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      1. Author :
        Danussi, C.; Petrucco, A.; Wassermann, B.; Modica, T. M.; Pivetta, E.; Del Bel Belluz, L.; Colombatti, A.; Spessotto, P.
      2. Title :
        An EMILIN1-negative microenvironment promotes tumor cell proliferation and lymph node invasion
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Cancer Prev Res (Phila)
      6. Products :

        Bioