.

    Directory of Open Access Journals (Sweden)

    Xianbo Peng

    Full Text Available BACKGROUND: Human non-small cell lung cancer (NSCLC patients exhibit a high propensity to develop skeletal metastasis, resulting in excessive osteolytic activity. The RANKL/RANK/OPG system, which plays a pivotal role in bone remodeling by regulating osteoclast formation and activity, is of potential interest in this context. MATERIALS AND METHODS: Reverse transcriptase polymerase chain reaction, western blotting, and immunohistochemical analysis were used to examine the expression of RANKL, RANK, and OPG in human NSCLC cell lines with different metastatic potentials, as well as in 52 primary NSCLC samples and 75 NSCLC bone metastasis samples. In primary NSCLC patients, the expression of these proteins was correlated with clinicopathological parameters. Recombinant human RANKL and transfected RANKL cDNA were added to the PAa cell line to evaluate the promoter action of RANKL during the process of metastasis in vitro and in vivo. RESULTS: Up-regulated RANKL, RANK, and OPG expression and increased RANKL:OPG ratio were detected in NSCLC cell lines and in tumor tissues with bone metastasis, and were correlated with higher metastatic potential. The metastatic potential of NSCLC in vitro and in vivo, including migration and invasion ability, was significantly enhanced by recombinant human RANKL and the transfection of RANKL cDNA, and was impaired after OPG was added. The increased expression of RANKL and OPG correlated with tumor stage, lymph node metastasis, and distant metastasis. CONCLUSIONS: Differential expression of RANKL, RANK, and OPG is associated with the metastatic potential of human NSCLC to skeleton, raising the possibility that the RANKL/RANK/OPG system could be a therapeutic target for the treatment of metastatic NSCLC patients.

  3. CD99 suppresses osteosarcoma cell migration through inhibition of ROCK2 activity.

    Science.gov (United States)

    Zucchini, C; Manara, M C; Pinca, R S; De Sanctis, P; Guerzoni, C; Sciandra, M; Lollini, P-L; Cenacchi, G; Picci, P; Valvassori, L; Scotlandi, K

    2014-04-10

    CD99, a transmembrane protein encoded by MIC2 gene is involved in multiple cellular events including cell adhesion and migration, apoptosis, cell differentiation and regulation of protein trafficking either in physiological or pathological conditions. In osteosarcoma, CD99 is expressed at low levels and functions as a tumour suppressor. The full-length protein (CD99wt) and the short-form harbouring a deletion in the intracytoplasmic domain (CD99sh) have been associated with distinct functional outcomes with respect to tumour malignancy. In this study, we especially evaluated modulation of cell-cell contacts, reorganisation of the actin cytoskeleton and modulation of signalling pathways by comparing osteosarcoma cells characterised by different metastasis capabilities and CD99 expression, to identify molecular mechanisms responsible for metastasis. Our data indicate that forced expression of CD99wt induces recruitment of N-cadherin and β-catenin to adherens junctions. In addition, transfection of CD99wt inhibits the expression of several molecules crucial to the remodelling of the actin cytoskeleton, such as ACTR2, ARPC1A, Rho-associated, coiled-coil containing protein kinase 2 (ROCK2) as well as ezrin, an ezrin/radixin/moesin family member that has been clearly associated with tumour progression and metastatic spread in osteosarcoma. Functional studies point to ROCK2 as a crucial intracellular mediator regulating osteosarcoma migration. By maintaining c-Src in an inactive conformation, CD99wt inhibits ROCK2 signalling and this leads to ezrin decrease at cell membrane while N-cadherin and β-catenin translocate to the plasma membrane and function as main molecular bridges for actin cytoskeleton. Taken together, we propose that the re-expression of CD99wt, which is generally present in osteoblasts but lost in osteosarcoma, through inhibition of c-Src and ROCK2 activity, manages to increase contact strength and reactivate stop-migration signals that counteract the

  4. GTSE1 is a microtubule plus-end tracking protein that regulates EB1-dependent cell migration.

    Directory of Open Access Journals (Sweden)

    Massimilano Scolz

    Full Text Available The regulation of cell migration is a highly complex process that is often compromised when cancer cells become metastatic. The microtubule cytoskeleton is necessary for cell migration, but how microtubules and microtubule-associated proteins regulate multiple pathways promoting cell migration remains unclear. Microtubule plus-end binding proteins (+TIPs are emerging as important players in many cellular functions, including cell migration. Here we identify a +TIP, GTSE1, that promotes cell migration. GTSE1 accumulates at growing microtubule plus ends through interaction with the EB1+TIP. The EB1-dependent +TIP activity of GTSE1 is required for cell migration, as well as for microtubule-dependent disassembly of focal adhesions. GTSE1 protein levels determine the migratory capacity of both nontransformed and breast cancer cell lines. In breast cancers, increased GTSE1 expression correlates with invasive potential, tumor stage, and time to distant metastasis, suggesting that misregulation of GTSE1 expression could be associated with increased invasive potential.

  5. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis.

    Science.gov (United States)

    Hood, Joshua L; San, Roman Susana; Wickline, Samuel A

    2011-06-01

    Exosomes are naturally occurring biological nanovesicles utilized by tumors to communicate signals to local and remote cells and tissues. Melanoma exosomes can incite a proangiogenic signaling program capable of remodeling tissue matrices. In this study, we show exosome-mediated conditioning of lymph nodes and define microanatomic responses that license metastasis of melanoma cells. Homing of melanoma exosomes to sentinel lymph nodes imposes synchronized molecular signals that effect melanoma cell recruitment, extracellular matrix deposition, and vascular proliferation in the lymph nodes. Our findings highlight the pathophysiologic role and mechanisms of an exosome-mediated process of microanatomic niche preparation that facilitates lymphatic metastasis by cancer cells.

  6. P-selectin-mediated platelet adhesion promotes the metastasis of murine melanoma cells.

    Science.gov (United States)

    Qi, Cui-Ling; Wei, Bo; Ye, Jie; Yang, Yang; Li, Bin; Zhang, Qian-Qian; Li, Jiang-Chao; He, Xiao-Dong; Lan, Tian; Wang, Li-Jing

    2014-01-01

    Studies have indicated that the aggregation of activated platelets with cancer cells facilitates tumor metastasis; the adhesion molecule P-selectin may be an important mediator of this process, but the detailed mechanism is unclear. In the current study, we established a B16F10 (B16) cell metastatic model in P-selectin knockout (P-sel-/-) mice to determine the effect of P-selectin-mediated platelet adhesion on metastasis. Compared with C57 mice, P-sel-/- mice developed fewer metastatic foci, and cell proliferation within the metastatic tumors was inhibited by P-selectin deficiency. The platelet refusion assay demonstrated that mice with P-sel-/- platelets developed fewer lung metastatic foci (PP-selectin deficiency inhibited the metastasis of B16 cells and that wild-type platelet refusion reversed this inhibition. The P-selectin-mediated interaction between platelets and B16 cells promoted angiogenesis by up-regulating VEGF.

  7. Squamous cell carcinoma of the pancreas with liver metastasis: a case report

    Institute of Scientific and Technical Information of China (English)

    CHEN Qiang-pu; OU Kun; GUAN Qing-hai; ZHANG Fan

    2008-01-01

    @@ Squamous cell carcinoma of the pancreas is an unusual cancer of ductal cell origin. In a review of 6668 cases of exocrine pancreatic cancer from various registries reported from 1950 through 1985, the incidence of squamous carcinoma and adenosquamous carcinoma was 0.005% and 0.01%, respectively.1 We report a case of squamous cell carcinoma of the pancreas with liver metastasis.

  8. Platelets alter tumor cell attributes to propel metastasis: programming in transit.

    Science.gov (United States)

    Gay, Laurie J; Felding-Habermann, Brunhilde

    2011-11-15

    Metastasis of epithelial tumors critically depends on acquisition of a disseminating phenotype that allows tumor cells to colonize distant organs. In this issue of Cancer Cell, Labelle et al. demonstrate that an epithelial-mesenchymal-like transition can be induced by interaction between platelets and tumor cells.

  9. Structural and functional aspects of the liver and liver sinusoidal cells in relation to colon carcinoma metastasis

    Institute of Scientific and Technical Information of China (English)

    Katrien Vekemans; Filip Braet

    2005-01-01

    Nowadays, liver metastasis remains difficult to cure. When tumor cells escape and arrive in the liver sinusoids, they encounter the local defense mechanism specific to the liver. The sinusoidal cells have been widely described in physiologic conditions and in relation to metastasis during the past 30 years. This paper provides an "overview" of how these cells function in health and in diseases such as liver metastasis.

  10. Reduction of metastasis, cell invasion, and adhesion in mouse osteosarcoma by YM529/ONO-5920-induced blockade of the Ras/MEK/ERK and Ras/PI3K/Akt pathway

    Energy Technology Data Exchange (ETDEWEB)

    Tsubaki, Masanobu [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502 (Japan); Satou, Takao; Itoh, Tatsuki [Department of Pathology, Kinki University School of Medicine, Osakasayama, Osaka 589-8511 (Japan); Imano, Motohiro [Department of Surgery, Kinki University School of Medicine, Osakasayama, Osaka 589-8511 (Japan); Ogaki, Mitsuhiko [Department of Pharmacy, Higahiosaka City General Hospital, Higashi-osaka, Osaka 578-8588 (Japan); Yanae, Masashi [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502 (Japan); Depeartment of Pharmacy, Sakai Hospital, Kinki University School of Medicine, Sakai, Osaka 590-0132 (Japan); Nishida, Shozo, E-mail: nishida@phar.kindai.ac.jp [Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502 (Japan)

    2012-03-15

    Osteosarcoma is one of the most common primary malignant bone tumors in children and adolescents. Some patients continue to have a poor prognosis, because of the metastatic disease. YM529/ONO-5920 is a nitrogen-containing bisphosphonate that has been used for the treatment of osteoporosis. YM529/ONO-5920 has recently been reported to induce apoptosis in various tumors including osteosarcoma. However, the mode of metastasis suppression in osteosarcoma by YM529/ONO-5920 is unclear. In the present study, we investigated whether YM529/ONO-5920 inhibited tumor cell migration, invasion, adhesion, or metastasis in the LM8 mouse osteosarcoma cell line. We found that YM529/ONO-5920 significantly inhibited metastasis, cell migration, invasion, and adhesion at concentrations that did not have antiproliferative effects on LM8 cells. YM529/ONO-5920 also inhibited the mRNA expression and protein activities of matrix metalloproteinases (MMPs). In addition, YM529/ONO-5920 suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and the serine/threonine protein kinase B (Akt) by the inhibition of Ras prenylation. Moreover, U0126, a mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, also inhibited LM8 cell migration, invasion, adhesion, and metastasis, as well as the mRNA expression and protein activities of MMP-1, MMP-2, MMP-9, and MT1-MMP. The results indicated that YM529/ONO-5920 suppressed the Ras/MEK/ERK and Ras/PI3K/Akt pathways, thereby inhibiting LM8 cell migration, invasion, adhesion, and metastasis. These findings suggest that YM529/ONO-5920 has potential clinical applications for the treatment of tumor cell metastasis in osteosarcoma. -- Highlights: ► We investigated whether YM529/ONO-5920 inhibited tumor metastasis in osteosarcoma. ► YM529/ONO-5920 inhibited metastasis, cell migration, invasion, and adhesion. ► YM529/ONO-5920 suppressed Ras signalings. ► YM529/ONO-5920

  11. Tinospora crispa extract inhibits MMP-13 and migration of head and neck squamous cell carcinoma cell lines

    Institute of Scientific and Technical Information of China (English)

    Hataipan; Phienwej; Ih-si; Swasdichira; Surattana; Amnuoypol; Prasit; Pavasant; Piyamas; Sumrejkanchanakij

    2015-01-01

    Objective: To investigate the effect of Tinospora crispa(T. crispa) extract on matrix metalloproteinase 13(MMP-13) expression and cell migration. Methods: The cytotoxicity of T. crispa extract was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay on head and neck squamous cell carcinoma(HNSCC) cell lines. The effect on expression of MMP-13 was analysed by RT-PCR and ELISA. The migration was assessed by wound healing assay. Results: MMP-13 m RNA was highly expressed in the metastatic human HNSCC cell lines, HN22 and HSC-3. T. crispa extract at a concentration of 100.0 μg/m L caused about 50% reduction of cell survival. T. crispa extract at a non-toxic concentration of 12.5, 25.0 and 50.0 μg/m L signii cantly suppressed MMP-13 m RNA expression and secreted MMP-13 in both HN22 and HSC-3. The expression of tissue inhibitors of metalloprotease by HSC-3 cells was attenuated by 25.0 and 50.0 μg/m L of T. crispa extract. Addition of the extract to cells in a wound healing assay showed inhibition of cell migration by HN22 cells. Conclusions: These data suggest that T. crispa could be considered as a potential therapeutic drug to prevent metastasis of HNSCC.

  12. Tinospora crispa extract inhibits MMP-13 and migration of head and neck squamous cell carcinoma cell lines

    Institute of Scientific and Technical Information of China (English)

    Hataipan Phienwej; Ih-si Swasdichira; Surattana Amnuoypol; Prasit Pavasant; Piyamas Sumrejkanchanakij

    2015-01-01

    To investigate the effect of Tinospora crispa (T. crispa) extract on matrix metalloproteinase 13 (MMP-13) expression and cell migration. Methods: The cytotoxicity of T. crispa extract was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay on head and neck squamous cell carcinoma (HNSCC) cell lines. The effect on expression of MMP-13 was analysed by RT-PCR and ELISA. The migration was assessed by wound healing assay. Results: MMP-13 mRNA was highly expressed in the metastatic human HNSCC cell lines, HN22 and HSC-3. T. crispa extract at a concentration of 100.0 µg/mL caused about 50% reduction of cell survival. T. crispa extract at a non-toxic concentration of 12.5, 25.0 and 50.0 µg/mL significantly suppressed MMP-13 mRNA expression and secreted MMP-13 in both HN22 and HSC-3. The expression of tissue inhibitors of metalloprotease by HSC-3 cells was attenuated by 25.0 and 50.0 µg/mL of T. crispa extract. Addition of the extract to cells in a wound healing assay showed inhibition of cell migration by HN22 cells. Conclusions: These data suggest that T. crispa could be considered as a potential therapeutic drug to prevent metastasis of HNSCC.

  13. Up-Regulated FASN Expression Promotes Transcoelomic Metastasis of Ovarian Cancer Cell through Epithelial-Mesenchymal Transition

    Directory of Open Access Journals (Sweden)

    Li Jiang

    2014-06-01

    Full Text Available Fatty acid synthase (FASN, responsible for the de novo synthesis of fatty acids, has been shown to act as an oncogene in various human cancers. However, the mechanisms by which FASN favors the progression of ovarian carcinoma remain unknown. In this study, we evaluated FASN expression in ovarian cancer and investigated how FASN regulates the aggressiveness of ovarian cancer cells. Our results show that increased FASN is associated with the peritoneal metastasis of ovarian cancers. Over-expression of FASN results in a significant increase of tumor burden in peritoneal dissemination, accompanied by augment in cellular colony formation and metastatic ability. Correspondingly, FASN knockdown using RNA interference in ovarian cancer cells inhibits the migration in vitro and experimental peritoneal dissemination in vivo. Mechanistic studies reveal that FASN promotes Epithelial-mesenchymal Transition (EMT via a transcriptional regulation of E-cadherin and N-cadherin, which is also confirmed by luciferase promoter activity analysis. Taken together, our work demonstrates that FASN promotes the peritoneal dissemination of ovarian cancer cells, at least in part through the induction of EMT. These findings suggest that FASN plays a critical role in the peritoneal metastasis of ovarian cancer. Targeting de novo lipogenesis may have a therapeutic potential for advanced ovarian cancer.

  14. Effects of Chemotherapy-Induced Alterations in Cell Mechanical Properties on Cancer Metastasis

    Science.gov (United States)

    Prathivadhi, Sruti; Ekpenyong, Andrew; Nichols, Michael; Taylor, Carolyn; Ning, Jianhao

    Biological cells can modulate their mechanical properties to suit their functions and in response to changes in their environment. Thus, mechanical phenotyping of cells has been employed for tracking stem cell differentiation, bacterial infection, cell death, etc. Malignant transformation of cells also involves changes in mechanical properties. However, the extent to which mechanical properties of cancer cells contribute to metastasis is not well understood. Yet, more than 90% of all cancer deaths are directly related to metastasis. Transit of cells through the microcirculation is one of the key features of metastasis. We hypothesize that cancer treatment regimens do inadvertently alter cell mechanical properties in ways that might promote cancer metastasis. We use a microfluidic microcirculation mimetic (MMM) platform which mimics the capillary constrictions of the pulmonary and peripheral microcirculation to determine if in-vivo-like mechanical stimuli can evoke different responses from cells subjected to various cancer drugs. In particular, we show that cancer cells treated with chemotherapeutic drugs such as daunorubicin, become more deformable at short timescales (0.1 s) and transit faster through the device. Our results are first steps in evaluating the pro- or anti-metastatic effects of chemotherapeutic drugs based on their induced alterations in cell mechanical properties.

  15. AHNAK is highly expressed and plays a key role in cell migration and invasion in mesothelioma.

    Science.gov (United States)

    Sudo, Hitomi; Tsuji, Atsushi B; Sugyo, Aya; Abe, Masaaki; Hino, Okio; Saga, Tsuneo

    2014-02-01

    The worldwide incidence of the highly aggressive tumor mesothelioma is expected to increase. Mesothelioma is classified into three main histological subtypes: epithelioid, sarcomatoid and biphasic. Although the pathological diagnostic markers for epithelioid are established, to date no adequate marker for sarcomatoid mesothelioma has been found. Thus, a reliable diagnostic marker of sarcomatoid mesothelioma is necessary. In this study, to identify an unknown protein with 120 kDa expressed only in the mesothelioma cell line 211H, we conducted proteomic analysis and found five candidate proteins. One such protein, AHNAK, was highly expressed in all seven mesothelioma cell lines (211H, H28, H226, H2052, H2452, MESO1 and MESO4), but not in the mesothelial cell line MeT-5A by RT-PCR and immunofluorescence staining. Furthermore, we confirmed high AHNAK expression not only in xenografts but also in human mesothelioma specimens including sarcomatoid, epithelioid and biphasic mesothelioma using immunohistochemical staining. These findings suggest that AHNAK has the potential to be a new marker for detecting mesothelioma. Since AHNAK is involved in cell migration and invasion in other metastatic tumor cells, we conducted migration and invasion assays in mesothelioma cell lines. The number of migrating cells in six of seven mesothelioma cell lines and the number of invading cells in all seven cell lines were significantly increased compared with those in MeT-5A. Knockdown of AHNAK significantly reduced the cell migration and invasion ability in all seven mesothelioma cell lines. These results support further clinical evaluation of the association of AHNAK and metastasis in mesothelioma.

  16. Pak3 regulates apical-basal polarity in migrating border cells during Drosophila oogenesis.

    Science.gov (United States)

    Felix, Martina; Chayengia, Mrinal; Ghosh, Ritabrata; Sharma, Aditi; Prasad, Mohit

    2015-11-01

    Group cell migration is a highly coordinated process that is involved in a number of physiological events such as morphogenesis, wound healing and tumor metastasis. Unlike single cells, collectively moving cells are physically attached to each other and retain some degree of apical-basal polarity during the migratory phase. Although much is known about direction sensing, how polarity is regulated in multicellular movement remains unclear. Here we report the role of the protein kinase Pak3 in maintaining apical-basal polarity in migrating border cell clusters during Drosophila oogenesis. Pak3 is enriched in border cells and downregulation of its function impedes border cell movement. Time-lapse imaging suggests that Pak3 affects protrusive behavior of the border cell cluster, specifically regulating the stability and directionality of protrusions. Pak3 functions downstream of guidance receptor signaling to regulate the level and distribution of F-actin in migrating border cells. We also provide evidence that Pak3 genetically interacts with the lateral polarity marker Scribble and that it regulates JNK signaling in the moving border cells. Since Pak3 depletion results in mislocalization of several apical-basal polarity markers and overexpression of Jra rescues the polarity of the Pak3-depleted cluster, we propose that Pak3 functions through JNK signaling to modulate apical-basal polarity of the migrating border cell cluster. We also observe loss of apical-basal polarity in Rac1-depleted border cell clusters, suggesting that guidance receptor signaling functions through Rac GTPase and Pak3 to regulate the overall polarity of the cluster and mediate efficient collective movement of the border cells to the oocyte boundary.

  17. Curcumin Suppresses Phthalate-Induced Metastasis and the Proportion of Cancer Stem Cell (CSC)-like Cells via the Inhibition of AhR/ERK/SK1 Signaling in Hepatocellular Carcinoma.

    Science.gov (United States)

    Tsai, Cheng-Fang; Hsieh, Tsung-Hua; Lee, Jau-Nan; Hsu, Chia-Yi; Wang, Yu-Chih; Kuo, Kung-Kai; Wu, Hua-Lin; Chiu, Chien-Chih; Tsai, Eing-Mei; Kuo, Po-Lin

    2015-12-09

    Recent evidence indicating that phthalates promote cancer development, including cell proliferation, migration, and invasion, has raised public health concerns. Here, we show that bis(2-ethylhexyl) phthalate promotes the migration, invasion, and epithelial-mesenchymal transition of hepatocellular carcinoma cells. In addition, bis(2-ethylhexyl) phthalate increased the proportion of cancer stem cell (CSC)-like cells and stemness maintenance in vitro as well as tumor growth and metastasis in vivo. The various activities of curcumin, including anticancer, anti-inflammation, antioxidation, and immunomodulation, have been investigated extensively. Curcumin suppressed phthalate-induced cell migration, invasion, and epithelial-mesenchymal transition, decreased the proportion of CSC-like cells in hepatocellular carcinoma cell lines in vitro, and inhibited tumor growth and metastasis in vivo. We also reveal that curcumin suppressed phthalate-induced migration, invasion, and CSC-like cell maintenance through inhibition of the aryl hydrocarbon receptor/ERK/SK1/S1P3 signaling pathway. Our results suggest that curcumin may be a potential antidote for phthalate-induced cancer progression.

  18. Rab25 upregulation correlates with the proliferation, migration, and invasion of renal cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yuanyuan; Jia, Qingzhu [Biomedical Analysis Center, Third Military Medical University, Chongqing (China); Chongqing Key Laboratory of Cytomics, Chongqing (China); Zhang, Qian [Department of Urology, Xinqiao Hospital, Third Military Medical University, Chongqing (China); Wan, Ying, E-mail: wanying_cn@163.com [Biomedical Analysis Center, Third Military Medical University, Chongqing (China); Chongqing Key Laboratory of Cytomics, Chongqing (China)

    2015-03-20

    Renal cell carcinoma (RCC) is a common urological cancer with a poor prognosis. A recent cohort study revealed that the median survival of RCC patients was only 1.5 years and that <10% of the patients in the study survived up to 5 years. In tumor development, Rab GTPase are known to play potential roles such as regulation of cell proliferation, migration, invasion, communication, and drug resistance in multiple tumors. However, the correlation between Rabs expression and the occurrence, development, and metastasis of RCC remains unclear. In this study, we analyzed the transcriptional levels of 52 Rab GTPases in RCC patients. Our results showed that high levels of Rab25 expression were significantly correlated with RCC invasion classification (P < 0.01), lymph-node metastasis (P < 0.001), and pathological stage (P < 0.01). Conversely, in 786-O and A-498 cells, knocking down Rab25 protein expression inhibited cell proliferation, migration, and invasion. Our results also demonstrated that Rab25 is a target gene of let-7d, and further suggested that Rab25 upregulation in RCC is due to diminished expression of let-7d. These findings indicate that Rab25 might be a novel candidate molecule involved in RCC development, thus identifying a potential biological therapeutic target for RCC. - Highlights: • The transcriptional levels of 52 Rab GTPases were analyzed in renal cell carcinoma (RCC). • High levels of Rab25 expression were significantly correlated with clinicopathological factors of RCC. • Knockdown of Rab25 protein expression reduced RCC cells proliferation, migration, and invasion. • Rab25 is a target gene of let-7d in RCC.

  19. Modeled microgravity suppressed invasion and migration of human glioblastoma U87 cells through downregulating store-operated calcium entry.

    Science.gov (United States)

    Shi, Zi-xuan; Rao, Wei; Wang, Huan; Wang, Nan-ding; Si, Jing-wen; Zhao, Jiao; Li, Jun-chang; Wang, Zong-ren

    2015-02-13

    Glioblastoma is the most common brain tumor and is characterized with robust invasion and migration potential resulting in poor prognosis. Previous investigations have demonstrated that modeled microgravity (MMG) could decline the cell proliferation and attenuate the metastasis potential in several cell lines. In this study, we studied the effects of MMG on the invasion and migration potentials of glioblastoma in human glioblastoma U87 cells. We found that MMG stimulation significantly attenuated the invasion and migration potentials, decreased thapsigargin (TG) induced store-operated calcium entry (SOCE) and downregulated the expression of Orai1 in U87 cells. Inhibition of SOCE by 2-APB or stromal interaction molecule 1 (STIM1) downregulation both mimicked the effects of MMG on the invasion and migration potentials in U87 cells. Furthermore, upregulation of Orai1 significantly weakened the effects of MMG on the invasion and migration potentials in U87 cells. Therefore, these findings indicated that MMG stimulation inhibited the invasion and migration potentials of U87 cells by downregulating the expression of Orai1 and sequentially decreasing the SOCE, suggesting that MMG might be a new potential therapeutic strategy in glioblastoma treatment in the future.

  20. MicroRNA and protein profiling of brain metastasis competent cell-derived exosomes.

    Directory of Open Access Journals (Sweden)

    Laura Camacho

    Full Text Available Exosomes are small membrane vesicles released by most cell types including tumor cells. The intercellular exchange of proteins and genetic material via exosomes is a potentially effective approach for cell-to-cell communication and it may perform multiple functions aiding to tumor survival and metastasis. We investigated microRNA and protein profiles of brain metastatic (BM versus non-brain metastatic (non-BM cell-derived exosomes. We studied the cargo of exosomes isolated from brain-tropic 70W, MDA-MB-231BR, and circulating tumor cell brain metastasis-selected markers (CTC1BMSM variants, and compared them with parental non-BM MeWo, MDA-MB-231P and CTC1P cells, respectively. By performing microRNA PCR array we identified one up-regulated (miR-210 and two down-regulated miRNAs (miR-19a and miR-29c in BM versus non-BM exosomes. Second, we analyzed the proteomic content of cells and exosomes isolated from these six cell lines, and detected high expression of proteins implicated in cell communication, cell cycle, and in key cancer invasion and metastasis pathways. Third, we show that BM cell-derived exosomes can be internalized by non-BM cells and that they effectively transport their cargo into cells, resulting in increased cell adhesive and invasive potencies. These results provide a strong rationale for additional investigations of exosomal proteins and miRNAs towards more profound understandings of exosome roles in brain metastasis biogenesis, and for the discovery and application of non-invasive biomarkers for new therapies combating brain metastasis.

  1. MicroRNA and protein profiling of brain metastasis competent cell-derived exosomes.

    Science.gov (United States)

    Camacho, Laura; Guerrero, Paola; Marchetti, Dario

    2013-01-01

    Exosomes are small membrane vesicles released by most cell types including tumor cells. The intercellular exchange of proteins and genetic material via exosomes is a potentially effective approach for cell-to-cell communication and it may perform multiple functions aiding to tumor survival and metastasis. We investigated microRNA and protein profiles of brain metastatic (BM) versus non-brain metastatic (non-BM) cell-derived exosomes. We studied the cargo of exosomes isolated from brain-tropic 70W, MDA-MB-231BR, and circulating tumor cell brain metastasis-selected markers (CTC1BMSM) variants, and compared them with parental non-BM MeWo, MDA-MB-231P and CTC1P cells, respectively. By performing microRNA PCR array we identified one up-regulated (miR-210) and two down-regulated miRNAs (miR-19a and miR-29c) in BM versus non-BM exosomes. Second, we analyzed the proteomic content of cells and exosomes isolated from these six cell lines, and detected high expression of proteins implicated in cell communication, cell cycle, and in key cancer invasion and metastasis pathways. Third, we show that BM cell-derived exosomes can be internalized by non-BM cells and that they effectively transport their cargo into cells, resulting in increased cell adhesive and invasive potencies. These results provide a strong rationale for additional investigations of exosomal proteins and miRNAs towards more profound understandings of exosome roles in brain metastasis biogenesis, and for the discovery and application of non-invasive biomarkers for new therapies combating brain metastasis.

  2. Multi-cellular logistics of collective cell migration.

    Directory of Open Access Journals (Sweden)

    Masataka Yamao

    Full Text Available During development, the formation of biological networks (such as organs and neuronal networks is controlled by multicellular transportation phenomena based on cell migration. In multi-cellular systems, cellular locomotion is restricted by physical interactions with other cells in a crowded space, similar to passengers pushing others out of their way on a packed train. The motion of individual cells is intrinsically stochastic and may be viewed as a type of random walk. However, this walk takes place in a noisy environment because the cell interacts with its randomly moving neighbors. Despite this randomness and complexity, development is highly orchestrated and precisely regulated, following genetic (and even epigenetic blueprints. Although individual cell migration has long been studied, the manner in which stochasticity affects multi-cellular transportation within the precisely controlled process of development remains largely unknown. To explore the general principles underlying multicellular migration, we focus on the migration of neural crest cells, which migrate collectively and form streams. We introduce a mechanical model of multi-cellular migration. Simulations based on the model show that the migration mode depends on the relative strengths of the noise from migratory and non-migratory cells. Strong noise from migratory cells and weak noise from surrounding cells causes "collective migration," whereas strong noise from non-migratory cells causes "dispersive migration." Moreover, our theoretical analyses reveal that migratory cells attract each other over long distances, even without direct mechanical contacts. This effective interaction depends on the stochasticity of the migratory and non-migratory cells. On the basis of these findings, we propose that stochastic behavior at the single-cell level works effectively and precisely to achieve collective migration in multi-cellular systems.

  3. HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via geranylgeranylation and RhoA activation

    Energy Technology Data Exchange (ETDEWEB)

    Al-Haidari, Amr A.; Syk, Ingvar; Thorlacius, Henrik, E-mail: henrik.thorlacius@med.lu.se

    2014-03-28

    Highlights: • Simvastatin blocked CCL17-induced and CCR4-dependent RhoA activation in HT29 cells. • CCL17/CCR4-mediated migration of colon cancer cells was antagonised by simvastatin. • Cell migration recovered by adding Mevalonate and geranylgeranyl pyrophosphate. • Targeting HMG-CoA reductase might be useful to inhibit colon cancer metastasis. - Abstract: Background: Simvastatin is widely used to lower cholesterol levels in patients with cardiovascular diseases, although accumulating evidence suggests that statins, such as simvastatin, also exert numerous anti-tumoral effects. Aim: The aim of this study was to examine the effect of simvastatin on colon cancer cell migration. Methods: Migration assays were performed to evaluate CCL17-induced colon cancer cell (HT-29) chemotaxis. In vitro tumor growth and apoptosis were assessed using a proliferation assay and annexin V assay, respectively. Active RhoA protein levels in CCL17-stimulated colon cancer cells were quantified using a G-LISA assay. Results: We found that simvastatin dose-dependently decreased CCL17-induced colon cancer cell migration. Simvastatin had no effect on colon cancer cell proliferation or apoptosis. Inhibition of beta chemokine receptor 4, CCR4, reduced CCL17-evoked activation of RhoA in colon cancer cells. Moreover, administration of mevalonate reversed the inhibitory effect of simvastatin on CCL17-induced colon cancer cell migration. Interestingly, co-incubation with geranylgeranyl pyrophosphate (GGPP) antagonized the inhibitory impact of simvastatin on colon cancer cell migration triggered by CCL17. Moreover, we observed that simvastatin decreased CCL17-induced activation of RhoA in colon cancer cells. Administration of mevalonate and GGPP reversed the inhibitory effect of simvastatin on CCL17-provoked RhoA activation in colon cancer cells. Conclusions: Taken together, our findings show for the first time that HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via

  4. HIF-1α Promotes A Hypoxia-Independent Cell Migration.

    Science.gov (United States)

    Li, Liyuan; Madu, Chikezie O; Lu, Andrew; Lu, Yi

    2010-01-01

    Hypoxia-inducible factor-1α (HIF-1α) is known as a transactivator for VEGF gene promoter. It can be induced by hypoxia. However, no study has been done so far to dissect HIF-1α-mediated effects from hypoxia or VEGF-mediated effects. By using a HIF-1α knockout (HIF-1α KO) cell system in mouse embryonic fibroblast (MEF) cells, this study analyzes cell migration and HIF-1α, hypoxia and VEGF activation. A hypoxia-mediated HIF-1α induction and VEGF transactivation were observed: both HIF-1α WT lines had significantly increased VEGF transactivation, as an indicator for HIF-1α induction, in hypoxia compared to normoxia; in contrast, HIF-1α KO line had no increased VEGF transactivation under hypoxia. HIF-1α promotes cell migration: HIF-1α-KO cells had a significantly reduced migration compared to that of the HIF-1α WT cells under both normoxia and hypoxia. The significantly reduced cell migration in HIF-1α KO cells can be partially rescued by the restoration of WT HIF-1α expression mediated by adenoviral-mediated gene transfer. Interestingly, hypoxia has no effect on cell migration: the cells had a similar cell migration rate under hypoxic and normoxic conditions for both HIF-1α WT and HIF-1α KO lines, respectively. Collectively, these data suggest that HIF-1α plays a role in MEF cell migration that is independent from hypoxia-mediated effects.

  5. Leader Cells Define Directionality of Trunk, but Not Cranial, Neural Crest Cell Migration.

    Science.gov (United States)

    Richardson, Jo; Gauert, Anton; Briones Montecinos, Luis; Fanlo, Lucía; Alhashem, Zainalabdeen Mohmammed; Assar, Rodrigo; Marti, Elisa; Kabla, Alexandre; Härtel, Steffen; Linker, Claudia

    2016-05-31

    Collective cell migration is fundamental for life and a hallmark of cancer. Neural crest (NC) cells migrate collectively, but the mechanisms governing this process remain controversial. Previous analyses in Xenopus indicate that cranial NC (CNC) cells are a homogeneous population relying on cell-cell interactions for directional migration, while chick embryo analyses suggest a heterogeneous population with leader cells instructing directionality. Our data in chick and zebrafish embryos show that CNC cells do not require leader cells for migration and all cells present similar migratory capacities. In contrast, laser ablation of trunk NC (TNC) cells shows that leader cells direct movement and cell-cell contacts are required for migration. Moreover, leader and follower identities are acquired before the initiation of migration and remain fixed thereafter. Thus, two distinct mechanisms establish the directionality of CNC cells and TNC cells. This implies the existence of multiple molecular mechanisms for collective cell migration.

  6. Leader Cells Define Directionality of Trunk, but Not Cranial, Neural Crest Cell Migration

    Directory of Open Access Journals (Sweden)

    Jo Richardson

    2016-05-01

    Full Text Available Collective cell migration is fundamental for life and a hallmark of cancer. Neural crest (NC cells migrate collectively, but the mechanisms governing this process remain controversial. Previous analyses in Xenopus indicate that cranial NC (CNC cells are a homogeneous population relying on cell-cell interactions for directional migration, while chick embryo analyses suggest a heterogeneous population with leader cells instructing directionality. Our data in chick and zebrafish embryos show that CNC cells do not require leader cells for migration and all cells present similar migratory capacities. In contrast, laser ablation of trunk NC (TNC cells shows that leader cells direct movement and cell-cell contacts are required for migration. Moreover, leader and follower identities are acquired before the initiation of migration and remain fixed thereafter. Thus, two distinct mechanisms establish the directionality of CNC cells and TNC cells. This implies the existence of multiple molecular mechanisms for collective cell migration.

  7. A cell-based fascin bioassay identifies compounds with potential anti-metastasis or cognition-enhancing functions

    Directory of Open Access Journals (Sweden)

    Robert Kraft

    2013-01-01

    The actin-bundling protein fascin is a key mediator of tumor invasion and metastasis and its activity drives filopodia formation, cell-shape changes and cell migration. Small-molecule inhibitors of fascin block tumor metastasis in animal models. Conversely, fascin deficiency might underlie the pathogenesis of some developmental brain disorders. To identify fascin-pathway modulators we devised a cell-based assay for fascin function and used it in a bidirectional drug screen. The screen utilized cultured fascin-deficient mutant Drosophila neurons, whose neurite arbors manifest the ‘filagree’ phenotype. Taking a repurposing approach, we screened a library of 1040 known compounds, many of them FDA-approved drugs, for filagree modifiers. Based on scaffold distribution, molecular-fingerprint similarities, and chemical-space distribution, this library has high structural diversity, supporting its utility as a screening tool. We identified 34 fascin-pathway blockers (with potential anti-metastasis activity and 48 fascin-pathway enhancers (with potential cognitive-enhancer activity. The structural diversity of the active compounds suggests multiple molecular targets. Comparisons of active and inactive compounds provided preliminary structure-activity relationship information. The screen also revealed diverse neurotoxic effects of other drugs, notably the ‘beads-on-a-string’ defect, which is induced solely by statins. Statin-induced neurotoxicity is enhanced by fascin deficiency. In summary, we provide evidence that primary neuron culture using a genetic model organism can be valuable for early-stage drug discovery and developmental neurotoxicity testing. Furthermore, we propose that, given an appropriate assay for target-pathway function, bidirectional screening for brain-development disorders and invasive cancers represents an efficient, multipurpose strategy for drug discovery.

  8. Role of Berberine on molecular markers involved in migration of esophageal cancer cells.

    Science.gov (United States)

    Mishan, M A; Ahmadiankia, N; Matin, M M; Heirani-Tabasi, A; Shahriyari, M; Bidkhori, H R; Naderi-Meshkin, H; Bahrami, A R

    2015-12-14

    Berberine is an isoquinoline alkaloid found in several plant species like famous chinese herb, Rhizoma coptidis which has been used locally as a strong gastrointestinal remedy for thousands of years. The inhibitory effects of berberine on tumor progression properties have been reported before. In this study, we investigated the effect of berberine on an esophageal cancer cell line, KYSE-30 with emphasis on its effects on the expression of certain chemokine receptors. The cytotoxic effect of berberine on KYSE-30 cells was analyzed by MTT assay. In vitro cell migration assay was also applied to the treated cells and the expression levels of the selected chemokine receptors (CXCR4 and CCR7) was measured at mRNA level. A retarded growth, associated with increasing concentrations of berberine, was obvious. On the other hand, the migration rate of the cells was decreased when they were treated with different concentrations of berberine and the expression levels of the two chemokine receptors, involved in the migration and metastasis of esophageal cancer cells, were decreased following the same treatments. With these results, we tend to conclude that berberine might be a proper candidate for further investigations, by targeting the chemokine receptors, and possible applications as anti-metastatic agent in cancer studies.

  9. The Multiple Roles of Exosomes in Metastasis.

    Science.gov (United States)

    Weidle, Ulrich H; Birzele, Fabian; Kollmorgen, Gwen; Rüger, Rüdiger

    2017-01-02

    Exosomes are important contributors to cell-cell communication and their role as diagnostic markers for cancer and the pathogenesis for cancer is under intensive investigation. Here, we focus on their role in metastasis-related processes. We discuss their impact regarding promotion of invasion and migration of tumor cells, conditioning of lymph nodes, generation of premetastatic niches and organotropism of metastasis. Furthermore, we highlight interactions of exosomes with bone marrow and stromal components such as fibroblasts, endothelial cells, myeloid- and other immune-related cells in the context of metastases. For all processes as described above, we outline molecular and cellular components for therapeutic intervention with metastatic processes.

  10. Metastin and its variant forms suppress migration of pancreatic cancer cells.

    Science.gov (United States)

    Masui, Toshihiko; Doi, Ryuichiro; Mori, Tomohiko; Toyoda, Eiji; Koizumi, Masayuki; Kami, Kazuhiro; Ito, Daisuke; Peiper, Stephen C; Broach, James R; Oishi, Shinya; Niida, Ayumu; Fujii, Nobutaka; Imamura, Masayuki

    2004-02-27

    Metastin, a post-translationally modified variant of KiSS1, was recently identified as an endogenous peptide agonist for a novel G-protein coupled receptor, hOT7T175 (AXOR12, GPR54). In this study, we analyzed the role of KiSS1 and hOT7T175 in both pancreatic cancer tissues and pancreatic cancer cell lines. Furthermore, we synthesized novel short variant forms of metastin and tested the inhibitory effect of those variants on in vitro cell functions that are relevant to metastasis. Pancreatic cancer tissues showed significantly lower expression of KiSS1 mRNA than normal tissues (p=0.018), while cancer tissues showed significantly higher expression of hOT7T175 mRNA than normal pancreatic tissues (p=0.027). In human pancreatic cancer cell lines, KiSS1 mRNA was highly expressed in 2 out of 6 pancreatic cancer cell lines, while hOT7T175 mRNA was expressed in all cell lines at various degrees. PANC-1 cells showed the highest expression of hOT7T175. Exogenous metastin did not suppress cell proliferation but significantly reduced the in vitro migration of PANC-1 cells (pMetastin induced activation of ERK1 in PANC-1 and AsPC-1 cells. Finally, we synthesized 3 novel short variant forms of metastin, FM053a2TFA, FM059a2TFA, and FM052a4TFA. These metastin variants significantly suppressed the migration of PANC-1 cells and activated ERK1. These data suggest that the metastin receptor, hOT7T175, is one of the promising targets for suppression of metastasis, and that small metastin variants could be an anti-metastatic agent to pancreatic cancer.

  11. Dietary Lipids, Cell Adhesion and Breast Cancer Metastasis

    Science.gov (United States)

    2003-10-01

    antitumor 38. Nakagawa K, Okuda S, and Miyazawa T: Dose-dependent incorpora- therapy. Nature 394, 287-291, 1998. tion of tea catechins ...39. Yang CS, Chen L, Lee M-J, Balentine D, Kuo MC, et al.: Blood and cer Metastasis Rev 9, 267-282, 1990. urine levels of tea catechins after...epigallocatechin-3-gallate and (-)-epigallo- 13. O’Reilly MS: Angiostatin: an endogenous inhibitor of angiogenesis catechin , into human plasma. Biosci

  12. Thyroid metastasis as initial presentation of clear cell renal carcinoma

    Directory of Open Access Journals (Sweden)

    César Pablo Ramírez-Plaza

    2015-01-01

    Conclusion: The possibility of finding of an incidental metastatic tumor in the thyroid gland from a previous unknown and non-diganosed primary (as CCRC in our case was is rare and account only for less than 1% of malignancies. Nonetheless, the thyroid gland is a frequent site of metastasis and the presence of “de novo” thyroid nodules in oncologic patients must be always considered and studied.

  13. Rhodanine-based PRL-3 inhibitors blocked the migration and invasion of metastatic cancer cells.

    Science.gov (United States)

    Min, Garam; Lee, Su-Kyung; Kim, Hye-Nan; Han, Young-Min; Lee, Rhan-Hee; Jeong, Dae Gwin; Han, Dong Cho; Kwon, Byoung-Mog

    2013-07-01

    PRL-3, phosphatase of regenerating liver-3, plays a role in cancer progression through its involvement in invasion, migration, metastasis, and angiogenesis. We synthesized rhodanine derivatives, CG-707 and BR-1, which inhibited PRL-3 enzymatic activity with IC50 values of 0.8 μM and 1.1 μM, respectively. CG-707 and BR-1 strongly inhibited the migration and invasion of PRL-3 overexpressing colon cancer cells without exhibiting cytotoxicity. The specificity of the inhibitors on PRL-3 phosphatase activity was confirmed by the phosphorylation recovery of known PRL-3 substrates such as ezrin and cytokeratin 8. The compounds selectively inhibited PRL-3 in comparison with other phosphatases, and CG-707 regulated epithelial-to-mesenchymal transition (EMT) marker proteins. The results of the present study reveal that rhodanine is a specific PRL-3 inhibitor and a good lead molecule for obtaining a selective PRL-3 inhibitor.

  14. Nanomolar concentration of blood-soluble drag-reducing polymer inhibits experimental metastasis of human breast cancer cells

    Science.gov (United States)

    Ding, Zhijie; Joy, Marion; Kameneva, Marina V; Roy, Partha

    2017-01-01

    Metastasis is the leading cause of cancer mortality. Extravasation of cancer cells is a critical step of metastasis. We report a novel proof-of-concept study that investigated whether non-toxic blood-soluble chemical agents capable of rheological modification of the near-vessel-wall blood flow can reduce extravasation of tumor cells and subsequent development of metastasis. Using an experimental metastasis model, we demonstrated that systemic administration of nanomolar concentrations of so-called drag-reducing polymer dramatically impeded extravasation and development of pulmonary metastasis of breast cancer cells in mice. This is the first proof-of-principle study to directly demonstrate physical/rheological, as opposed to chemical, way to prevent cancer cells from extravasation and developing metastasis and, thus, it opens the possibility of a new direction of adjuvant interventional approach in cancer. PMID:28280386

  15. Glycation of extracellular matrix proteins impairs migration of immune cells.

    Science.gov (United States)

    Haucke, Elisa; Navarrete-Santos, Alexander; Simm, Andreas; Silber, Rolf-Edgar; Hofmann, Britt

    2014-01-01

    The immune response during aging and diabetes is disturbed and may be due to the altered migration of immune cells in an aged tissue. Our study should prove the hypothesis that age and diabetes-related advanced glycation end products (AGEs) have an impact on the migration and adhesion of human T-cells. To achieve our purpose, we used in vitro AGE-modified proteins (soluble albumin and fibronectin [FN]), as well as human collagen obtained from bypass graft. A Boyden chamber was used to study cell migration. Migrated Jurkat T-cells were analyzed by flow cytometry and cell adhesion by crystal violet staining. Actin polymerization was determined by phalloidin-Alexa-fluor 488-labeled antibody and fluorescence microscopy. We found that significantly fewer cells (50%, p = 0.003) migrated through methylglyoxal modified FN. The attachment to FN in the presence of AGE-bovine serum albumin (BSA) was also reduced (p < 0.05). In ex vivo experiments, isolated collagen from human vein graft material negatively affected the migration of the cells depending on the grade of AGE modification of the collagen. Collagen with a low AGE level reduced the cell migration by 30%, and collagen with a high AGE level by 60%. Interaction of the cells with an AGE-modified matrix, but not with soluble AGEs like BSA-AGE per se, was responsible for a disturbed migration. The reduced migration was accompanied by an impaired actin polymerization. We conclude that AGEs-modified matrix protein inhibits cell migration and adhesion of Jurkat T-cells.

  16. Meloxicam suppresses hepatocellular carcinoma cell proliferation and migration by targeting COX-2/PGE2-regulated activation of the β-catenin signaling pathway.

    Science.gov (United States)

    Li, Tao; Zhong, Jingtao; Dong, Xiaofeng; Xiu, Peng; Wang, Fuhai; Wei, Honglong; Wang, Xin; Xu, Zongzhen; Liu, Feng; Sun, Xueying; Li, Jie

    2016-06-01

    Recurrence and metastasis are the two leading causes of poor prognosis of hepatocellular carcinoma (HCC) patients. Cyclooxygenase (COX)-2 is overexpressed in many types of cancers including HCC and promotes its metastasis. Meloxicam is a selective COX-2 inhibitor that has been reported to exert an anti-proliferation and invasion/migration response in various tumors. In this study, we examined the role of meloxicam on HCC cell proliferation and migration and explored the molecular mechanisms underlying this effect. We found that meloxicam inhibited HCC cell proliferation and had a cell cycle arrest effect in human HCC cells. Furthermore, meloxicam suppressed the ability of HCC cells expressing higher levels of COX-2 and prostaglandin E2 (PGE2) to migration via potentiating expression of E-cadherin and alleviating expression of matrix metalloproteinase (MMP)-2 and -9. COX-2/PGE2 has been considered to activate the β-catenin signaling pathway which promotes cancer cell migration. We found that treatment with PGE2 significantly enhanced nuclear accumulation of β-catenin and the activation of GSK3β which could be reversed by meloxicam in HCC cells. We also observed that HCC cell migration and upregulation of the level of MMP-2/9 and downregulation of E-cadherin induced by PGE2 were suppressed by FH535, an inhibitor of β-catenin. Taken together, these findings provide a new treatment strategy against HCC proliferation and migration.

  17. Piperlongumine Inhibits Migration of Glioblastoma Cells via Activation of ROS-Dependent p38 and JNK Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Qian Rong Liu

    2014-01-01

    Full Text Available Piperlongumine (PL is recently found to kill cancer cells selectively and effectively via targeting reactive oxygen species (ROS responses. To further explore the therapeutic effects of PL in cancers, we investigated the role and mechanisms of PL in cancer cell migration. PL effectively inhibited the migration of human glioma (LN229 or U87 MG cells but not normal astrocytes in the scratch-wound culture model. PL did not alter EdU+-cells and cdc2, cdc25c, or cyclin D1 expression in our model. PL increased ROS (measured by DCFH-DA, reduced glutathione, activated p38 and JNK, increased IκBα, and suppressed NFκB in LN229 cells after scratching. All the biological effects of PL in scratched LN229 cells were completely abolished by the antioxidant N-acetyl-L-cysteine (NAC. Pharmacological administration of specific p38 (SB203580 or JNK (SP600125 inhibitors significantly reduced the inhibitory effects of PL on LN229 cell migration and NFκB activity in scratch-wound and/or transwell models. PL prevented the deformation of migrated LN229 cells while NAC, SB203580, or SP600125 reversed PL-induced morphological changes of migrated cells. These results suggest potential therapeutic effects of PL in the treatment and prevention of highly malignant tumors such as glioblastoma multiforme (GBM in the brain by suppressing tumor invasion and metastasis.

  18. High-level expression of Notch1 increased the risk of metastasis in T1 stage clear cell renal cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Qing Ai

    Full Text Available BACKGROUND: Although metastasis of clear cell renal cell carcinoma (ccRCC is basically observed in late stage tumors, T1 stage metastasis of ccRCC can also be found with no definite molecular cause resulting inappropriate selection of surgery method and poor prognosis. Notch signaling is a conserved, widely expressed signal pathway that mediates various cellular processes in normal development and tumorigenesis. This study aims to explore the potential role and mechanism of Notch signaling in the metastasis of T1 stage ccRCC. METHODOLOGY/PRINCIPAL FINDINGS: The expression of Notch1 and Jagged1 were analyzed in tumor tissues and matched normal adjacent tissues obtained from 51 ccRCC patients. Compared to non-tumor tissues, Notch1 and Jagged1 expression was significantly elevated both in mRNA and protein levels in tumors. Tissue samples of localized and metastatic tumors were divided into three groups based on their tumor stages and the relative mRNA expression of Notch1 and Jagged1 were analyzed. Compared to localized tumors, Notch1 expression was significantly elevated in metastatic tumors in T1 stage while Jagged1 expression was not statistically different between localized and metastatic tumors of all stages. The average size of metastatic tumors was significantly larger than localized tumors in T1 stage ccRCC and the elevated expression of Notch1 was significantly positive correlated with the tumor diameter. The functional significance of Notch signaling was studied by transfection of 786-O, Caki-1 and HKC cell lines with full-length expression plasmids of Notch1 and Jagged1. Compared to the corresponding controls, all cell lines demonstrated significant promotion in cell proliferation and migration while cell cycle remained unaffected. CONCLUSIONS/SIGNIFICANCE: High-level expression of Notch signaling increased the risk of metastasis in T1 stage ccRCC by stimulating the proliferation and migration of tumor cells, which may be helpful for the

  19. CCR7 regulates cell migration and invasion through JAK2/STAT3 in metastatic squamous cell carcinoma of the head and neck.

    Science.gov (United States)

    Liu, Fa-Yu; Safdar, Jawad; Li, Zhen-Ning; Fang, Qi-Gen; Zhang, Xu; Xu, Zhong-Fei; Sun, Chang-Fu

    2014-01-01

    Squamous cell carcinoma of the head and neck (SCCHN) frequently involves metastasis at diagnosis. Our previous research has demonstrated that CCR7 plays a key role in regulating SCCHN metastasis, and this process involves several molecules, such as PI3K/cdc42, pyk2, and Src. In this study, the goals are to identify whether JAK2/STAT3 also participates in CCR7's signal network, its relationship with other signal pathways, and its role in SCCHN cell invasion and migration. The results showed that stimulation of CCL19 could induce JAK2/STAT3 phosphorylation, which can be blocked by Src and pyk2 inhibitors. After activation, STAT3 was able to promote low expression of E-cadherin and had no effect on vimentin. This JAk2/STAT3 pathway not only mediated CCR7-induced cell migration but also mediated invasion speed. The immunohistochemistry results also showed that the phosphorylation of STAT3 was correlated with CCR7 expression in SCCHN, and CCR7 and STAT3 phosphorylation were all associated with lymph node metastasis. In conclusion, JAk2/STAT3 plays a key role in CCR7 regulating SCCHN metastasis.

  20. Splenic and portal vein thrombosis in pancreatic metastasis from Renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Loos Martin

    2006-05-01

    Full Text Available Abstract Background Pancreatic metastases from previously treated renal cell carcinoma are uncommon. Surgical resection of pancreatic metastasis remains the only worthwhile modality of treatment. Case presentation A case where pancreatic metastasis from previously resected right sided renal cell carcinoma was resected with a subtotal left pancreatectomy is described. An unusual feature was the presence of a large splenic vein tumor thrombus extending into the portal vein with associated portal hypertension. The patient underwent an uneventful portal vein resection with primary anastomosis. Conclusion This is possibly the first documented case of portal vein renal tumor thrombosis in a case of isolated pancreatic metastasis from previously operated renal cell carcinoma in published world surgical literature.

  1. Involvement of highly sulfated chondroitin sulfate in the metastasis of the Lewis lung carcinoma cells.

    NARCIS (Netherlands)

    Li, F.; Dam, G.B. ten; Murugan, S.; Yamada, S.; Hashiguchi, T.; Mizumoto, S.; Oguri, K.; Okayama, M.; Kuppevelt, A.H.M.S.M. van; Sugahara, K.

    2008-01-01

    The altered expression of cell surface chondroitin sulfate (CS) and dermatan sulfate (DS) in cancer cells has been demonstrated to play a key role in malignant transformation and tumor metastasis. However, the functional highly sulfated structures in CS/DS chains and their involvement in the process

  2. Stathmin1 overexpression in hypopharyngeal squamous cell carcinoma: A new promoter in FaDu cell proliferation and migration

    Science.gov (United States)

    Chen, Yan; Zhang, Qicheng; Ding, Chuanjin; Zhang, Xiaobo; Qiu, Xiaoxia; Zhang, Zhenxin

    2017-01-01

    Stathmin1, a microtubule-destabilizing phosphoprotein, is considered to play a crucial role in regulating cellular microtubule dynamics and controlling mitosis. Previous studies have showed that STMN1 is highly expressed in many human malignancies and is related to development, invasion and metastasis of tumors. However, its expression pattern, clinical performance and functional roles in hypopharyngeal squamous cell carcinoma (HSCC) have not been addressed. In this study, we found that STMN1 was significantly elevated in HSCC and its expression level was correlated with poor differentiation (P<0.001), clinical stage (P<0.001), large tumor size (P=0.001) and lymph node metastasis (P=0.008). A positive correlation between STMN1 and Ki-67 expression was also exhibited. High STMN1 expression predicted poor survival. Furthermore, we found that knockdown of STMN1 by siRNAs inhibited the FaDu cell proliferation and migration. Moreover, decreased STMN1 expression in FaDu cells reversed the acquisition of EMT phenotype by upregulating E-cadherin, as well as reduced vimentin expression at protein and mRNA levels. These results suggested that STMN1 plays an important role in proliferation and migration of HSCC and may be used as a potential prognostic biomarker or therapeutic target of HSCC. PMID:27878293

  3. Significance and therapeutic implications of endothelial progenitor cells in angiogenic-mediated tumour metastasis.

    Science.gov (United States)

    Flamini, Valentina; Jiang, Wen G; Lane, Jane; Cui, Yu-Xin

    2016-04-01

    Cancer conveys profound social and economic consequences throughout the world. Metastasis is responsible for approximately 90% of cancer-associated mortality and, when it occurs, cancer becomes almost incurable. During metastatic dissemination, cancer cells pass through a series of complex steps including the establishment of tumour-associated angiogenesis. The human endothelial progenitor cells (hEPCs) are a cell population derived from the bone marrow which are required for endothelial tubulogenesis and neovascularization. They also express abundant inflammatory cytokines and paracrine angiogenic factors. Clinically hEPCs are highly correlated with relapse, disease progression, metastasis and treatment response in malignancies such as breast cancer, ovarian cancer and non-small-cell lung carcinoma. It has become evident that the hEPCs are involved in the angiogenesis-required progression and metastasis of tumours. However, it is not clear in what way the signalling pathways, controlling the normal cellular function of human BM-derived EPCs, are hijacked by aggressive tumour cells to facilitate tumour metastasis. In addition, the actual roles of hEPCs in tumour angiogenesis-mediated metastasis are not well characterised. In this paper we reviewed the clinical relevance of the hEPCs with cancer diagnosis, progression and prognosis. We further summarised the effects of tumour microenvironment on the hEPCs and underlying mechanisms. We also hypothesized the roles of altered hEPCs in tumour angiogenesis and metastasis. We hope this review may enhance our understanding of the interaction between hEPCs and tumour cells thus aiding the development of cellular-targeted anti-tumour therapies.

  4. CAV1 promotes HCC cell progression and metastasis through Wnt/β-catenin pathway.

    Directory of Open Access Journals (Sweden)

    Hongxiu Yu

    Full Text Available Caveolin-1 (CAV1 has significant roles in many primary tumors and metastasis, despite the fact that malignant cells from different cancer types have different profiles of CAV1 expression. There is little information concerning CAV1 expression and role in hepatocellular carcinoma (HCC progresion and metastasis. The role of CAV1 in HCC progression was explored in this study. We reported that CAV1 was overexpressed in highly invasive HCC cell lines compared with poorly invasive ones. The immunohistochemical staining was obviously stronger in metastatic HCC samples than in the non-metastatic specimens via tissue microarrays. Furthermore, CAV1 overexpression enhanced HCC cell invasiveness in vitro, and promoted tumorigenicity and lung metastasis in vivo. By contrast, CAV1 stable knockdown markedly reduced these malignant behaviors. Importantly, we found that CAV1 could induce EMT process through Wnt/β-catenin pathway to promote HCC metastasis. We also identify MMP-7 as a novel downstream target of CAV1. We have determined that CAV1 acts as a mediator between hyperactive ERK1/2 signaling and regulation of MMP-7 transcription. Together, these studies mechanistically show a previously unrecognized interplay between CAV1, EMT, ERK1/2 and MMP-7 that is likely significant in the progression of HCC toward metastasis.

  5. Radiation promotes cancer cell metastasis via EMT induction in mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jongkuk; Kang, Sungwook; Hwang, Sanggu; Um, Hongduck [Department of Radiation Cancer, New York (United States); Jang, Su Jin; Kang, Joohyun [Molecular Imaging Research Center, Charlestown (United States); Park, Sunhoo [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Wunjae [Chungbuk National Univ., Cheongju (Korea, Republic of)

    2013-05-15

    Whether γ-IR-induced invasion and metastasis are stimulated in our in vitro C6L cell line and in vivo systems, and further identify the associated changes in signal pathways or mice physiology. We constructed an animal model system with a view to clarifying the intracellular molecular events underlying the promotion of metastasis after γ-IR treatment for primary cancer and developing effective anti-metastatic reagents. Our results demonstrate that γ-IR treatment of cancer cell lines and mice xenografts triggers invasion and metastasis. In particular, γ-IR-treated cancer cells or mouse xenografts and metastatic lesions in mice bearing γ-IR-treated xenografts also display typical EMT marker expression patterns, such as increased venetum or MMP-2 expression, decreased E-chondron, and enhanced activity of MMP-2. Our results collectively suggest that γ-IR-induced invasion or metastasis results from induction of EMT, and inhibition of EMT may thus be a means to enhance the effectiveness of radiation therapy. Our results also suggested EMT might be one of the major therapeutic targets to block metastasis.

  6. Activin type IB receptor signaling in prostate cancer cells promotes lymph node metastasis in a xenograft model

    Energy Technology Data Exchange (ETDEWEB)

    Nomura, Masatoshi, E-mail: nomura@med.kyushu-u.ac.jp [Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Tanaka, Kimitaka; Wang, Lixiang; Goto, Yutaka; Mukasa, Chizu; Ashida, Kenji; Takayanagi, Ryoichi [Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)

    2013-01-04

    Highlights: Black-Right-Pointing-Pointer ActRIB signaling induces Snail and S100A4 expressions in prostate cancer cells. Black-Right-Pointing-Pointer The prostate cancer cell lines expressing an active form of ActRIB were established. Black-Right-Pointing-Pointer ActRIB signaling promotes EMT and lymph node metastasis in xenograft model. -- Abstract: Activin, a member of the transforming growth factor-{beta} family, has been known to be a growth and differentiating factor. Despite its pluripotent effects, the roles of activin signaling in prostate cancer pathogenesis are still unclear. In this study, we established several cell lines that express a constitutive active form of activin type IB receptor (ActRIBCA) in human prostate cancer cells, ALVA41 (ALVA-ActRIBCA). There was no apparent change in the proliferation of ALVA-ActRIBCA cells in vitro; however, their migratory ability was significantly enhanced. In a xenograft model, histological analysis revealed that the expression of Snail, a cell-adhesion-suppressing transcription factor, was dramatically increased in ALVA-ActRIBCA tumors, indicating epithelial mesenchymal transition (EMT). Finally, mice bearing ALVA-ActRIBCA cells developed multiple lymph node metastases. In this study, we demonstrated that ActRIBCA signaling can promote cell migration in prostate cancer cells via a network of signaling molecules that work together to trigger the process of EMT, and thereby aid in the aggressiveness and progression of prostate cancers.

  7. Functional transcriptomics of a migrating cell in Caenorhabditis elegans.

    Science.gov (United States)

    Schwarz, Erich M; Kato, Mihoko; Sternberg, Paul W

    2012-10-02

    In both metazoan development and metastatic cancer, migrating cells must carry out a detailed, complex program of sensing cues, binding substrates, and moving their cytoskeletons. The linker cell in Caenorhabditis elegans males undergoes a stereotyped migration that guides gonad organogenesis, occurs with precise timing, and requires the nuclear hormone receptor NHR-67. To better understand how this occurs, we performed RNA-seq of individually staged and dissected linker cells, comparing transcriptomes from linker cells of third-stage (L3) larvae, fourth-stage (L4) larvae, and nhr-67-RNAi-treated L4 larvae. We observed expression of 8,000-10,000 genes in the linker cell, 22-25% of which were up- or down-regulated 20-fold during development by NHR-67. Of genes that we tested by RNAi, 22% (45 of 204) were required for normal shape and migration, suggesting that many NHR-67-dependent, linker cell-enriched genes play roles in this migration. One unexpected class of genes up-regulated by NHR-67 was tandem pore potassium channels, which are required for normal linker-cell migration. We also found phenotypes for genes with human orthologs but no previously described migratory function. Our results provide an extensive catalog of genes that act in a migrating cell, identify unique molecular functions involved in nematode cell migration, and suggest similar functions in humans.

  8. The Role of Immunoglobulin Superfamily Cell Adhesion Molecules in Cancer Metastasis

    Directory of Open Access Journals (Sweden)

    Chee Wai Wong

    2012-01-01

    Full Text Available Metastasis is a major clinical problem and results in a poor prognosis for most cancers. The metastatic pathway describes the process by which cancer cells give rise to a metastatic lesion in a new tissue or organ. It consists of interconnecting steps all of which must be successfully completed to result in a metastasis. Cell-cell adhesion is a key aspect of many of these steps. Adhesion molecules belonging to the immunoglobulin superfamily (Ig-SF commonly play a central role in cell-cell adhesion, and a number of these molecules have been associated with cancer progression and a metastatic phenotype. Surprisingly, the contribution of Ig-SF members to metastasis has not received the attention afforded other cell adhesion molecules (CAMs such as the integrins. Here we examine the steps in the metastatic pathway focusing on how the Ig-SF members, melanoma cell adhesion molecule (MCAM, L1CAM, neural CAM (NCAM, leukocyte CAM (ALCAM, intercellular CAM-1 (ICAM-1 and platelet endothelial CAM-1 (PECAM-1 could play a role. Although much remains to be understood, this review aims to raise the profile of Ig-SF members in metastasis formation and prompt further research that could lead to useful clinical outcomes.

  9. Mesenchymal stem cell 1 (MSC1-based therapy attenuates tumor growth whereas MSC2-treatment promotes tumor growth and metastasis.

    Directory of Open Access Journals (Sweden)

    Ruth S Waterman

    Full Text Available BACKGROUND: Currently, there are many promising clinical trials using mesenchymal stem cells (MSCs in cell-based therapies of numerous diseases. Increasingly, however, there is a concern over the use of MSCs because they home to tumors and can support tumor growth and metastasis. For instance, we established that MSCs in the ovarian tumor microenvironment promoted tumor growth and favored angiogenesis. In parallel studies, we also developed a new approach to induce the conventional mixed pool of MSCs into two uniform but distinct phenotypes we termed MSC1 and MSC2. METHODOLOGY/PRINCIPAL FINDINGS: Here we tested the in vitro and in vivo stability of MSC1 and MSC2 phenotypes as well as their effects on tumor growth and spread. In vitro co-culture of MSC1 with various cancer cells diminished growth in colony forming units and tumor spheroid assays, while conventional MSCs or MSC2 co-culture had the opposite effect in these assays. Co-culture of MSC1 and cancer cells also distinctly affected their migration and invasion potential when compared to MSCs or MSC2 treated samples. The expression of bioactive molecules also differed dramatically among these samples. MSC1-based treatment of established tumors in an immune competent model attenuated tumor growth and metastasis in contrast to MSCs- and MSC2-treated animals in which tumor growth and spread was increased. Also, in contrast to these groups, MSC1-therapy led to less ascites accumulation, increased CD45+leukocytes, decreased collagen deposition, and mast cell degranulation. CONCLUSION/SIGNIFICANCE: These observations indicate that the MSC1 and MSC2 phenotypes may be convenient tools for the discovery of critical components of the tumor stroma. The continued investigation of these cells may help ensure that cell based-therapy is used safely and effectively in human disease.

  10. Ischiogluteal bursitis mimicking soft-tissue metastasis from a renal cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Voelk, M.; Gmeinwieser, J.; Manke, C.; Strotzer, M. [Department of Radiology, University Hospital, Regensburg (Germany); Hanika, H. [Department of Urology, St. Josef Hospital, Regensburg (Germany)

    1998-09-01

    We report a case of ischiogluteal bursitis mimicking a soft-tissue metastasis from a renal cell carcinoma. A 66-year-old woman suffered from pain over the left buttock 6 months after she was operated on for renal cell carcinoma of the left kidney. CT of the abdomen and pelvis revealed a tumor-like lesion adjacent to the left os ischii, which was suspected to be a soft-tissue metastasis. Percutaneous biopsy revealed no evidence of malignancy, but the histopathological diagnosis of chronic bursitis. (orig.) With 2 figs., 8 refs.

  11. Silk film topography directs collective epithelial cell migration.

    Directory of Open Access Journals (Sweden)

    Brian D Lawrence

    Full Text Available The following study provides new insight into how surface topography dictates directed collective epithelial cell sheet growth through the guidance of individual cell movement. Collective cell behavior of migrating human corneal limbal-epithelial cell sheets were studied on highly biocompatible flat and micro-patterned silk film surfaces. The silk film edge topography guided the migratory direction of individual cells making up the collective epithelial sheet, which resulted in a 75% increase in total culture elongation. This was due to a 3-fold decrease in cell sheet migration rate efficiency for movement perpendicular to the topography edge. Individual cell migration direction is preferred in the parallel approach to the edge topography where localization of cytoskeletal proteins to the topography's edge region is reduced, which results in the directed growth of the collective epithelial sheet. Findings indicate customized biomaterial surfaces may be created to direct both the migration rate and direction of tissue epithelialization.

  12. Cross-linked hyaluronic acid gel inhibits metastasis and growth of gastric and hepatic cancer cells: in vitro and in vivo studies

    Science.gov (United States)

    Lan, Ting; Pang, Ji; Wu, Yan; Zhu, Miaolin; Yao, Xiaoyuan; Wu, Min; Qian, Hai; Zhang, Zhenyu; Gao, Jizong; Chen, Yongchang

    2016-01-01

    Cross-linked hyaluronic acid gel (CHAG) has been used to prevent postoperative adhesion of abdominal tumorectomy. However, its effect on tumor cells is still unknown. This paper was designed to investigate the effect of CHAG on metastasis and growth of tumor cells. Migration and invasion assays, Western blotting, pull down assay, siRNA interference, and nude mice implantation tumor model were applied in this study. The results of in vitro experiments with gastric cancer cell line AGS and hepatic cancer cell line HepG2 showed that CHAG inhibited the migration and invasion activities, the MAPK and PI3K/Akt mediated signaling, the activation of small G proteins Rac1 and RhoA, and the expression of MMPs and PCNA initiated by EGF, through blocking the activation of EGFR. CHAG also had inhibitory effect on activation of other membrane receptors, including integrin and VEGFR. When the expression of hyaluronic acid receptors (CD44 or RHAMM) was interfered, the above inhibitory effects of CHAG still existed. In vivo experimental results showed that CHAG suppressed colonization, growth and metastasis of gastric cancer cell line SGC-7901 in peritoneal cavity of nude mice. In conclusion, CHAG had inhibitory effect on tumor cells, through covering cell surface and blocking the interaction between extracellular stimulative factors and their receptors. PMID:27589842

  13. H19 non coding RNA-derived miR-675 enhances tumorigenesis and metastasis of breast cancer cells by downregulating c-Cbl and Cbl-b.

    Science.gov (United States)

    Vennin, Constance; Spruyt, Nathalie; Dahmani, Fatima; Julien, Sylvain; Bertucci, François; Finetti, Pascal; Chassat, Thierry; Bourette, Roland P; Le Bourhis, Xuefen; Adriaenssens, Eric

    2015-10-06

    H19 is a long non-coding RNA precursor of miR-675 microRNA. H19 is increasingly described to play key roles in the progression and metastasis of cancers from different tissue origins. We have previously shown that the H19 gene is activated by growth factors and increases breast cancer cell invasion. In this study, we established H19/miR-675 ectopic expression models of MDA-MB-231 breast cancer cells to further investigate the underlying mechanisms of H19 oncogenic action. We showed that overexpression of H19/miR-675 enhanced the aggressive phenotype of breast cancer cells including increased cell proliferation and migration in vitro, and increased tumor growth and metastasis in vivo. Moreover, we identified ubiquitin ligase E3 family (c-Cbl and Cbl-b) as direct targets of miR-675 in breast cancer cells. Using a luciferase assay, we demonstrated that H19, through its microRNA, decreased both c-Cbl and Cbl-b expression in all breast cancer cell lines tested. Thus, by directly binding c-Cbl and Cbl-b mRNA, miR-675 increased the stability and the activation of EGFR and c-Met, leading to sustained activation of Akt and Erk as well as enhanced cell proliferation and migration. Our data describe a novel mechanism of protumoral action of H19 in breast cancer.

  14. Modulation of tumor cell stiffness and migration by type IV collagen through direct activation of integrin signaling pathway.

    Science.gov (United States)

    Chen, Sheng-Yi; Lin, Jo-Shi; Yang, Bei-Chang

    2014-08-01

    Excessive collagen deposition plays a critical role in tumor progression and metastasis. To understand how type IV collagen affects mechanical stiffness and migration, low-collagen-IV-expressing transfectants of B16F10, U118MG, and Huh7 (denoted shCol cells) were established by the lentiviral-mediated delivery of small interfering RNA against type IV-α1 collagen (Col4A1). Although having similar growth rates, shCol cells showed a flatter morphology compared to that of the corresponding controls. Notably, knocking down the Col4A1 gene conferred the cells with higher levels of elasticity and lower motility. Exposure to blocking antibodies against human β1 integrin or α2β1 integrin or the pharmacological inhibition of Src and ERK activity by PP1 and U0126, respectively, effectively reduced cell motility and raised cell stiffness. Reduced Src and ERK activities in shCol cells indicate the involvement of a collagen IV/integrin signaling pathway. The forced expression of β1 integrin significantly stimulated Src and ERK phosphorylation, reduced cell stiffness, and accelerated cell motility. In an experimental metastasis assay using C57BL/6 mice, B16F10 shCol cells formed significantly fewer and smaller lung nodules, confirming the contribution of collagen to metastasis. In summary, the integrin signaling pathway activated in a tumor environment with collagen deposition is responsible for low cell elasticity and high metastatic ability.

  15. MicroRNA-409-3p inhibits osteosarcoma cell migration and invasion by targeting catenin-δ1.

    Science.gov (United States)

    Wu, Shifeng; Du, Xinjie; Wu, Manwu; Du, Hechun; Shi, Xiaoliang; Zhang, Tao

    2016-06-10

    Osteosarcoma is the most common primary bone cancer which is associated with early metastatic potential and poor prognosis. However, the molecular mechanisms underlying osteosarcoma progression are not well characterized. Here, we investigated the role of miR-409-3p in osteosarcoma metastasis. Osteosarcoma tissue showed decreased expression of miR-409-3p compared to adjacent non-tumorous tissue. The expression level of miR-409-3p was negatively correlated with osteosarcoma metastasis. Overexpression of miR-409-3p in osteosarcoma cells (U2OS) inhibited cell migration and invasion. Bioinformatics analysis showed that catenin-δ1 (CTNND1, p120-catenin) is a direct target of miR-409-3p. Overexpression of miR-409-3p repressed the expression of catenin-δ1 in U2OS cells at both mRNA and protein levels. Meanwhile, miR-409-3p repressed the activity of luciferase reporter containing the 3'-untranslated region (3'UTR) of CTNND1 gene. Furthermore, expression of catenin-δ1 rescued the inhibitory effect of miR-409-3p on cell migration and invasion. Altogether, these results indicated that miR-409-3p targets catenin-δ1 to repress osteosarcoma metastasis.

  16. Immunohistochemical markers of distant metastasis in laryngeal and hypopharyngeal squamous cell carcinomas.

    Science.gov (United States)

    Rodrigo, Juan P; Martínez, Patricia; Allonca, Eva; Alonso-Durán, Laura; Suárez, Carlos; Astudillo, Aurora; García-Pedrero, Juana María

    2014-03-01

    Metastasis remains a major cause of mortality in head and neck squamous cell carcinoma (HNSCC). Current clinicopathological features have shown limited predictability for the risk of distant metastasis in individual patients, and therefore more accurate and reliable markers are needed. The aim of this study was to investigate the ability of various molecular markers present in primary tumors to predict the risk of developing distant metastasis. Restrictive clinical criteria were applied for patient selection in order to carry out a case-control study with comparable clinical features on a group-wide basis and a similar risk of metastasis. All patients were surgically treated (with postoperative radiotherapy when appropriate) and classified as stage IV disease. Immunohistochemical analysis was performed for a panel of proteins known to participate in cellular processes relevant to metastatic dissemination (E-cadherin, annexin A2, cortactin, FAK, EGFR, p53, and p-AKT). Results showed that the loss of E-cadherin expression was significantly correlated with the risk of distant metastasis (P = 0.002; log-rank test), while the loss of annexin A2 expression was nearly statistically significant (P = 0.06). None of the other protein markers assessed were associated with the development of distant metastasis. Therefore, according to our data the loss of epithelial adhesion seems to play a central role in the development of metastasis in HNSCC, and more importantly, immunohistochemical assessment of key proteins involved in cell adhesion regulation, such as E-cadherin could represent a useful tool to evaluate easily and routinely the metastatic potential of these carcinomas.

  17. Non-small cell lung carcinoma metastasis to the anus.

    Science.gov (United States)

    Dhandapani, Ramya Gowri; Anosike, Chinedum; Ganguly, Akash

    2016-04-29

    A 70-year-old man presenting with a lung mass was investigated and treated with pneumonectomy for adenocarcinoma of the lung. He re-presented 3 months later with a large perianal abscess and mass. Subsequent investigations and biopsies showed disseminated metastases from the lung primary. Immunohistochemical staining confirmed the nature of the anal metastasis from the lung adenocarcinoma. Lung cancer is notorious for metastases, hence it is important to be aware of the uncommon modes of spread, which will help obtain early diagnosis and optimise treatment.

  18. Role of Acid Sphingomyelinase-Induced Signaling in Melanoma Cells for Hematogenous Tumor Metastasis

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    Alexander Carpinteiro

    2016-01-01

    Full Text Available Background: Hematogenous metastasis of malignant tumor cells is a multistep process that requires release of tumor cells from the local tumor mass, interaction of the tumor cells with platelets in the blood, and adhesion of either the activated tumor cells or the complexes of platelets and tumor cells to the endothelial cells of the target organ. We have previously shown that the interaction of melanoma cells with platelets results in the release of acid sphingomyelinase (Asm from activated platelets. Secreted platelet-derived Asm acts on malignant tumor cells to cluster and activate integrins; such clustering and activation are necessary for tumor cell adhesion to endothelial cells and for metastasis. Methods: We examined the response of tumor cells to treatment with extracellular sphingomyelinase or co-incubation with wild-type and Asm-deficient platelets. We determined the phosphorylation and activation of several intracellular signaling molecules, in particular p38 kinase (p38K, phospholipase Cγ (PLCγ, ezrin, and extracellular signal-regulated kinases. Results: Incubation of B16F10 melanoma cells with Asm activates p38 MAP kinase (p38K, phospholipase Cγ (PLCγ, ezrin, and extracellular signal-regulated kinases. Co-incubation of B16F10 melanoma cells with wild-type or Asm-deficient platelets showed that the phosphorylation/activation of p38K is dependent on Asm. Pharmacological blockade of p38K prevents activation of β1 integrin and adhesion in vitro. Most importantly, inhibition of p38K activity in B16F10 melanoma cells prevents tumor cell adhesion and metastasis to the lung in vivo, a finding indicating the importance of p38K for metastasis. Conclusions: Asm, secreted from activated platelets after tumor cell-platelet contact, induces p38K phosphorylation in tumor cells. This in turn stimulates β1 integrin activation that is necessary for adhesion and subsequent metastasis of tumor cells. Thus, inhibition of p38K might be a novel

  19. Gemifloxacin, a Fluoroquinolone Antimicrobial Drug, Inhibits Migration and Invasion of Human Colon Cancer Cells

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    Jung-Yu Kan

    2013-01-01

    Full Text Available Gemifloxacin (GMF is an orally administered broad-spectrum fluoroquinolone antimicrobial agent used to treat acute bacterial exacerbation of pneumonia and bronchitis. Although fluoroquinolone antibiotics have also been found to have anti-inflammatory and anticancer effects, studies on the effect of GMF on treating colon cancer have been relatively rare. To the best of our knowledge, this is the first report to describe the antimetastasis activities of GMF in colon cancer and the possible mechanisms involved. Results have shown that GMF inhibits the migration and invasion of colon cancer SW620 and LoVo cells and causes epithelial mesenchymal transition (EMT. In addition, GMF suppresses the activation of NF-κB and cell migration and invasion induced by TNF-α and inhibits the TAK1/TAB2 interaction, resulting in decreased IκB phosphorylation and NF-κB nuclear translocation in SW620 cells. Furthermore, Snail, a critical transcriptional factor of EMT, was downregulated after GMF treatment. Overexpression of Snail by cDNA transfection significantly decreases the inhibitory effect of GMF on EMT and cell migration and invasion. In conclusion, GMF may be a novel anticancer agent for the treatment of metastasis in colon cancer.

  20. USP33 mediates Slit-Robo signaling in inhibiting colorectal cancer cell migration.

    Science.gov (United States)

    Huang, Zhaohui; Wen, Pushuai; Kong, Ruirui; Cheng, Haipeng; Zhang, Binbin; Quan, Cao; Bian, Zehua; Chen, Mengmeng; Zhang, Zhenfeng; Chen, Xiaoping; Du, Xiang; Liu, Jianghong; Zhu, Li; Fushimi, Kazuo; Hua, Dong; Wu, Jane Y

    2015-04-15

    Originally discovered in neuronal guidance, the Slit-Robo pathway is emerging as an important player in human cancers. However, its involvement and mechanism in colorectal cancer (CRC) remains to be elucidated. Here, we report that Slit2 expression is reduced in CRC tissues compared with adjacent noncancerous tissues. Extensive promoter hypermethylation of the Slit2 gene has been observed in CRC cells, which provides a mechanistic explanation for the Slit2 downregulation in CRC. Functional studies showed that Slit2 inhibits CRC cell migration in a Robo-dependent manner. Robo-interacting ubiquitin-specific protease 33 (USP33) is required for the inhibitory function of Slit2 on CRC cell migration by deubiquitinating and stabilizing Robo1. USP33 expression is downregulated in CRC samples, and reduced USP33 mRNA levels are correlated with increased tumor grade, lymph node metastasis and poor patient survival. Taken together, our data reveal USP33 as a previously unknown tumor-suppressing gene for CRC by mediating the inhibitory function of Slit-Robo signaling on CRC cell migration. Our work suggests the potential value of USP33 as an independent prognostic marker of CRC.

  1. Toll-like receptor 4 prompts human breast cancer cells invasiveness via lipopolysaccharide stimulation and is overexpressed in patients with lymph node metastasis.

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    Huan Yang

    Full Text Available Toll-like receptor (TLR4-mediated signaling has been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. This study investigated the expression and biological role of TLR4 in human breast cancer metastasis. MCF-7 and MDA-MB-231 are human breast cancer cell lines with low and high metastatic potential, respectively. Using lipopolysaccharide (LPS to stimulate MCF-7 and MDA-MB-231 cells, expression of TLR4 mRNA and protein increased compared with that in control cells. TLR4 activation notably up-regulated expression of matrix metalloproteinase (MMP-2, MMP-9 and vascular endothelial growth factor(VEGF mRNA and their secretion in the supernatants of both cell lines. LPS enhanced invasion of MDA-MB-231 cells by transwell assay and MCF-7 cells by wound healing assay. LPS triggered increased expression of TLR4 downstream signaling pathway protein myeloid differentiation factor 88(MyD88 and resulted in interleukin (IL-6 and IL-10 higher production by human breast cancer cells. Stimulation of TLR4 with LPS promoted tumorigenesis and formed metastatic lesions in liver of nude mice. Moreover, expression of TLR4 and MyD88 as well as invasiveness and migration of the cells could be blocked by TLR4 antagonist. Combined with clinicopathological parameters, TLR4 was overexpressed in human breast cancer tissue and correlated with lymph node metastasis. These findings indicated that TLR4 may participate in the progression and metastasis of human breast cancer and provide a new therapeutic target.

  2. Toll-like receptor 4 prompts human breast cancer cells invasiveness via lipopolysaccharide stimulation and is overexpressed in patients with lymph node metastasis.

    Science.gov (United States)

    Yang, Huan; Wang, Bo; Wang, Tao; Xu, Longjiang; He, Chunyan; Wen, Huiyan; Yan, Jie; Su, Honghong; Zhu, Xueming

    2014-01-01

    Toll-like receptor (TLR)4-mediated signaling has been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. This study investigated the expression and biological role of TLR4 in human breast cancer metastasis. MCF-7 and MDA-MB-231 are human breast cancer cell lines with low and high metastatic potential, respectively. Using lipopolysaccharide (LPS) to stimulate MCF-7 and MDA-MB-231 cells, expression of TLR4 mRNA and protein increased compared with that in control cells. TLR4 activation notably up-regulated expression of matrix metalloproteinase (MMP)-2, MMP-9 and vascular endothelial growth factor(VEGF) mRNA and their secretion in the supernatants of both cell lines. LPS enhanced invasion of MDA-MB-231 cells by transwell assay and MCF-7 cells by wound healing assay. LPS triggered increased expression of TLR4 downstream signaling pathway protein myeloid differentiation factor 88(MyD88) and resulted in interleukin (IL)-6 and IL-10 higher production by human breast cancer cells. Stimulation of TLR4 with LPS promoted tumorigenesis and formed metastatic lesions in liver of nude mice. Moreover, expression of TLR4 and MyD88 as well as invasiveness and migration of the cells could be blocked by TLR4 antagonist. Combined with clinicopathological parameters, TLR4 was overexpressed in human breast cancer tissue and correlated with lymph node metastasis. These findings indicated that TLR4 may participate in the progression and metastasis of human breast cancer and provide a new therapeutic target.

  3. MicroRNA-218 inhibits the proliferation and metastasis of esophageal squamous cell carcinoma cells by targeting BMI1.

    Science.gov (United States)

    Wang, Ting; Chen, Tengfei; Niu, Hua; Li, Chang; Xu, Chun; Li, Yuanyuan; Huang, Rui; Zhao, Jun; Wu, Shuyan

    2015-07-01

    MicroRNAs (miRNAs or miRs) play a pivotal role in esophageal carcinogenesis either as oncogenes or as tumor suppressor genes. In the present study, we found that the expression level of miR-218 was significantly reduced in esophageal squamous cell carcinoma (ESCC) tissues and ESCC cell lines. Moreover, its expression was found to correlate with the clinicopathological stage of ESCC; miR-218 expression was lower in the stage III tissue samples than in the stage I and II tissue samples. Furthermore, the decreased expression of miR-218 was found to be associated with an enhanced ESCC cell proliferation and metastasis. Western blot analysis and luciferase reporter assay revealed that miR-218 decreased BMI1 expression by binding to the putative binding sites in its 3'-untranslated region (3'-UTR). The BMI1 mRNA expression levels were markedly increased and negatively correlated with the miR-218 expression level in the ESCC tissues. Functional analyses revealed that the restoration of miR-218 expression inhibited ESCC cell proliferation, migration and invasion and promoted apoptosis. The knockdown of BMI1 by siRNA showed the same phenocopy as the effect of miR-218 on ESCC cells, indicating that BMI1 was a major target of miR-218. In the present study, our findings confirm miR-218 as a tumor suppressor and identify BMI1 as a novel target of miR-218 in ESCC. Therefore, miR-218 may prove to be a useful biomarker for monitoring the initiation and development of ESCC, and may thus be an effective therapeutic target in ESCC.

  4. Siegesbeckia orientalis Extract Inhibits TGFβ1-Induced Migration and Invasion of Endometrial Cancer Cells

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    Chi-Chang Chang

    2016-08-01

    Full Text Available Type II endometrial carcinoma typically exhibits aggressive metastasis and results in a poor prognosis. Siegesbeckia orientalis Linne is a traditional Chinese medicinal herb with several medicinal benefits, including the cytotoxicity against various cancers. This study investigates the inhibitory effects of S. orientalis ethanol extract (SOE on the migration and invasion of endometrial cancer cells, which were stimulated by transforming growth factor β (TGFβ. The inhibitory effects were evaluated by determining wound healing and performing the Boyden chamber assay. This study reveals that SOE can inhibit TGFβ1-induced cell wound healing, cell migration, and cell invasion in a dose-dependent manner in RL95-2 and HEC-1A endometrial cancer cells. SOE also reversed the TGFβ1-induced epithelial-mesenchymal transition, including the loss of the cell-cell junction and the lamellipodia-like structures. Western blot analysis revealed that SOE inhibited the phosphorylation of ERK1/2, JNK1/2, and Akt, as well as the expression of MMP-9, MMP-2, and u-PA in RL95-2 cells dose-dependently. The results of this investigation suggest that SOE is a potential anti-metastatic agent against human endometrial tumors.

  5. A Synchronous Pancreatic Metastasis from Renal Clear Cell Carcinoma, with Unusual CT Characteristics, Completely Regressed after Therapy with Sunitinib

    Directory of Open Access Journals (Sweden)

    Salvatore Lauro

    2014-01-01

    Full Text Available We present a case report of a 75-years-old woman affected by renal clear cell carcinoma with a synchronous pancreatic metastasis and a metachronous lung metastasis. This case has two peculiarities. First the pancreatic metastasis was treated just with medical therapy, that is, Sunitinib, instead of the surgical therapy that is mostly considered. Secondly, the pancreatic lesion showed different characteristics on the computed tomography scan compared to the usual pancreatic metastases from renal clear cell carcinoma. The pancreatic metastasis totally regressed after medical treatment and nowadays, four years after the diagnosis, the patient is disease-free.

  6. Pharmacologic inhibition of MLK3 kinase activity blocks the in vitro migratory capacity of breast cancer cells but has no effect on breast cancer brain metastasis in a mouse xenograft model.

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    Kun Hyoe Rhoo

    Full Text Available Brain metastasis of breast cancer is an important clinical problem, with few therapeutic options and a poor prognosis. Recent data have implicated mixed lineage kinase 3 (MLK3 in controlling the in vitro migratory capacity of breast cancer cells, as well as the metastasis of MDA-MB-231 breast cancer cells from the mammary fat pad to distant lymph nodes in a mouse xenograft model. We therefore set out to test whether MLK3 plays a role in brain metastasis of breast cancer cells. To address this question, we used a novel, brain penetrant, MLK3 inhibitor, URMC099. URMC099 efficiently inhibited the migration of breast cancer cells in an in vitro cell monolayer wounding assay, and an in vitro transwell migration assay, but had no effect on in vitro cell growth. We also tested the effect of URMC099 on tumor formation in a mouse xenograft model of breast cancer brain metastasis. This analysis showed that URMC099 had no effect on the either the frequency or size of breast cancer brain metastases. We conclude that pharmacologic inhibition of MLK3 by URMC099 can reduce the in vitro migratory capacity of breast cancer cells, but that it has no effect on either the frequency or size of breast cancer brain metastases, in a mouse xenograft model.

  7. Taiwanin E inhibits cell migration in human LoVo colon cancer cells by suppressing MMP-2/9 expression via p38 MAPK pathway.

    Science.gov (United States)

    Hsu, Hsi-Hsien; Kuo, Wei-Wen; Day, Cecilia Hsuan; Shibu, Marthandam Asokan; Li, Shin-Yi; Chang, Sheng-Huang; Shih, Hui-Nung; Chen, Ray-Jade; Viswanadha, Vijaya Padma; Kuo, Yueh-Hsiung; Huang, Chih-Yang

    2016-11-03

    Taiwanin E is a natural compound which is structurally analogous to estrogen II and is abundantly found in Taiwania cryptomerioides. It has been previously reported for its anticancer effects; however, the pharmaceutical effect of Taiwanin E on Human LoVo colon cancer cells is not clear. In this study, we investigated the effects of Taiwanin E on metastasis and the associated mechanism of action on Human LoVo colon cancer cells with respect to the modulations in their cell migration and signaling pathways associated with migration. The results showed that Taiwanin E inhibited cell migration ability correlated with reduced expression and activity of MMP-2 and MMP-9. In addition, Taiwanin E induced activation of p38 through phosphorylation. Inhibition of p38α/β significantly abolished the effect of Taiwanin E on cell migration and MMP-2/-9 activity. Our results conclude that Taiwanin E inhibited cell migration chiefly via p38α MAPK pathway and in a lesser extend via p38β MAPK. The results elucidate the potential of the phytoestrogen natural compound Taiwanin E as a cancer therapeutic agent in inhibiting the cell migration. © 2016 Wiley Periodicals, Inc. Environ Toxicol, 2016.

  8. VI-14, a novel flavonoid derivative, inhibits migration and invasion of human breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Li, Fanni; Li, Chenglin; Zhang, Haiwei; Lu, Zhijian [State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009 (China); Li, Zhiyu; You, Qidong [Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009 (China); Lu, Na [State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009 (China); Guo, Qinglong, E-mail: anticancer_drug@yahoo.com.cn [State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009 (China)

    2012-06-01

    It has been well characterized that flavonoids possess pronounced anticancer potentials including anti-angiogenesis, anti-metastasis, and pro-apoptosis. Herein, we report, for the first time, that VI-14, a novel flavonoid derivative, possesses anti-cancer properties. The purpose of this study is to investigate the anti-migration and anti-invasion activities of VI-14 in breast cancer cells. Our data indicate that VI-14 inhibits adhesion, migration and invasion of MDA-MB-231 and MDA-MB-435 human breast cancer cells. MDA-MB-231 cells treated with VI-14 display reduced activities and expressions of ECM degradation-associated proteins including matrix metalloproteinase 2 (MMP-2) and 9 (MMP-9) at both the protein and mRNA levels. Meanwhile, VI-14 treatment induces an up-regulated expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) and 2 (TIMP-2) in MDA-MB-231 cells. Western blotting results show that phosphorylation levels of critical components of the MAPK signaling pathway, including ERK, JNK and P38, are dramatically decreased in VI-14-treated MDA-MB-231 cells. Furthermore, treatment of VI-14 significantly decreases the nuclear levels and the binding ability of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). Taken together, our data suggest that VI-14 treatment suppresses migration and motility of breast cancer cells, and VI-14 may be a potential compound for cancer therapy. Highlights: ► We report for the first time that VI-14 possesses anti-cancer properties. ► VI-14 weakens the adhesion, migration and invasion of human breast cancer cells. ► VI-14 decreases the activities and expressions of MMP-2/9. ► VI-14 suppresses the phosphorylation levels of the MAPK signaling pathway. ► VI-14 decreases the nuclear levels and the binding ability of NF-κB and AP-1.

  9. α-Solanine inhibits human melanoma cell migration and invasion by reducing matrix metalloproteinase-2/9 activities.

    Science.gov (United States)

    Lu, Ming-Kun; Shih, Yuan-Wei; Chang Chien, Tzu-Tsung; Fang, Li-Heng; Huang, Hsiang-Ching; Chen, Pin-Shern

    2010-01-01

    α-Solanine, a naturally occurring steroidal glycoalkaloid in potato sprouts, was found to possess anti-carcinogenic properties, such as inhibiting proliferation and inducing apoptosis of tumor cells. However, the effect of α-solanine on cancer metastasis remains unclear. In the present study, we examined the effect of α-solanine on metastasis in vitro. Data demonstrated that α-solanine inhibited proliferation of human melanoma cell line A2058 in a dose-dependent manner. When treated with non-toxic doses of α-solanine, cell migration and invasion were markedly suppressed. Furthermore, α-solanine reduced the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9, which are involved in the migration and invasion of cancer cells. Our biochemical assays indicated that α-solanine potently suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), phosphatidylinositide-3 kinase (PI3K) and Akt, while it did not affect phosphorylation of extracellular signal regulating kinase (ERK). In addition, α-solanine significantly decreased the nuclear level of nuclear factor kappa B (NF-κB), suggesting that α-solanine inhibited NF-κB activity. Taken together, the results suggested that α-solanine inhibited migration and invasion of A2058 cells by reducing MMP-2/9 activities. It also inhibited JNK and PI3K/Akt signaling pathways as well as NF-κB activity. These findings reveal new therapeutic potential for α-solanine in anti-metastatic therapy.

  10. CIZ1 is upregulated in hepatocellular carcinoma and promotes the growth and migration of the cancer cells.

    Science.gov (United States)

    Wu, Jinsheng; Lei, Liu; Gu, Dianhua; Liu, Hui; Wang, Shaochuang

    2016-04-01

    Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, and the prognosis for the HCC remains very poor. Although dys-regulation of CIZ1 (Cip1 interacting zinc finger protein 1) has been observed in various cancer types, its expression and functions in HCC remain unknown. In this study, the mRNA level of CIZ1 in the HCC tissues were examined using real-time polymerase chain reaction, and the effects of CIZ1 on the growth, migration, and metastasis of HCC cells were examined by crystal violet assay, Boyden chamber assay, and in vivo image system, respectively. In addition, the molecular mechanisms were investigated by luciferase assay. Upregulation of CIZ1 in the clinical HCC samples was observed. Forced expression of CIZ1 promoted the growth and migration of HCC cells, while knocking down the expression of CIZ1 inhibited the growth, migration, and metastasis of HCC cells. Molecular mechanism studies revealed that CIZ1 activated YAP/TAZ signaling in HCC cells. Taken together, our study demonstrated the oncogenic roles of CIZ1 in HCC cells and CIZ1 might be a promising therapeutic target for HCC.

  11. Honokiol inhibits migration of renal cell carcinoma through activation of RhoA/ROCK/MLC signaling pathway.

    Science.gov (United States)

    Cheng, Shujie; Castillo, Victor; Welty, Matt; Eliaz, Isaac; Sliva, Daniel

    2016-10-01

    Honokiol, a biologically active compound isolated from Magnolia bark, has been shown to possess promising anticancer effect through induction of apoptosis. However, there is a relative lack of information regarding its anti‑metastatic activity. Renal cell carcinoma (RCC) is the most common malignancy of the adult kidney and is known for high risk of metastasis. Clinically, therapeutic methods for metastatic RCC cases are limited and efforts to exploit new treatments are still ongoing. The results of our current investigation first revealed that honokiol suppressed the proliferation of different human RCCs without affecting cell viability. In addition, honokiol inhibited migration of highly metastatic RCC 786‑0 cells and stimulated the activity of small GTPase, RhoA. Furthermore, phosphorylated myosin light chain (MLC) and excessive formation of actin stress fibers were identified in 786‑0 cells treated with honokiol. Interestingly, the pharmacological Rho‑associated protein kinase (ROCK) inhibitor Y‑27632 attenuated contraction of actin stress fibers induced by honokiol and abrogated honokiol‑mediated inhibition of cell migration. Together these important findings suggest that honokiol suppresses the migration of highly metastatic RCC through activation of RhoA/ROCK/MLC signaling and warrants attention in the treatment of RCC metastasis as a novel therapeutic approach.

  12. Analysis of primary cilia in directional cell migration in fibroblasts

    DEFF Research Database (Denmark)

    Christensen, Søren Tvorup; Veland, Iben; Schwab, Albrecht;

    2013-01-01

    Early studies of migrating fibroblasts showed that primary cilia orient in front of the nucleus and point toward the leading edge. Recent work has shown that primary cilia coordinate a series of signaling pathways critical to fibroblast cell migration during development and in wound healing. In p...

  13. Zerumbone suppresses IL-1β-induced cell migration and invasion by inhibiting IL-8 and MMP-3 expression in human triple-negative breast cancer cells.

    Science.gov (United States)

    Han, Jeonghun; Bae, Soo Youn; Oh, Soo-Jin; Lee, Jeongmin; Lee, Jun Ho; Lee, Hyun-Chul; Lee, Se Kyung; Kil, Won Ho; Kim, Seok Won; Nam, Seok Jin; Kim, Sangmin; Lee, Jeong Eon

    2014-11-01

    Inflammation is a key regulatory process in cancer development. Prolonged exposure of breast tumor cells to inflammatory cytokines leads to epithelial-mesenchymal transition, which is the principal mechanism involved in metastasis and tumor invasion. Interleukin (IL)-1β is a major inflammatory cytokine in a variety of tumors. To date, the regulatory mechanism of IL-1β-induced cell migration and invasion has not been fully elucidated. Here, we investigated the effect of zerumbone (ZER) on IL-1β-induced cell migration and invasion in breast cancer cells. The levels of IL-8 and matrix metalloproteinase (MMP)-3 mRNA were analyzed by real-time polymerase chain reaction. The levels of secreted IL-8 and MMP-3 protein were analyzed by enzyme-linked immunosorbent assay and western blot analysis, respectively. Cell invasion and migration was detected by Boyden chamber assay. The levels of IL-8 and MMP-3 expression were significantly increased by IL-1β treatment in Hs578T and MDA-MB231 cells. On the other hand, IL-1β-induced IL-8 and MMP-3 expression was decreased by ZER. Finally, IL-1β-induced cell migration and invasion were decreased by ZER in Hs578T and MDA-MB231 cells. ZER suppresses IL-1β-induced cell migration and invasion by inhibiting IL-8 expression and MMP-3 expression in TNBC cells. ZER could be a promising therapeutic drug for treatment of triple-negative breast cancer patients.

  14. Knockdown of STAT3 by iRNA Inhibiting Migration and Invasion of Epithelial Ovarian Cancer Cells

    Institute of Scientific and Technical Information of China (English)

    LI Qin-hua; ZHU Ji-hong; LIU Lei; YUE Ying

    2012-01-01

    Signal transducer and activator of transcription 3(STAT3) is a dual functional transcription factor with the functions of signal transduction and transcription regulation.It is reported that the expression of STAT3 in ovarian cancer is significantly higher and STAT3 can facilitate ovarian cancer growth and metastasis.To clarify the definite effect and molecular mechanism of STAT3 involved in ovarian cancer growth and metastasis,STAT3 expression was significantly downregulated by transfeeting ovarian cancer model SK-OV-3 cells with the plasmid vector which express specific RNAi that targets human STAT3.The downregulated STAT3 not only decreased the invasion and migration but also inhibited the proliferation of SK-OV-3 cells.Western blot assay shows that the expression of vascular endothelial growth factor(VEGF) and that of Survivin were reduced in the cells with the plasma vector expressing specific RNAi that targets human STATY These results demonstrate that STAT3 involved in the invasion and migration of SK-OV-3 regulates the expression of VEGF and Survivin.In addition,VEGF and Survivin could play an important role in ovarian cancer growth and metastasis.

  15. TKTL1 promotes cell proliferation and metastasis in esophageal squamous cell carcinoma.

    Science.gov (United States)

    Li, Juan; Zhu, Shu-Chai; Li, Shu-Guang; Zhao, Yan; Xu, Jin-Rui; Song, Chun-Yang

    2015-08-01

    Transketolase-like-1 (TKTL1), which is a rate-limiting enzyme in the non-oxidative part of the pentose-phosphate pathway, has been demonstrated to promote carcinogenesis through enhanced aerobic glycolysis. Dysregulation of TKTL1 expression also leads to poor prognosis in patients with urothelial and colorectal cancer. However, the expression pattern and underlying cellular functions in human esophageal squamous cell carcinoma (ESCC) remain largely unexplored. In this study, we measured TKTL1 expression in ESCC cell lines and paraffin-embedded ESCC tumor tissues. Our results revealed that TKTL1 expression was upregulated in all of the four ESCC cell lines and in 61.25% (98/160) of ESCC specimens detected, while only 27.5% (11/40) in normal epithelium. Silencing of TKTL1 expression decreased cell proliferation through inhibiting the expression of MKI67 and cyclins including Ccna2, Ccnb1, Ccnd1 and Ccne1. Meanwhile, down-regulation of TKTL1 also associated with increased apoptotic ratio and altered protein expression of Bcl-2 family in ESCC cells. Furthermore, knockdown of TKTL1 significantly reduced the invasive potential of ESCC cells through up-regulation of anti-metastasis genes (MTSS1, TIMP2 and CTSK) and down-regulation of pr-metastasis genes (MMP2, MMP9, MMP10 and MMP13). Taken together, our results indicate that TKTL1 is associated with a more aggressive behavior in ESCC cells and suppresses its expression or enzyme activity might represents a potential target for developing novel therapies in human ESCCs.

  16. Tetrathiomolybdate inhibits head and neck cancer metastasis by decreasing tumor cell motility, invasiveness and by promoting tumor cell anoikis

    Directory of Open Access Journals (Sweden)

    Merajver Sofia D

    2010-08-01

    Full Text Available Abstract Background The metastatic spread of solid tumors is directly or indirectly responsible for most cancer-related deaths. Tumor metastasis is very complex and this process requires a tumor cell to acquire enhanced motility, invasiveness and anoikis resistance to successfully establish a tumor at a distal site. Metastatic potential of tumor cells is directly correlated with the expression levels of several angiogenic cytokines. Copper is a mandatory cofactor for the function of many of these angiogenic mediators as well as other proteins that play an important role in tumor cell motility and invasiveness. We have previously shown that tetrathiomolybdate (TM is a potent chelator of copper and it mediates its anti-tumor effects by suppressing tumor angiogenesis. However, very little is known about the effect of TM on tumor cell function and tumor metastasis. In this study, we explored the mechanisms underlying TM-mediated inhibition of tumor metastasis. Results We used two in vivo models to examine the effects of TM on tumor metastasis. Animals treated with TM showed a significant decrease in lung metastasis in both in vivo models as compared to the control group. In addition, tumor cells from the lungs of TM treated animals developed significantly smaller colonies and these colonies had significantly fewer tumor cells. TM treatment significantly decreased tumor cell motility and invasiveness by inhibiting lysyl oxidase (LOX activity, FAK activation and MMP2 levels. Furthermore, TM treatment significantly enhanced tumor cell anoikis by activating p38 MAPK cell death pathway and by downregulating XIAP survival protein expression. Conclusions Taken together, these results suggest that TM is a potent suppressor of head and neck tumor metastasis by modulating key regulators of tumor cell motility, invasiveness and anoikis resistance.

  17. Inhibitory effect of Trolox on the migration and invasion of human lung and cervical cancer cells.

    Science.gov (United States)

    Sung, Ho Joong; Kim, Yoonseo; Kang, Hyereen; Sull, Jae Woong; Kim, Yoon Suk; Jang, Sung-Wuk; Ko, Jesang

    2012-02-01

    The antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) is implicated in migration and invasion of metastatic tumors. However, the molecular mechanism underlying the effect of Trolox on metastatic cancer cells is not known. We found that a non-cytotoxic dose of Trolox decreased phorbol 12-myristate 13-acetate (PMA)-induced invasion and migration of both A549 and HeLa cancer cells. We also found that Trolox suppressed both the expression and the proteolytic activity of matrix metalloproteinase-9 (MMP-9), and that the promoter activity of PMA-induced MMP-9 was inhibited by Trolox. Our results show that Trolox inhibits the transcriptional activity of MMP-9 by suppression of NF-κB transactivation. These results indicate that Trolox inhibits NF-κB-mediated MMP-9 expression, leading to the suppression of migration and invasion in lung and cervical cancer cells. Trolox is a potential agent for clinical use in preventing the invasion and metastasis of human malignant lung and cervical cancers.

  18. Dynamic cell adhesion and migration on nanoscale grooved substrates.

    Science.gov (United States)

    Lamers, E; te Riet, J; Domanski, M; Luttge, R; Figdor, C G; Gardeniers, J G E; Walboomers, X F; Jansen, J A

    2012-01-01

    Organised nanotopography mimicking the natural extracellular matrix can be used to control morphology, cell motility, and differentiation. However, it is still unknown how specific cell types react with specific patterns. Both initial adhesion and preferential cell migration may be important to initiate and increase cell locomotion and coverage with cells, and thus achieve an enhanced wound healing response around an implantable material. Therefore, the aim of this study was to evaluate how MC3T3-E1 osteoblast initial adhesion and directional migration are influenced by nanogrooves with pitches ranging from 150 nm up to 1000 nm. In this study, we used a multi-patterned substrate with five different groove patterns and a smooth area with either a concentric or radial orientation. Initial cell adhesion measurements after 10 s were performed using atomic force spectroscopy-assisted single-cell force spectroscopy, and demonstrated that nascent cell adhesion was highly induced by a 600 nm pitch and reduced by a 150 nm pitch. Addition of RGD peptide significantly reduced adhesion, indicating that integrins and cell adhesive proteins (e.g. fibronectin or vitronectin) are key factors in specific cell adhesion on nanogrooved substrates. Also, cell migration was highly dependent on the groove pitch; the highest directional migration parallel to the grooves was observed on a 600 nm pitch, whereas a 150 nm pitch restrained directional cell migration. From this study, we conclude that grooves with a pitch of 600 nm may be favourable to enhance fast wound closure, thereby promoting tissue regeneration.

  19. Sinomenine prevents metastasis of human osteosarcoma cells via S phase arrest and suppression of tumor-related neovascularization and osteolysis through the CXCR4-STAT3 pathway.

    Science.gov (United States)

    Xie, Tao; Ren, Hai-Yong; Lin, Hai-Qing; Mao, Jin-Ping; Zhu, Ting; Wang, Sheng-Dong; Ye, Zhao-Ming

    2016-05-01

    Osteosarcoma is the most common primary malignant tumor of the bone. The long-term survivals continue to be unsatisfactory for patients with metastatic and recurrent disease. Metastasis is still a severe challenge in osteosarcoma treatment. Sinomenine, an alkaloid from traditional Chinese medicine, has been proved to possess potent antitumor and anti-invasion effect on various cancers. However, the effect of sinomenine on human osteosarcoma and the underlying mechanisms remains unknown. We report here that sinomenine inhibited proliferation by inducing S phase arrest and suppressing the clone formation. Significant inhibitory effects were found in invasion and metastasis in osteosarcoma, but little cytotoxicity was observed in tested concentrations. Exposure to sinomenine resulted in suppression of invasion and migration in osteosarcoma cells as well as tube formation ability in the human umbilical vein endothelial cells (HUVEC) and U2OS cells. Furthermore, it demonstrated that CXCR4 played a key role contributing to invasion in osteosarcoma which is considered to be a core target site in sinomenine treatment. Sinomenine inhibited invasion by suppressing CXCR4 and STAT3 phosphorylation then downregulating the expression of MMP-2, MMP-9, RANKL, VEGF downstream. In addition, then RANKL-mediated bone destruction stimulated by osteoclastogenesis and VEGF-related neovascularization were restrained. Importantly, in vivo, sinomenine suppressed proliferation, osteoclastogenesis and bone destruction. Through these various comprehensive means, sinomenine inhibits metastasis in osteosarcoma. Taken together, our results revealed that sinomenine caused S phase arrest, inhibited invasion and metastasis via suppressing the CXCR4-STAT3 pathway and then osteoclastogenesis-mediated bone destruction and neovascularization in osteosarcoma. Sinomenine is therefore a promising adjuvant agent for metastasis control in osteosarcoma.

  20. [Targeted Therapy and Immunotherapy for Non-small Cell Lung Cancer 
with Brain Metastasis].

    Science.gov (United States)

    Song, Qi; Jiao, Shunchang; Li, Fang

    2016-08-20

    Brain metastasis, a common complication of non-small cell lung cancer (NSCLC) with an incidence rate of 30%-50%, significantly affects the patients' quality of life. The prognosis of patients of NSCLC with brain metastasis is extremely poor, the average median survival is only 1 m-2 m without treatment. The targeted therapy based on lung cancer driven gene is a new treatment. Besides, the immunotherapy which can enhance the effect of anti-cancer by simulating the immune system is a new approach. The combination of targeted therapy and immunotherapy can greatly benefit patients in clinical work.

  1. Targeted Therapy and Immunotherapy for Non-small Cell Lung Cancer 
with Brain Metastasis

    Directory of Open Access Journals (Sweden)

    Qi SONG

    2016-08-01

    Full Text Available Brain metastasis, a common complication of non-small cell lung cancer (NSCLC with an incidence rate of 30%-50%, significantly affects the patients’ quality of life. The prognosis of patients of NSCLC with brain metastasis is extremely poor, the average median survival is only 1 m-2 m without treatment. The targeted therapy based on lung cancer driven gene is a new treatment. Besides, the immunotherapy which can enhance the effect of anti-cancer by simulating the immune system is a new approach. The combination of targeted therapy and immunotherapy can greatly benefit patients in clinical work.

  2. Targeted Therapy and Immunotherapy for Non-small Cell Lung Cancer 
with Brain Metastasis

    OpenAIRE

    Song, Qi; Jiao, Shunchang; Li, Fang

    2016-01-01

    Brain metastasis, a common complication of non-small cell lung cancer (NSCLC) with an incidence rate of 30%-50%, significantly affects the patients’ quality of life. The prognosis of patients of NSCLC with brain metastasis is extremely poor, the average median survival is only 1 m-2 m without treatment. The targeted therapy based on lung cancer driven gene is a new treatment. Besides, the immunotherapy which can enhance the effect of anti-cancer by simulating the immune system is a new approa...

  3. Arctigenin Inhibits Lung Metastasis of Colorectal Cancer by Regulating Cell Viability and Metastatic Phenotypes

    OpenAIRE

    2016-01-01

    Arctigenin (ARC) has been shown to have an anti-cancer effect in various cell types and tissues. However, there have been no studies concerning metastatic colorectal cancer (CRC). In this study, we investigated the anti-metastatic properties of ARC on colorectal metastasis and present a potential candidate drug. ARC induced cell cycle arrest and apoptosis in CT26 cells through the intrinsic apoptotic pathway via MAPKs signaling. In several metastatic phenotypes, ARC controlled epithelial-mese...

  4. A case of peritoneal metastasis during treatment for hypopharyngeal squamous cell carcinoma

    OpenAIRE

    Wakasaki, Takahiro; Omori, Hirofumi; Sueyoshi, Shintaro; Rikimaru, Fumihide; Toh, Satoshi; Taguchi, Kenichi; Higaki, Yuichiro; Morita, Masaru; Masuda, Muneyuki

    2016-01-01

    Background Advanced head and neck squamous cell carcinomas frequently develop distant metastases to limited organs, including the lungs, bone, mediastinal lymph nodes, brain, and liver. Peritoneal carcinomatosis as an initial distant metastasis from hypopharyngeal squamous cell carcinoma is quite rare. Case presentation A 75-year-old man diagnosed with hypopharyngeal squamous cell carcinoma and his clinical stage was determined as T2N2cM0. Notably, the right retropharyngeal lymph node surroun...

  5. Targeting SPARC by lentivirus-mediated RNA interference inhibits cervical cancer cell growth and metastasis

    Directory of Open Access Journals (Sweden)

    Chen Jie

    2012-10-01

    Full Text Available Abstract Background Secreted protein acidic and rich in cysteine (SPARC, a calcium-binding matricellular glycoprotein, is implicated in the progressions of some cancers. However, no information has been available to date regarding the function of SPARC in cervical cancer cell growth and metastasis. Methods In this study, we isolated and established high invasive subclones and low invasive subclones from human cervical cancer cell lines HeLa and SiHa by the limited dilution method. Real-time q-RT-PCR, Western Blot and ICC were performed to investigate SPARC mRNA and protein expressions in high invasive subclones and low invasive subclones. Then lentivirus vector with SPARC shRNA was constructed and infected the highly invasive subclones. Real-time q-RT-PCR, Western Blot and ICC were also performed to investigate the changes of SPARC expression after viral infection. In functional assays, effects of SPARC knockdown on the biological behaviors of cervical cancer cells were investigated. The mechanisms of SPARC in cervical cancer proliferation, apoptosis and invasion were also researched. Results SPARC was over-expressed in the highly invasive subclones compared with the low invasive subclones. Knockdown of SPARC significantly suppressed cervical cancer cell proliferation, and induced cell cycle arrest at the G1/G0 phase through the p53/p21 pathway, also caused cell apoptosis accompanied by the decreased ratio of Bcl-2/Bax, and inhibited cell invasion and metastasis accompanied by down-regulated MMP2 and MMP9 expressions and up-regulated E-cadherin expression. Conclusion SPARC is related to the invasive phenotype of cervical cancer cells. Knockdown of SPARC significantly suppresses cervical cancer cell proliferation, induces cell apoptosis and inhibits cell invasion and metastasis. SPARC as a promoter improves cervical cancer cell growth and metastasis.

  6. Renal T-cell lymphoma with cerebral metastasis in a dog with chronic canine ehrlichiosis

    Directory of Open Access Journals (Sweden)

    E.P. Lane

    2002-07-01

    Full Text Available A renal T-cell lymphoma with exclusive cerebral metastasis was diagnosed in a 5-year-old Staffordshire bull terrier bitch euthanased for aggression. This is the first recorded case of primary renal lymphoma in a dog. Immune suppression, due to chronic canine monocytic ehrlichiosis, mayaccount for the unusual primary site and metastatic patternof the tumour.

  7. Screening of Differently Expressed Genes in Human Prostate Cancer Cell Lines with Different Metastasis Potentials

    Institute of Scientific and Technical Information of China (English)

    SONG Anping; LIAO Guoning; WU Mingfu; LU Yunping; MA Ding

    2007-01-01

    In order to screen the genes differentially expressed in two human prostate cancer cells with different metastasis potentials, suppression subtractive hybridization (SSH) was done twice on human prostate cancer cell line with high potential of metastasis PC3M-1E8 and its synogenetic cell line PC3M-2B4 with low metastasis potential. In the first subtraction PC3M-2B4 was used as tester and PC3M-1E8 as driver and the forward subtractive library was constructed. In the second one the tester and driver were interchanged and the reverse subtractive library was constructed. The screened clones of both libraries were sequenced and Gene Bank homology search was performed. Some clones were confirmed by quantitative real-time PCR. The results showed that two subtrac-tive libraries containing 238 positive clones were constructed. Analysis of 16 sequenced clones ran-domly picked from two libraries showed that 4 differentially expressed gene fragments were identi-fied as new EST with unknown functions. It was concluded that two subtractive libraries of human prostate cancer cell lines with different metastasis potentials were constructed successfully.

  8. Evidence for Natural Killer Cell-Mediated Protection from Metastasis Formation in Uveal Melanoma Patients

    NARCIS (Netherlands)

    Maat, Willem; van der Slik, Arno R.; Verhoeven, Dirk H. J.; Alizadeh, Behrooz Z.; Ly, Long V.; Verduijn, Willem; Luyten, Gregorius P. M.; Mulder, Arend; van Hall, Thorbald; Koning, Frits; Jager, Martine J.; van Bergen, Jeroen

    2009-01-01

    PURPOSE. In uveal melanoma, low human leukocyte antigen (HLA) class I expression on primary tumors is associated with a decreased risk of metastasis. Consequently, it has been suggested that natural killer (NK) cells, which detect decreased expression of HLA class I, are involved in the immune contr

  9. The histone demethylase UTX regulates stem cell migration and hematopoiesis.

    Science.gov (United States)

    Thieme, Sebastian; Gyárfás, Tobias; Richter, Cornelia; Özhan, Günes; Fu, Jun; Alexopoulou, Dimitra; Muders, Michael H; Michalk, Irene; Jakob, Christiane; Dahl, Andreas; Klink, Barbara; Bandola, Joanna; Bachmann, Michael; Schröck, Evelin; Buchholz, Frank; Stewart, A Francis; Weidinger, Gilbert; Anastassiadis, Konstantinos; Brenner, Sebastian

    2013-03-28

    Regulated migration of hematopoietic stem cells is fundamental for hematopoiesis. The molecular mechanisms underlying stem cell trafficking are poorly defined. Based on a short hairpin RNA library and stromal cell-derived factor-1 (SDF-1) migration screening assay, we identified the histone 3 lysine 27 demethylase UTX (Kdm6a) as a novel regulator for hematopoietic cell migration. Using hematopoietic stem and progenitor cells from our conditional UTX knockout (KO) mice, we were able to confirm the regulatory function of UTX on cell migration. Moreover, adult female conditional UTX KO mice displayed myelodysplasia and splenic erythropoiesis, whereas UTX KO males showed no phenotype. During development, all UTX KO female and a portion of UTX KO male embryos developed a cardiac defect, cranioschisis, and died in utero. Therefore, UTY, the male homolog of UTX, can compensate for UTX in adults and partially during development. Additionally, we found that UTX knockdown in zebrafish significantly impairs SDF-1/CXCR4-dependent migration of primordial germ cells. Our data suggest that UTX is a critical regulator for stem cell migration and hematopoiesis.

  10. MiR-200c promotes bladder cancer cell migration and invasion by directly targeting RECK

    Directory of Open Access Journals (Sweden)

    Cheng Y

    2016-08-01

    Full Text Available Yidong Cheng,* Xiaolei Zhang,* Peng Li,* Chengdi Yang, Jinyuan Tang, Xiaheng Deng, Xiao Yang, Jun Tao, Qiang Lu, Pengchao Li Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Background: Increasing evidence suggests that the dysregulation of certain microRNAs plays an important role in tumorigenesis and metastasis. MiR-200c exhibits a disordered expression in many tumors and presents dual roles in bladder cancer (BC. Therefore, the definite role of miR-200c in BC needs to be investigated further.Materials and methods: Quantitative reverse transcription polymerase chain reaction was used to assess miR-200c expression. Cell invasion and migration were evaluated using wound healing and transwell assays. The luciferase reporter assay was used to identify the direct target of miR-200c. The expression of reversion-inducing cysteine-rich protein with kazal motifs (RECK in BC tissues and adjacent nontumor tissues, as well as in BC cell lines, was detected through quantitative reverse transcription polymerase chain reaction, Western blot assay, and immunohistochemistry.Results: The miR-200c expression was significantly upregulated in the BC tissues compared with the adjacent nontumor tissues. The downregulation of miR-200c significantly inhibited cell migration and invasion in the BC cell lines. The luciferase reporter assay showed that RECK was a direct target of miR-200c. The knockdown of RECK in the BC cell lines treated with anti-miR-200c elevated the previously attenuated cell migration and invasion.Conclusion: Our findings indicated that miR-200c functions as oncogenes in BC and may provide a novel therapeutic strategy for the treatment of BC. Keywords: miR-200c, bladder cancer, migration, invasion, RECK

  11. Signet Ring Cell Carcinoma of the Gallbladder with Skin Metastasis: A Case Report

    Directory of Open Access Journals (Sweden)

    Erdal KARAGÜLLE

    2010-05-01

    Full Text Available The aim of this case report is to attract the attention of related clinicians to similar cases because of their rarity. We believe this case and other similar cases in the literature could initiate studies that may explain the pathways of metastasis.A 50-year-old female patient underwent laparoscopic cholecystectomy because of symptomatic cholelithiasis. Postoperative pathologic examination of the specimen led to a diagnosis of signet ring carcinoma in the wall of gallbladder. After this incidental diagnosis, this patient underwent a second operation, which was a radical cholecystectomy. After pathological examination of the second operation material, we decided to call this patient for periodic controls, as the tumor was graded as stage I. A cutaneous lesion 33 months after the second operation was diagnosed as metastasis of signet ring cell carcinoma.Signet ring carcinoma of the gallbladder is a rarely seen malignancy. Cutaneous metastasis of this rare malignancy is also quite rare. There are only a few reports of cutaneous metastasis of signet ring carcinoma of the gallbladder. It is necessary to explain the reasons of this unusual metastasis with further studies.

  12. Cancer Stem Cells and Side Population Cells in Breast Cancer and Metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Britton, Kelly M. [Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle-upon-Tyne, NE1 3BZ (United Kingdom); Kirby, John A. [Institute of Cellular Medicine, Newcastle University, 3rd Floor William Leech Building, Framlington Place, Newcastle-upon-Tyne, NE2 4HH (United Kingdom); Lennard, Thomas W.J. [Faculty of Medical Sciences, Newcastle University, 3rd Floor William Leech Building, Framlington Place, Newcastle-upon-Tyne, NE2 4HH (United Kingdom); Meeson, Annette P., E-mail: annette.meeson@ncl.ac.uk [Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle-upon-Tyne, NE1 3BZ (United Kingdom); North East England Stem Cell Institute, Bioscience Centre, International Centre for Life, Central Parkway, Newcastle-upon-Tyne, NE1 3BZ (United Kingdom)

    2011-04-19

    In breast cancer it is never the primary tumour that is fatal; instead it is the development of metastatic disease which is the major cause of cancer related mortality. There is accumulating evidence that suggests that Cancer Stem Cells (CSC) may play a role in breast cancer development and progression. Breast cancer stem cell populations, including side population cells (SP), have been shown to be primitive stem cell-like populations, being long-lived, self-renewing and highly proliferative. SP cells are identified using dual wavelength flow cytometry combined with Hoechst 33342 dye efflux, this ability is due to expression of one or more members of the ABC transporter family. They have increased resistance to chemotherapeutic agents and apoptotic stimuli and have increased migratory potential above that of the bulk tumour cells making them strong candidates for the metastatic spread of breast cancer. Treatment of nearly all cancers usually involves one first-line agent known to be a substrate of an ABC transporter thereby increasing the risk of developing drug resistant tumours. At present there is no marker available to identify SP cells using immunohistochemistry on breast cancer patient samples. If SP cells do play a role in breast cancer progression/Metastatic Breast Cancer (MBC), combining chemotherapy with ABC inhibitors may be able to destroy both the cells making up the bulk tumour and the cancer stem cell population thus preventing the risk of drug resistant disease, recurrence or metastasis.

  13. Histochemical evidence of osteoclastic degradation of extracellular matrix in osteolytic metastasis originating from human lung small carcinoma (SBC-5) cells.

    Science.gov (United States)

    Li, Minqi; Amizuka, Norio; Takeuchi, Kiichi; Freitas, Paulo H L; Kawano, Yoshiro; Hoshino, Masaaki; Oda, Kimimitsu; Nozawa-Inoue, Kayoko; Maeda, Takeyasu

    2006-02-01

    The aim of this study was to assess the dynamics of osteoclast migration and the degradation of unmineralized extracellular matrix in an osteolytic metastasis by examining a well-standardized lung cancer metastasis model of nude mice. SBC-5 human lung small carcinoma cells were injected into the left cardiac ventricle of 6-week-old BALB/c nu/nu mice under anesthesia. At 25-30 days after injection, the animals were sacrificed and their femora and/or tibiae were removed for histochemical analyses. Metastatic lesions were shown to occupy a considerable area extending from the metaphyses to the bone marrow region. Tartrate resistant acid phosphatase (TRAPase)-positive osteoclasts were found in association with an alkaline phosphatase (ALPase)-positive osteoblastic layer lining the bone surface, but could also be localized in the ALPase-negative stromal tissues that border the tumor nodules. These stromal tissues were markedly positive for osteopontin, and contained a significant number of TRAPase-positive osteoclasts expressing immunoreactivity for CD44. We thus speculated that, mediating its affinity for CD44, osteopontin may serve to facilitate osteoclastic migration after their formation associated with ALPase-positive osteoblasts. We next examined the localization of cathepsin K and matrix metallo-proteinase-9 (MMP-9) in osteoclasts. Osteoclasts adjacent to the bone surfaces were positive for both proteins, whereas those in the stromal tissues in the tumor nests showed only MMP-9 immunoreactivity. Immunoelectron microscopy disclosed the presence of MMP-9 in the Golgi apparatus and in vesicular structures at the baso-lateral cytoplasmic region of the osteoclasts found in the stromal tissue. MMP-9-positive vesicular structures also contained fragmented extracellular materials. Thus, osteoclasts appear to either select an optimized function, namely secreting proteolytic enzymes from ruffled borders during bone resorption, or recognize the surrounding extracellular

  14. Metastasis of renal clear-cell carcinoma to the oral mucosa, an atypical location.

    Science.gov (United States)

    Maestre-Rodríguez, Oscar; González-García, Raúl; Mateo-Arias, Jesús; Moreno-García, Carlos; Serrano-Gil, Herminia; Villanueva-Alcojol, Laura; Campos-de-Orellana, Ana Ma; Monje-Gil, Florencio

    2009-11-01

    The majority of cases of metastatic tumors involve the mandible and some the maxilla but they are considerably less common in intraoral soft tissues. In addition, the primary tumor is known in the majority of cases; although in one-third of such cases, metastasis is the first clinical manifestation. The most common primary tumors metastasizing to the mouth are lung carcinoma in men and breast carcinoma in women. An oral metastasis implies a serious prognosis, as in the majority of patients there is multiple organ involvement at the time of diagnosis. We present the case of a 52-year old patient with renal pathology who came to the emergency room due to a rapidly increasing gingival tumor. With the provisional clinical diagnosis of a pyogenic granuloma,the tumor was excised. Subsequent anatomopathological analysis revealed a tumor metastasis compatible with clear-cell carcinoma, and its renal origin was confirmed by means of immunohistochemical techniques.

  15. Scalp metastasis as the first sign of small-cell lung cancer: management and literature review.

    Science.gov (United States)

    Salemis, Nikolaos S; Veloudis, Georgios; Spiliopoulos, Kyriakos; Nakos, Georgios; Vrizidis, Nikolaos; Gourgiotis, Stavros

    2014-01-01

    Cutaneous metastasis from primary visceral malignancy is a relatively uncommon clinical entity, with a reported incidence ranging from 0.22% to 10% among various series. However, the presence of cutaneous metastasis as the first sign of a clinically silent visceral cancer is exceedingly rare. We describe here a case of an asymptomatic male patient who presented with a solitary scalp metastasis as the initial manifestation of an underlying small-cell lung cancer. Diagnostic evaluation revealed advanced disease. We conclude that the possibility of metastatic skin disease should always be considered in the differential diagnosis in patients with a history of smoking or lung cancer presenting with cutaneous nodules. Physicians should be aware of this rare clinical entity, and appropriate investigation should be arranged for early diagnosis and initiation of the appropriate treatment. The prognosis for most patients remains poor.

  16. Anti-S100A4 antibody suppresses metastasis formation by blocking stroma cell invasion

    DEFF Research Database (Denmark)

    Klingelhöfer, Jörg; Grum-Schwensen, Birgitte; Beck, Mette K

    2012-01-01

    The small Ca-binding protein, S100A4, has a well-established metastasis-promoting activity. Moreover, its expression is tightly correlated with poor prognosis in patients with numerous types of cancer. Mechanistically, the extracellular S100A4 drives metastasis by affecting the tumor...... microenvironment, making it an attractive target for anti-cancer therapy. In this study, we produced a function-blocking anti-S100A4 monoclonal antibody with metastasis-suppressing activity. Antibody treatment significantly reduced metastatic burden in the lungs of experimental animals by blocking the recruitment...... its activity by suppressing stroma cell recruitment to the site of the growing tumor. Our epitope mapping studies suggested that the antibody recognition site overlaps with the target binding interface of human S100A4. We conclude here that this antibody could serve as a solid basis for development...

  17. microRNA-183 plays as oncogenes by increasing cell proliferation, migration and invasion via targeting protein phosphatase 2A in renal cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Qiu, Mingning, E-mail: lcuzfy@163.com; Liu, Lei, E-mail: leiliulab@163.com; Chen, Lieqian, E-mail: lieqianchen@163.com; Tan, Guobin, E-mail: guobintan@163.com; Liang, Ziji, E-mail: zijilianglab@163.com; Wang, Kangning, E-mail: kangningwanglab@163.com; Liu, Jianjun, E-mail: jianjunliulab@163.com; Chen, Hege, E-mail: hegechen@163.com

    2014-09-12

    Highlights: • miR-183 was up-regulated in renal cancer tissues. • Inhibition of endogenous miR-183 suppressed renal cancer cell growth and metastasis. • miR-183 increased cell growth and metastasis. • miR-183 regulated renal cancer cell growth and metastasis via directly targeting tumor suppressor protein phosphatase 2A. - Abstract: The aim of this study was to investigate the function of miR-183 in renal cancer cells and the mechanisms miR-183 regulates this process. In this study, level of miR-183 in clinical renal cancer specimens was detected by quantitative real-time PCR. miR-183 was up- and down-regulated in two renal cancer cell lines ACHN and A498, respectively, and cell proliferation, Caspase 3/7 activity, colony formation, in vitro migration and invasion were measured; and then the mechanisms of miR-183 regulating was analyzed. We found that miR-183 was up-regulated in renal cancer tissues; inhibition of endogenous miR-183 suppressed in vitro cell proliferation, colony formation, migration, and invasion and stimulated Caspase 3/7 activity; up-regulated miR-183 increased cell growth and metastasis and suppressed Caspase 3/7 activity. We also found that miR-183 directly targeted tumor suppressor, specifically the 3′UTR of three subunits of protein phosphatase 2A (PP2A-Cα, PP2A-Cβ, and PP2A-B56-γ) transcripts, inhibiting their expression and regulated the downstream regulators p21, p27, MMP2/3/7 and TIMP1/2/3/4. These results revealed the oncogenes role of miR-183 in renal cancer cells via direct targeting protein phosphatase 2A.

  18. Migration

    NARCIS (Netherlands)

    Gienapp, P.; Candolin, Ulrika; Wong, Bob

    2012-01-01

    This chapter examines how human-induced environmental changes affect migration. It explores how such changes affect conditions along the migration route, as well as the cues that are used in the timing of migration such as the celestial bodies and the planet's magnetic field. It emphasizes the effec

  19. Long Non Coding RNA MALAT1 Promotes Tumor Growth and Metastasis by inducing Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma.

    Science.gov (United States)

    Zhou, Xuan; Liu, Su; Cai, Guoshuai; Kong, Lingping; Zhang, Tingting; Ren, Yu; Wu, Yansheng; Mei, Mei; Zhang, Lun; Wang, Xudong

    2015-11-02

    The prognosis of advanced oral squamous cell carcinoma (OSCC) patients remains dismal, and a better understanding of the underlying mechanisms is critical for identifying effective targets with therapeutic potential to improve the survival of patients with OSCC. This study aims to clarify the clinical and biological significance of metastasis-associated long non-coding RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in OSCC. We found that MALAT1 is overexpressed in OSCC tissues compared to normal oral mucosa by real-time PCR. MALAT1 served as a new prognostic factor in OSCC patients. When knockdown by small interfering RNA (siRNA) in OSCC cell lines TSCCA and Tca8113, MALAT1 was shown to be required for maintaining epithelial-mesenchymal transition (EMT) mediated cell migration and invasion. Western blot and immunofluorescence staining showed that MALAT1 knockdown significantly suppressed N-cadherin and Vimentin expression but induced E-cadherin expression in vitro. Meanwhile, both nucleus and cytoplasm levels of β-catenin and NF-κB were attenuated, while elevated MALAT1 level triggered the expression of β-catenin and NF-κB. More importantly, targeting MALAT1 inhibited TSCCA cell-induced xenograft tumor growth in vivo. Therefore, these findings provide mechanistic insight into the role of MALAT1 in regulating OSCC metastasis, suggesting that MALAT1 is an important prognostic factor and therapeutic target for OSCC.

  20. Plakoglobin: Role in Tumorigenesis and Metastasis

    Directory of Open Access Journals (Sweden)

    Zackie Aktary

    2012-01-01

    Full Text Available Plakoglobin (γ-catenin is a member of the Armadillo family of proteins and a homolog of β-catenin. As a component of both the adherens junctions and desmosomes, plakoglobin plays a pivotal role in the regulation of cell-cell adhesion. Furthermore, similar to β-catenin, plakoglobin is capable of participating in cell signaling. However, unlike β-catenin that has well-documented oncogenic potential through its involvement in the Wnt signaling pathway, plakoglobin generally acts as a tumor/metastasis suppressor. The exact roles that plakoglobin plays during tumorigenesis and metastasis are not clear; however, recent evidence suggests that it may regulate gene expression, cell proliferation, apoptosis, invasion, and migration. In this paper, we describe plakoglobin, its discovery and characterization, its role in regulating cell-cell adhesion, and its signaling capabilities in regulation of tumorigenesis and metastasis.

  1. Preliminary Observation on the Influence of Tumor Osseous Metastasis on Autologous Peripheral Blood Stem Cell Collection

    Institute of Scientific and Technical Information of China (English)

    Xiaoming Si; Wenchao Liu; Yan Xue; Hongmei Zhang; Rong Sheng; Ying Huang; Jie Cheng

    2007-01-01

    OBJECTIVE To examine the influence of tumor osseous metastasis on the patients undergoing autologous peripheral blood stem cell collection. METHODS A total of 36 patients with malignant diseases who received an autologous peripheral blood stem cell transplantation, during a period from April 2004 to June 2006, were chosen. The patients were divided into two groups, I.e. Group A were patients with a complication of tumor osseous metastasis, and group B were without metastasis. Both groups were treated with Taxotere 120 mg/m2 plus granulocyte colony-stimulating factor (G-CSF) 5 ug/kg/d, for a mobilization regimen. A blood cell separator was used to collect the mononuclear cells. The proportion of harvested CD34+ cells in the peripheral blood and the collected mononuclear cells were detected by flow cytometry. The number of CD34+ cells was used to determine the difference in the nature of the collections between the two groups. RESULTS After mobilization in groups A and B, the number of the peripheral blood mononuclear cells (PBMC) was 39.3 ±14.7% and 41.±12.4 % and the proportion of CD34 + cells was 0.16±0.07% and 0.17 ± 0.10%, respectively. Following administration of the drugs, there was no significant difference between the number of harvested PBMC and CD34+ cells of the two groups, I.e., 3.47 ± 1.16 x 108/Kg and 2.52 ± 1.43 × 106/Kg in group A and 4.02 ± 1.31 × 108/Kg and 2.73 ± 1.87 x 108/Kg in group B, respectively. CONCLUSION Osseous metastasis, as a single factor, may have no impact on mobilization and harvesting of hematopoietic stem cells and their engraftment after autotransplantation.

  2. Melanoma cell metastasis via P-selectin-mediated activation of acid sphingomyelinase in platelets.

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    Becker, Katrin Anne; Beckmann, Nadine; Adams, Constantin; Hessler, Gabriele; Kramer, Melanie; Gulbins, Erich; Carpinteiro, Alexander

    2017-01-01

    Metastatic dissemination of cancer cells is one of the hallmarks of malignancy and accounts for approximately 90 % of human cancer deaths. Within the blood vasculature, tumor cells may aggregate with platelets to form clots, adhere to and spread onto endothelial cells, and finally extravasate to form metastatic colonies. We have previously shown that sphingolipids play a central role in the interaction of tumor cells with platelets; this interaction is a prerequisite for hematogenous tumor metastasis in at least some tumor models. Here we show that the interaction between melanoma cells and platelets results in rapid and transient activation and secretion of acid sphingomyelinase (Asm) in WT but not in P-selectin-deficient platelets. Stimulation of P-selectin resulted in activation of p38 MAPK, and inhibition of p38 MAPK in platelets prevented the secretion of Asm after interaction with tumor cells. Intravenous injection of melanoma cells into WT mice resulted in multiple lung metastases, while in P-selectin-deficient mice pulmonary tumor metastasis and trapping of tumor cells in the lung was significantly reduced. Pre-incubation of tumor cells with recombinant ASM restored trapping of B16F10 melanoma cells in the lung in P-selectin-deficient mice. These findings indicate a novel pathway in tumor metastasis, i.e., tumor cell mediated activation of P-selectin in platelets, followed by activation and secretion of Asm and in turn release of ceramide and tumor metastasis. The data suggest that p38 MAPK acts downstream from P-selectin and is necessary for the secretion of Asm.

  3. Predictive factors of occult neck metastasis in patients with oral squamous cell carcinoma

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    Renato Fortes Bittar

    Full Text Available ABSTRACT INTRODUCTION: It is well established that cervical lymph node metastasis is the most important prognostic factor in patients with oral squamous cell carcinoma of the upper aerodigestive tract. The definition of parameters and classifications that could separate patients in groups of low, intermediate and high-risk is being attempted for several years. OBJECTIVE: The objective of this study was to determine possible predictive factors related to the occurrence of occult cervical lymph node metastasis through the analysis of histopathological reports of surgical specimens obtained after oral squamous cell carcinoma resection and selective neck dissections of patients initially classified as N0. METHODS: This was a primary, retrospective, observational, case-control study. Histopathological reports were reviewed to determine if some findings were related to the occurrence of occult lymph node metastasis. The events analyzed were oral cavity subsites, pT-stage, muscular infiltration, desmoplasia, vascular emboli, perineural infiltration, tumor thickness and compromised margins. RESULTS: Occult cervical metastasis accounted for 19.10 percent of the cases. Desmoplasia, perineural infiltration, tumor thickness and pT4a stage are predictive factors of occult neck metastasis (p-value = 0.0488, 0.0326, 0.0395, 0.0488, respectively. CONCLUSION: The accurate definition of predictive factors of occult cervical metastasis may guide the selection of patients that should be referred to radiotherapy, avoiding the unnecessary exposure of low-risk patients to radiation and allowing a better regional control of the disease in those of moderate or high risk.

  4. Long-Term Live Cell Imaging of Cell Migration: Effects of Pathogenic Fungi on Human Epithelial Cell Migration.

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    Wöllert, Torsten; Langford, George M

    2016-01-01

    Long-term live cell imaging was used in this study to determine the responses of human epithelial cells to pathogenic biofilms formed by Candida albicans. Epithelial cells of the skin represent the front line of defense against invasive pathogens such as C. albicans but under certain circumstances, especially when the host's immune system is compromised, the skin barrier is breached. The mechanisms by which the fungal pathogen penetrates the skin and invade the deeper layers are not fully understood. In this study we used keratinocytes grown in culture as an in vitro model system to determine changes in host cell migration and the actin cytoskeleton in response to virulence factors produced by biofilms of pathogenic C. albicans. It is clear that changes in epithelial cell migration are part of the response to virulence factors secreted by biofilms of C. albicans and the actin cytoskeleton is the downstream effector that mediates cell migration. Our goal is to understand the mechanism by which virulence factors hijack the signaling pathways of the actin cytoskeleton to alter cell migration and thereby invade host tissues. To understand the dynamic changes of the actin cytoskeleton during infection, we used long-term live cell imaging to obtain spatial and temporal information of actin filament dynamics and to identify signal transduction pathways that regulate the actin cytoskeleton and its associated proteins. Long-term live cell imaging was achieved using a high resolution, multi-mode epifluorescence microscope equipped with specialized light sources, high-speed cameras with high sensitivity detectors, and specific biocompatible fluorescent markers. In addition to the multi-mode epifluorescence microscope, a spinning disk confocal long-term live cell imaging system (Olympus CV1000) equipped with a stage incubator to create a stable in vitro environment for long-term real-time and time-lapse microscopy was used. Detailed descriptions of these two long-term live

  5. An open data ecosystem for cell migration research

    NARCIS (Netherlands)

    Masuzzo, P.; Martens, L.; Ampe, C.; Anderson, K.I.; Barry, J.; Wever, O. De; Debeir, O.; Decaestecker, C.; Dolznig, H.; Friedl, P.H.A.; Gaggioli, C.; Geiger, B.; Goldberg, I.G.; Horn, E.; Horwitz, R.; Kam, Z.; Devedec, S.E. Le; Vignjevic, D.M.; Moore, J.; Olivo-Marin, J.C.; Sahai, E.; Sansone, S.A.; Sanz-Moreno, V.; Stromblad, S.; Swedlow, J.; Textor, J.C.; Troys, M. Van; Zantl, R.

    2015-01-01

    Cell migration research has recently become both a high content and a high throughput field thanks to technological, computational, and methodological advances. Simultaneously, however, urgent bioinformatics needs regarding data management, standardization, and dissemination have emerged. To address

  6. A review of histopathological and immunohistochemical parameters in diagnosis of metastatic renal cell carcinoma with a case of gingival metastasis

    Directory of Open Access Journals (Sweden)

    Seema Sikka

    2013-01-01

    Full Text Available The oral cavity constitutes a site of low prevalence for metastasis of malignant tumors. However, oral metastasis of a renal origin is relatively more common and represents 2% of all cancer deaths. Renal cancer may metastasize to any part of the body, with a 15% risk of metastasis to the head and neck regions, and pose one of the greatest diagnostic challenges in medical sciences. Approximately 25% of patients have a metastatic disease at initial assessment, which is often responsible for initiating the diagnosis in the first place. Here we present a review of literature of renal cell carcinoma along with a case of gingival metastasis.

  7. Migration of epithelial cells on laminins: RhoA antagonizes directionally persistent migration.

    Science.gov (United States)

    Zhang, Zhigang; Chometon, Gretel; Wen, Tingting; Qu, Haiyan; Mauch, Cornelia; Krieg, Thomas; Aumailley, Monique

    2011-01-01

    Spatial and temporal expression of laminin isoforms is assumed to provide specific local information to neighboring cells. Here, we report the remarkably selective presence of LM-111 at the very tip of hair follicles where LM-332 is absent, suggesting that epithelial cells lining the dermal-epidermal junction at this location may receive different signals from the two laminins. This hypothesis was tested in vitro by characterizing with functional and molecular assays the comportment of keratinocytes exposed to LM-111 and LM-332. The two laminins induced morphologically distinct focal adhesions, and LM-332, but not LM-111, elicited persistent migration of keratinocytes. The different impact on cellular behavior was associated with distinct activation patterns of Rho GTPases and other signaling intermediates. In particular, while LM-111 triggered a robust activation of Cdc42, LM-332 provoked a strong and sustained activation of FAK. Interestingly, activation of Rac1 was necessary but not sufficient to promote migration because there was no directed migration on LM-111 despite Rac1 activation. In contrast, RhoA antagonized directional migration, since silencing of RhoA by RNA interference boosted unidirectional migration on LM-332. Molecular analysis of the role of RhoA strongly suggested that the mechanisms involve disassembly of cell-cell contacts, loss of the cortical actin network, mobilization of α6β4 integrin out of stable adhesions, and displacement of the integrin from its association with the insoluble pool of intermediate filaments.

  8. MiR-525-3p enhances the migration and invasion of liver cancer cells by downregulating ZNF395.

    Directory of Open Access Journals (Sweden)

    Fei Pang

    Full Text Available Liver cancer is one of leading causes of cancer-related deaths. A deeper mechanistic understanding of liver cancer could lead to the development of more effective therapeutic strategies. In our previous work, we screened 646 miRNAs and identified 11 that regulate liver cancer cell migration. The current study shows that miR-525-3p is frequently up-regulated in liver cancer tissues, and enhanced expression of miR-525-3p can promote liver cancer cell migration and invasion. Zinc finger protein 395 (ZNF395 is the direct functional target gene for miR-525-3p, and it is frequently down-regulated in liver cancer tissues. High expression of ZNF395 can significantly inhibit while knockdown of ZNF395 expression can markedly enhance the migration and invasion of liver cancer cells, suggesting that ZNF395 suppresses metastasis in liver cancer. Down-regulation of ZNF395 can mediate miR-525-3p induced liver cancer cell migration and invasion. In conclusion, miR-525-3p promotes liver cancer cell migration and invasion by directly targeting ZNF395, and the fact that miR-525-3p and ZNF395 both play important roles in liver cancer progression makes them potential therapeutic targets.

  9. Phosphorylation of actopaxin regulates cell spreading and migration

    Science.gov (United States)

    Clarke, Dominic M.; Brown, Michael C.; LaLonde, David P.; Turner, Christopher E.

    2004-01-01

    Actopaxin is an actin and paxillin binding protein that localizes to focal adhesions. It regulates cell spreading and is phosphorylated during mitosis. Herein, we identify a role for actopaxin phosphorylation in cell spreading and migration. Stable clones of U2OS cells expressing actopaxin wild-type (WT), nonphosphorylatable, and phosphomimetic mutants were developed to evaluate actopaxin function. All proteins targeted to focal adhesions, however the nonphosphorylatable mutant inhibited spreading whereas the phosphomimetic mutant cells spread more efficiently than WT cells. Endogenous and WT actopaxin, but not the nonphosphorylatable mutant, were phosphorylated in vivo during cell adhesion/spreading. Expression of the nonphosphorylatable actopaxin mutant significantly reduced cell migration, whereas expression of the phosphomimetic increased cell migration in scrape wound and Boyden chamber migration assays. In vitro kinase assays demonstrate that extracellular signal-regulated protein kinase phosphorylates actopaxin, and treatment of U2OS cells with the MEK1 inhibitor UO126 inhibited adhesion-induced phosphorylation of actopaxin and also inhibited cell migration. PMID:15353548

  10. Discoidin domain receptor 2 (DDR2) promotes breast cancer cell metastasis and the mechanism implicates epithelial-mesenchymal transition programme under hypoxia.

    Science.gov (United States)

    Ren, Tingting; Zhang, Wei; Liu, Xinping; Zhao, Hu; Zhang, Jian; Zhang, Jing; Li, Xia; Zhang, Yan; Bu, Xin; Shi, Man; Yao, Libo; Su, Jin

    2014-12-01

    A wide range of genes involved in breast cancer metastasis have been reported to be related to the microenvironment. We studied the role of discoidin domain receptor 2 (DDR2), a collagen-binding receptor, in breast cancer progression under hypoxic conditions. We showed that DDR2 protein expression closely correlated with the expression of hypoxic marker HIF-1α in clinical breast cancer specimens. The in vitro data demonstrated that hypoxia treatment increased the levels of both expression and phosphorylation of DDR2 in human breast cancer cell lines. In vivo, orthotopic breast tumour xenografts with DDR2 knockdown displayed reduced dissemination and significant prevention in pulmonary and lymphatic metastasis; conversely, these processes were significantly facilitated by the enforced expression of the activated form of DDR2. Further mechanism studies indicated that DDR2 plays an indispensable role in a series of hypoxia-induced behaviours of breast cancer cells, including migration, invasion, and epithelial-mesenchymal transition (EMT). The transcription factor Snail was found to mediate DDR2-induced down-regulation of the cell-cell adhesion molecule E-cadherin. It was also documented that there is a correlation between DDR2 and E-cadherin expression with the presence of lymph node metastases in 160 cases of invasive human breast carcinoma. In addition, we provided evidence that DDR2 silencing in breast cancer cells prevents the hypoxia-induced activation of ERK MAPK, suggesting its potential involvement in mediating the effect of DDR2 on hypoxia-induced signalling. Based on the results of this study, we conclude that DDR2 participates in hypoxia-induced breast cancer metastasis through the regulation of cell migration, invasion, and EMT, and thus may serve as an accessible therapeutic target for the treatment of breast cancer.

  11. Docosahexaenoic acid suppresses breast cancer cell metastasis by targeting matrix-metalloproteinases

    Science.gov (United States)

    Shin, Soyeon; Kim, Soyeon; Heo, Jun-Young; Kweon, Gi-Ryang; Wu, Tong; Park, Jong-Il; Lim, Kyu

    2016-01-01

    Breast cancer is one of the most prevalent cancers in women, and nearly half of breast cancer patients develop distant metastatic disease after therapy. Despite the significant advances that have been achieved in understanding breast cancer metastasis in the past decades, metastatic cancer is still hard to cure. Here, we demonstrated an anti-cancer mechanism of docosahexaenoic acid (DHA) that suppressed lung metastasis in breast cancer. DHA could inhibit proliferation and invasion of breast cancer cells in vitro, and this was mainly through blocking Cox-2-PGE2-NF-κB-MMPs cascades. DHA treatment significantly decreased Cox-2 and NF-κB expression as well as nuclear translocation of NF-κB in MDA-MB-231 cells. In addition, DHA also reduced NF-κB binding to DNA which may lead to inactivation of MMPs. Moreover, in vivo studies using Fat-1 transgenic mice showed remarkable decrease of tumor growth and metastasis to EO771 cells to lung in DHA-rich environment. In conclusion, DHA attenuated breast cancer progression and lung metastasis in part through suppressing MMPs, and these findings suggest chemoprevention and potential therapeutic strategy to overcome malignant breast cancer. PMID:27363023

  12. Cell and Signal Components of the Microenvironment of Bone Metastasis Are Affected by Hypoxia

    Science.gov (United States)

    Bendinelli, Paola; Maroni, Paola; Matteucci, Emanuela; Desiderio, Maria Alfonsina

    2016-01-01

    Bone metastatic cells release bone microenvironment proteins, such as the matricellular protein SPARC (secreted protein acidic and rich in cysteine), and share a cell signaling typical of the bone metabolism controlled by Runx2. The megakaryocytes in the bone marrow engrafted by the metastases seem to be one of the principal microenvironment sources of the biological stimuli, implicated in the formation of an osteoblastic niche, and affecting metastasis phenotype and colonization. Educated platelets in the circulation might derive from megakaryocytes in bone metastasis. The evaluation of predictive markers in the circulating platelets might be useful for the stratification of patients for therapeutic purposes. The hypoxic environment in bone metastasis is one of the key regulators of the network of the biological soluble and structural components of the matrix. In bone metastatic cells under hypoxia, similar patterns of Runx2 and SPARC are observed, both showing downregulation. Conversely, hypoxia induces Endothelin 1, which upregulates SPARC, and these biological stimuli may be considered prognostic markers of bone metastasis in breast carcinoma patients. PMID:27187355

  13. Cell and Signal Components of the Microenvironment of Bone Metastasis Are Affected by Hypoxia

    Directory of Open Access Journals (Sweden)

    Paola Bendinelli

    2016-05-01

    Full Text Available Bone metastatic cells release bone microenvironment proteins, such as the matricellular protein SPARC (secreted protein acidic and rich in cysteine, and share a cell signaling typical of the bone metabolism controlled by Runx2. The megakaryocytes in the bone marrow engrafted by the metastases seem to be one of the principal microenvironment sources of the biological stimuli, implicated in the formation of an osteoblastic niche, and affecting metastasis phenotype and colonization. Educated platelets in the circulation might derive from megakaryocytes in bone metastasis. The evaluation of predictive markers in the circulating platelets might be useful for the stratification of patients for therapeutic purposes. The hypoxic environment in bone metastasis is one of the key regulators of the network of the biological soluble and structural components of the matrix. In bone metastatic cells under hypoxia, similar patterns of Runx2 and SPARC are observed, both showing downregulation. Conversely, hypoxia induces Endothelin 1, which upregulates SPARC, and these biological stimuli may be considered prognostic markers of bone metastasis in breast carcinoma patients.

  14. Gallbladder Metastasis of Non-small Cell Lung Cancer Presenting as Acute Cholecystitis

    Institute of Scientific and Technical Information of China (English)

    Yu-Sook Jeong; Seung-Taik Kim; Hye-Suk Han; Sung-Nam Lim; Mi-Jin Kim; Joung-Ho Han; Min-Ho Kang; Dong-Hee Ryu; Ok-Jun Lee; Ki-Hyeong Lee

    2012-01-01

    Although non-small cell lung cancer (NSCLC) can metastasize to almost any organ,metastasis to the gallbladder with significant clinical manifestation is relatively rare.Here,we report a case of gallbladder metastasis of NSCLC presenting as acute cholecystitis.A 79-year-old man presented with pain in the right upper quadrant and fever.A computed tomography (CT) scan of the chest and abdomen showed a cavitary mass in the right lower lobe of the lung and irregular wall thickening of the gallbladder.Open cholecystectomy and needle biopsy of the lung mass were performed.Histological examination of the gallbladder revealed a moderately-differentiated squamous cell carcinoma displaying the same morphology as the lung mass assessed by needle biopsy.Subsequent immunohistochemical examination of the gallbladder and lung tissue showed that the tumor cells were positive for P63 but negative for cytokeratin 7,cytokeratin 20 and thyroid transcription factor-1.A second primary tumor of the gallbladder was excluded by immunohistochemical methods,and the final pathological diagnosis was gallbladder metastasis of NSCLC.Although the incidence is extremely rare,acute cholecystitis can occur in association with lung cancer metastasis to the gallbladder.

  15. Cancer Cell Adhesion and Metastasis: Selectins, Integrins, and the Inhibitory Potential of Heparins

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    Gerd Bendas

    2012-01-01

    Full Text Available Cell adhesion molecules play a significant role in cancer progression and metastasis. Cell-cell interactions of cancer cells with endothelium determine the metastatic spread. In addition, direct tumor cell interactions with platelets, leukocytes, and soluble components significantly contribute to cancer cell adhesion, extravasation, and the establishment of metastatic lesions. Clinical evidence indicates that heparin, commonly used for treatment of thromboembolic events in cancer patients, is beneficial for their survival. Preclinical studies confirm that heparin possesses antimetastatic activities that lead to attenuation of metastasis in various animal models. Heparin contains several biological activities that may affect several steps in metastatic cascade. Here we focus on the role of cellular adhesion receptors in the metastatic cascade and discuss evidence for heparin as an inhibitor of cell adhesion. While P- and L-selectin facilitation of cellular contacts during hematogenous metastasis is being accepted as a potential target of heparin, here we propose that heparin may also interfere with integrin activity and thereby affect cancer progression. This review summarizes recent findings about potential mechanisms of tumor cell interactions in the vasculature and antimetastatic activities of heparin.

  16. Laminins 411 and 421 differentially promote tumor cell migration via α6β1 integrin and MCAM (CD146).

    Science.gov (United States)

    Ishikawa, Taichi; Wondimu, Zenebech; Oikawa, Yuko; Gentilcore, Giusy; Kiessling, Rolf; Egyhazi Brage, Suzanne; Hansson, Johan; Patarroyo, Manuel

    2014-09-01

    α4-laminins, such as laminins 411 and 421, are mesenchymal laminins expressed by blood and lymphatic vessels and some tumor cells. Laminin-411 promotes migration of leukocytes and endothelial cells, but the effect of this laminin and laminin-421 on tumor cells is poorly understood. In the present study, we demonstrate that laminin-411 and, to a greater extent, laminin-421 significantly promote migration of tumor cells originated from melanomas, gliomas and different carcinomas via α6β1 integrin. In solid-phase binding assays, both laminins similarly bound α6β1 integrin but only laminin-421, among several laminin isoforms, readily bound MCAM (CD146), a cell-surface adhesion molecule strongly associated with tumor progression. Accordingly, a function-blocking mAb to MCAM inhibited tumor cell migration on laminin-421 but not on laminins 411 or 521. In tumor tissues, melanoma cells co-expressed MCAM, laminin α4, β1, β2 and γ1 chains, and integrin α6 and β1 chains. The present data highlight the novel role of α4-laminins in tumor cell migration and identify laminin-421 as a primary ligand for MCAM and a putative mediator of tumor invasion and metastasis.

  17. The Effect of dcEFs on migration behavior of A549 cells and Integrin beta1 expression

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    Yunjie WANG

    2008-04-01

    Full Text Available Background and objective The effect of direct-current electric fields (dcEFs on cells attracted extensive attention. Moreover the metastasis and its potential are considered to be related to dcEFs. The aim is to study the effect of dcEFs on migration behavior of A549 cells, Integrin ?1 and its signal pathways. Methods According to exposure to 5 V/cm dcEFs or not and the time of exposure, the A549 cells were divided into 4 groups. Images were taken per 5 min within 2 h to recode the migration of the cells. The data of results were analyzed statistically. Results Most of A549cells exposed to the dcEFs aligned and elongated perpendicularly to the electric field lines and migrated to the cathode continually during 2 h. On the contrary, cells unexposed to dcEFs showed slightly random movements. Immunofluorescence showed that Integrin ?1 on plasma membrane polarized to the cathode of the dcEFs. Western blot showed that Integrin beta1 downstream signal pathways p-FAK and p-ERK were overexpressed in the dcEFs. Conclusion A549 cells have a galvanotatic feature of cathodal directed migration while exposed to the dcEFs. The polarization of Integrin beta1 and the promotion of its downstream signal pathways may play an important roles in the galvanotaxis of A549 cells.

  18. Primary ovarian carcinomas and abdominal metastasis contain 4,6-disulfated chondroitin sulfate rich regions, which provide adhesive properties to tumour cells.

    Directory of Open Access Journals (Sweden)

    Myrtille J E Vallen

    Full Text Available High mortality in ovarian cancer patients is primarily caused through rapid metastasis of the tumour, but the underlying mechanisms are poorly understood. Glycosaminoglycans, are abundantly present in tumours and chondroitin sulfate-E (CSE, a highly 4,6-sulfated glycosaminoglycan, has been indicated to play a role in carcinogenesis. In this study we investigated the presence of CSE in ovarian cancer metastasis and studied its role in tumour cell adhesiveness and migration. CSE was studied immunohistochemically in primary ovarian carcinomas and abdominal metastases using the single chain antibody GD3G7. The role of CSE was studied in 2D (scratch assays and 3D (collagen matrices, spheroids systems using SKOV3 cells applying 1: overexpression of CSE by stable transfection with DNA encoding GalNAc4S-6 sulfotransferase, 2: enzymatic removal of CS, and 3: addition of CSE. In ovarian cancer tissue, CSE expression was predominantly seen in the stromal compartment of both primary ovarian carcinomas and metastases, with a comparable degree of intensity and extent. Overexpression of CSE disaccharide units by tumour cells increased their adhesive properties which was especially seen in tumour spheroid formation. Increased expression of CSE reduced cell migration. Addition of free CSE had similar effects. The data presented here indicate that CSE is associated with metastatic lesions and that it provides tumours with adhesive properties. CSE rich motifs are put forward as a potential target for ovarian cancer therapy.

  19. Smurf1 regulation of DAB2IP controls cell proliferation and migration

    Science.gov (United States)

    Wan, Lixin; Inuzuka, Hiroyuki; Sun, Liankun; North, Brian J.

    2016-01-01

    Tumor cell proliferation, survival and migration are regulated by the deletion of ovarian carcinoma 2/disabled homolog 2 (DOC-2/DAB2) interacting protein (DAB2IP), a tumor suppressor that serves as a scaffold protein for H-Ras and TRAF2. Importantly, the oncogenic histone methyl-transferase EZH2 epigenetically down-regulates DAB2IP in a variety of tumors. Recently, we demonstrated that DAB2IP is negatively regulated by Akt-dependent phosphorylation and SCFFbw7-mediated degradation. Here, we further identify the oncoprotein Smurf1, an E3-ubiquitin ligase, as a novel negative regulator of DAB2IP. Smurf1-mediated cellular proliferation and migration are largely dependent on the presence of DAB2IP, suggesting that DAB2IP is a key effector molecule of Smurf1 oncogenic function. Additionally, we identify that similar to DAB2IP, Smurf1 is also a target of phosphorylation by both Akt1 and Akt2 kinases, which enhances Smurf1 abundance, leading to a reduction in DAB2IP. Given the role of DAB2IP in tumorigenesis and metastasis, our data identify Smurf1 as an upstream oncogenic factor that negatively regulates DAB2IP to govern aberrant cell growth and migration. PMID:27036023

  20. 3D printing of biomimetic microstructures for cancer cell migration

    Science.gov (United States)

    Huang, Tina Qing; Qu, Xin; Liu, Justin; Chen, Shaochen

    2013-01-01

    To understand the physical behavior and migration of cancer cells, a 3D in vitro micro-chip in hydrogel was created using 3D projection printing. The micro-chip has a honeycomb branched structure, aiming to mimic 3D vascular morphology to test, monitor, and analyze differences in the behavior of cancer cells (i.e. HeLa) vs. non-cancerous cell lines (i.e. 10T1/2). The 3D Projection Printing system can fabricate complex structures in seconds from user-created designs. The fabricated microstructures have three different channel widths of 25, 45, and 120 microns wide to reflect a range of blood vessel diameters. HeLa and 10T1/2 cells seeded within the micro-chip were then analyzed for morphology and cell migration speed. 10T1/2 cells exhibited greater changes in morphology due to channel size width than HeLa cells; however, channel width had a limited effect on 10T1/2 cell migration while HeLa cancer cell migration increased as channel width decreased. This physiologically relevant 3D cancer tissue model has the potential to be a powerful tool for future drug discoveries and cancer migration studies PMID:24150602

  1. Solitary Laryngeal Metastasis from Transitional Cell Carcinoma of the Kidney: Clinical Case and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Tarek Assi

    2015-01-01

    Full Text Available The urogenital tract is a rare origin of laryngeal metastasis; transitional cell carcinoma with laryngeal metastases had never been reported previously. In this paper, we describe the clinical and pathological characteristics, evolution, and treatment of the first reported case of a laryngeal metastasis of a TCC followed by a brief review of the literature.

  2. Antithrombin reduces reperfusion-induced hepatic metastasis of colon cancer cells

    Institute of Scientific and Technical Information of China (English)

    Masanao Kurata; Kenji Okajima; Toru Kawamoto; Mitsuhiro Uchiba; Nobuhiro Ohkohchi

    2006-01-01

    AIM: To examine whether antithrombin (AT) could prevent hepatic ischemia/reperfusion (I/R)-induced hepatic metastasis by inhibiting tumor necrosis factor (TNF)-α-induced expression of E-selectin in rats.METHODS: Hepatic I/R was induced in rats and mice by clamping the left branches of the portal vein and the hepatic artery. Cancer cells were injected intrasplenically.The number of metastatic nodules was counted on day 7after I/R. TNF-α and E-selectin mRNA in hepatic tissue,serum fibrinogen degradation products and hepatic tissue levels of 6-keto-PGF1α, a stable metabolite of PGI2,were measured.RESULTS: AT inhibited increases in hepatic metastasis of tumor cells and hepatic tissue mRNA levels of TNF-αand E-selectin in animals subjected to hepatic I/R.Argatroban, a thrombin inhibitor, did not suppress any of these changes. Both AT and argatroban inhibited I/R-induced coagulation abnormalities. I/R-induced increases of hepatic tissue levels of 6-keto-PGF1αwere significantly enhanced by AT. Pretreatment with indomethacin completely reversed the effects of AT.Administration of OP-2507, a stable PGI2 analog, showed effects similar to those of AT in this model. Hepatic metastasis in congenit.al AT-deficient mice subjected to hepatic I/R was significantly increased compared to that observed in wild-type mice. Administration of AT significantly reduced the number of hepatic metastases in congenital AT-deficient mice.CONCLUSION: AT might reduce I/R-induced hepatic metastasis of colon cancer cells by inhibiting TNF-α-induced expression of E-selectin through an increase in the endothelial production of PGI2. These findings also raise the possibility that AT might prevent hepatic metastasis of tumor cells if administered during the resection of liver tumors.

  3. microRNA-141 inhibits thyroid cancer cell growth and metastasis by targeting insulin receptor substrate 2.

    Science.gov (United States)

    Dong, Su; Meng, Xianying; Xue, Shuai; Yan, Zewen; Ren, Peiyou; Liu, Jia

    2016-01-01

    microRNA-141 (miR-141), a member of the miR-200 family, and has been reported to involve in tumor initiation and development in many types of cancers. However, the function and underlying molecular mechanism of miR-141 in thyroid cancer remains unclear. Therefore, the aim of this study is to identify its expression, function, and molecular mechanism in thyroid cancer. In this study, we found that miR-141 expression levels were downregulated in human thyroid cancer specimens compared to the adjacent normal tissues, and its expression were strongly correlated with clinical stages and lymph node metastases. Function assays showed that overexpression of miR-141 inhibited cell proliferation, induced cell apoptosis, and decreased migration, invasion in thyroid cancer cells, as well as tumor growth in nude mice. Moreover, insulin receptor substrate 2 (IRS2), a known oncogene, was confirmed as a direct target of miR-141, and IRS2 expression levels were upregulated in thyroid cancer, and its expression were inversely correlated with miR-141 expression levels in human thyroid cancer specimens. Forced expression of IRS2 reversed the inhibition effect induced by miR-141 overexpression in thyroid cancer cells. Taken together, our study provides the first evidence that miR-141 suppressed thyroid cancer cell growth and metastasis through inhibition of IRS2. Thus, miR-141 might serve as a promising therapeutic strategy for thyroid cancer treatment.

  4. Unnatural killer cells to prevent bloodborne metastasis: inspiration from biology and engineering.

    Science.gov (United States)

    Mitchell, Michael J; King, Michael R

    2014-06-01

    Metastasis contributes to over 90% of cancer-related deaths. Many types of cancer metastasize via the bloodstream, where circulating tumor cells (CTCs) originating from the primary tumor can undergo selectin-mediated adhesion with the blood vessel wall and subsequently transmigrate to anatomically distant organs. In an effort to neutralize CTCs with the potential to form metastases, a new therapeutic approach has been developed in which circulating leukocytes are functionalized to target and kill cancer cells in the bloodstream. This approach mimics the cytotoxic activity of natural killer cells and the chemical engineering concept of a fluidized bed reactor, which increases the surface area for surface-catalyzed reactions. The resulting 'unnatural killer cells', proven effective in vitro with human blood and also in the living mouse, holds promise in neutralizing CTCs to interrupt the metastasis process.

  5. SKA1 regulates the metastasis and cisplatin resistance of non-small cell lung cancer

    Science.gov (United States)

    SHEN, LIHUA; YANG, MIN; LIN, QIONGHUA; ZHANG, ZHONGWEI; MIAO, CHANGHONG; ZHU, BIAO

    2016-01-01

    Currently, chemotherapy with platinum-based drugs including cisplatin is the most effective therapy for the treatment of non-small cell lung carcinoma (NSCLC). However, the efficacy of chemotherapy is limited due to commonly developed drug resistance. Spindle and kinetochore-associated complex subunit 1 (SKA1) is part of a complex essential for stabilizing the attachment of spindle microtubules to kinetochores and for maintaining the metaphase plate during mitosis. In the present study, we aimed to investigate the role of SKA1 in the process of metastasis and drug resistance of NSCLC. We completed a series of experiments to investigate the function of SKA1 in NSCLC metastasis and drug resistance including qRT-PCR, immunohistochemistry and western blotting, as well as MTT, BrdU, wounded healing, Transwell and gelatin zymography assays. We demonstrated that the expression levels of SKA1 were elevated in NSCLC and were correlated with cancer progression and malignancy. We also reported that SKA1 positively regulated the proliferation and metastatic ability of NSCLC cells. In addition, we determined that SKA1 contributed to cisplatin resistance in NSCLC cells by protecting these cells from cisplatin-induced cell apoptosis. SKA1 also appeared to regulate the ERK1/2 and the Akt-mediated signaling pathways in NSCLC cells. SKA1 is required for metastasis and cisplatin resistance of non-small cell lung cancer. PMID:26985856

  6. Laser-photophoretic migration and fractionation of human blood cells.

    Science.gov (United States)

    Monjushiro, Hideaki; Tanahashi, Yuko; Watarai, Hitoshi

    2013-05-13

    Laser photophoretic migration behavior of human blood cells in saline solution was investigated under the irradiation of Nd:YAG laser beam (532 nm) in the absence and the presence of the flow in a fused silica capillary. Red blood cells (RBC) were migrated faster than white blood cells (WBC) and blood pellets to the direction of propagation of laser light. The observed photophoretic velocity of RBC was about 11 times faster than those of others. This was understood from the larger photophoretic efficiency of RBC than that of WBC, which was simulated based on the Mie scattering theory. Furthermore, it was found that, during the photophoretic migration, RBCs spontaneously orientated parallel to the migration direction so as to reduce the drag force. Finally, it was demonstrated that RBC and WBC were separated in a micro-channel flow system by the laser photophoresis.

  7. Modelling Rho GTPase biochemistry to predict collective cell migration

    Science.gov (United States)

    Merchant, Brian; Feng, James

    The collective migration of cells, due to individual cell polarization and intercellular contact inhibition of locomotion, features prominently in embryogenesis and metastatic cancers. Existing methods for modelling collectively migrating cells tend to rely either on highly abstracted agent-based models, or on continuum approximations of the group. Both of these frameworks represent intercellular interactions such as contact inhibition of locomotion as hard-coded rules defining model cells. In contrast, we present a vertex-dynamics framework which predicts polarization and contact inhibition of locomotion naturally from an underlying model of Rho GTPase biochemistry and cortical mechanics. We simulate the interaction between many such model cells, and study how modulating Rho GTPases affects migratory characteristics of the group, in the context of long-distance collective migration of neural crest cells during embryogenesis.

  8. The Role of Breast Cancer Stem Cells in Metastasis and Therapeutic Implications

    OpenAIRE

    2011-01-01

    Cancer stem cells (CSCs) possess the capacity to self-renew and to generate heterogeneous lineages of cancer cells that comprise tumors. A substantial body of evidence supports a model in which CSCs play a major role in the initiation, maintenance, and clinical outcome of cancers. In contrast, analysis of the role of CSCs in metastasis has been mainly conceptual and speculative. This review summarizes recent data that support the theory of CSCs as the source of metastatic lesions in breast ca...

  9. Isolated Liver Metastasis in Hürthle Cell Thyroid Cancer Treated with Microwave Ablation

    OpenAIRE

    Konstantinos Segkos; Carl Schmidt; Fadi Nabhan

    2017-01-01

    Hürthle cell thyroid cancer (HCTC) is a less common form of differentiated thyroid cancer. It rarely metastasizes to the liver, and when it does, the metastasis is almost never isolated. Here we report a 62-year-old male with widely invasive Hürthle cell thyroid cancer, who underwent total thyroidectomy and received adjuvant treatment with I-131 with posttreatment scan showing no evidence of metastatic disease. His thyroglobulin however continued to rise after that and eventually an isolated ...

  10. The Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer-Associated Fibroblasts

    Directory of Open Access Journals (Sweden)

    Anna Kuchnio

    2015-08-01

    Full Text Available Several questions about the role of the oxygen sensor prolyl-hydroxylase 2 (PHD2 in cancer have not been addressed. First, the role of PHD2 in metastasis has not been studied in a spontaneous tumor model. Here, we show that global PHD2 haplodeficiency reduced metastasis without affecting tumor growth. Second, it is unknown whether PHD2 regulates cancer by affecting cancer-associated fibroblasts (CAFs. We show that PHD2 haplodeficiency reduced metastasis via two mechanisms: (1 by decreasing CAF activation, matrix production, and contraction by CAFs, an effect that surprisingly relied on PHD2 deletion in cancer cells, but not in CAFs; and (2 by improving tumor vessel normalization. Third, the effect of concomitant PHD2 inhibition in malignant and stromal cells (mimicking PHD2 inhibitor treatment is unknown. We show that global PHD2 haplodeficiency, induced not only before but also after tumor onset, impaired metastasis. These findings warrant investigation of PHD2’s therapeutic potential.

  11. Adrenalectomy for isolated metastasis from operable non-small-cell lung cancer

    Science.gov (United States)

    Sastry, Priya; Tocock, Adam; Coonar, Aman S.

    2014-01-01

    A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was ‘in [patients with isolated adrenal metastasis from operable/operated non-small cell lung cancer] is [adrenalectomy] superior [to chemo/radiotherapy alone for achieving long-term survival]?’ Altogether >160 papers were found using the reported search, of which 3 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that the body of evidence is small, retrospective and not formally controlled. As such interpretation is limited by selection bias in assignment of patients. These limitations notwithstanding, surgical resection is associated with prolonged survival for patients with isolated adrenal metastasis from non-small cell lung cancer (NSCLC). Patient selection is probably critical. Factors that are important are: otherwise early tumour, node (TN) status of the lung primary and R0 resection, long disease-free interval and confidence that there are no other sites of metastasis. Patients with ipsilateral adrenal metastasis may derive the greatest survival benefit from adrenalectomy, since spread to the ipsilateral gland may occur via direct lymphatic channels in the retroperitoneum. Involvement of the contralateral adrenal may signify haematogenous spread and therefore, a more aggressive process. Adrenalectomy must be accompanied by regional lymph node clearance to reduce the chance of further spread from the adrenal itself. PMID:24357471

  12. Transforming growth factor alpha (TGFα regulates granulosa cell tumor (GCT cell proliferation and migration through activation of multiple pathways.

    Directory of Open Access Journals (Sweden)

    Cheng Wang

    Full Text Available Granulosa cell tumors (GCTs are the most common ovarian estrogen producing tumors, leading to symptoms of excessive estrogen such as endometrial hyperplasia and endometrial adenocarcinoma. These tumors have malignant potential and often recur. The etiology of GCT is unknown. TGFα is a potent mitogen for many different cells. However, its function in GCT initiation, progression and metastasis has not been determined. The present study aims to determine whether TGFα plays a role in the growth of GCT cells. KGN cells, which are derived from an invasive GCT and have many features of normal granulosa cells, were used as the cellular model. Immunohistochemistry, Western blot and RT-PCR results showed that the ErbB family of receptors is expressed in human GCT tissues and GCT cell lines. RT-PCR results also indicated that TGFα and EGF are expressed in the human granulosa cells and the GCT cell lines, suggesting that TGFα might regulate GCT cell function in an autocrine/paracrine manner. TGFα stimulated KGN cell DNA synthesis, cell proliferation, cell viability, cell cycle progression, and cell migration. TGFα rapidly activated EGFR/PI3K/Akt and mTOR pathways, as indicated by rapid phosphorylation of Akt, TSC2, Rictor, mTOR, P70S6K and S6 proteins following TGFα treatment. TGFα also rapidly activated the EGFR/MEK/ERK pathway, and P38 MAPK pathways, as indicated by the rapid phosphorylation of EGFR, MEK, ERK1/2, P38, and CREB after TGFα treatment. Whereas TGFα triggered a transient activation of Akt, it induced a sustained activation of ERK1/2 in KGN cells. Long-term treatment of KGN cells with TGFα resulted in a significant increase in cyclin D2 and a decrease in p27/Kip1, two critical regulators of granulosa cell proliferation and granulosa cell tumorigenesis. In conclusion, TGFα, via multiple signaling pathways, regulates KGN cell proliferation and migration and may play an important role in the growth and metastasis of GCTs.

  13. Dynamic Cell Adhesion and Migration on Nanoscale Grooved Substrates

    NARCIS (Netherlands)

    Lamers, E.; Riet, te J.; Domanski, M.; Luttge, R.; Figdor, C.G.; Gardeniers, J.G.E.; Walboomers, X.F.; Jansen, J.A.

    2012-01-01

    Organised nanotopography mimicking the natural extracellular matrix can be used to control morphology, cell motility, and differentiation. However, it is still unknown how specific cell types react with specific patterns. Both initial adhesion and preferential cell migration may be important to init

  14. Dynamic cell adhesion and migration on nanoscale grooved substrates.

    NARCIS (Netherlands)

    Lamers, E.; Riet, J. te; Domanski, M.; Luttge, R.; Figdor, C.G.; Gardeniers, J.G.E.; Walboomers, X.F.; Jansen, J.B.M.J.

    2012-01-01

    Organised nanotopography mimicking the natural extracellular matrix can be used to control morphology, cell motility, and differentiation. However, it is still unknown how specific cell types react with specific patterns. Both initial adhesion and preferential cell migration may be important to init

  15. Cell Fusion as a Cofactor in Prostate Cancer Metastasis

    Science.gov (United States)

    2010-01-01

    mechanisms that control the fate of fused cells, and the fate of tetraploid cells in general, are poorly understood. To learn these mechanisms better...of the resulting binuclear cells, and delineated basic mechanisms through which apoptosis was induced. Remarkably, we found that tetraploid cells...survival of tetraploid cells, while expressing a dominant negative mutant of the tumor suppressor p53 did (Figure 2). These findings implied that

  16. PRDM14 Promotes the Migration of Human Non-small Cell Lung Cancer Through Extracellular Matrix Degradation in vitro

    Institute of Scientific and Technical Information of China (English)

    Hong-Xia Bi; Han-Bing Shi; Ting Zhang; Ge Cui

    2015-01-01

    Background:As a novel molecular markerof non-small cell lung cancer (NSCLC),PRDI-BF1 and RIZ homology domain containing protein 14 (PRDM 14) is over-expressed in NSCLC tumor tissues.Extracellular matrix degradation mediated by the balance between matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) is one of the most important mechanism in lung cancer metastasis.This study aimed to determine if PRDM 14 promoted the migration of NSCLC cells through extracellular matrix degradation mediated by change of MMP/TIMP expression.Methods:The expression of PRDM14 was down-regulated in human cell line A 549 after transfection with lentiviral vector-mediated short-hairpin ribonucleic acids (shRNAs) which targeted the PRDM 14 promoter.Cellular migration ofshRNA-infected cells was detected by a scratch wound healing assay and transwell cell migration assay.Expression levels of MMP1,MMP2,TIMP1,and TIMP2 were measured by quantitative real-time polymerase chain reaction (RT-PCR).Results:Migration ofPRDM 14-shRNA-infected cells was significantly inhibited relative to control cells as measured by the scratch wound healing (P < 0.05) and transwell cell migration assays (P < 0.01).The expression of MMP1 in A549 cells infected by PRDM14-shRNA was down-regulated significantly (P < 0.01),whereas the expression of TIMPl and TIMP2 was up-regulated significantly (P < 0.01).Conclusions:PRDM 14 accelerates A549 cells migration in vitro through extracellular matrix degradation.PRDM 14 is considered as a potential therapeutic target in metastatic NSCLC.

  17. Soluble fibrin inhibits monocyte adherence and cytotoxicity against tumor cells: implications for cancer metastasis

    Directory of Open Access Journals (Sweden)

    Patel Shonak

    2006-08-01

    Full Text Available Abstract Background Soluble fibrin (sFn is a marker for disseminated intravascular coagulation and may have prognostic significance, especially in metastasis. However, a role for sFn in the etiology of metastatic cancer growth has not been extensively studied. We have reported that sFn cross-linked platelet binding to tumor cells via the major platelet fibrin receptor αIIbβ3, and tumor cell CD54 (ICAM-1, which is the receptor for two of the leukocyte β2 integrins (αLβ2 and aMβ2. We hypothesized that sFn may also affect leukocyte adherence, recognition, and killing of tumor cells. Furthermore, in a rat experimental metastasis model sFn pre-treatment of tumor cells enhanced metastasis by over 60% compared to untreated cells. Other studies have shown that fibrin(ogen binds to the monocyt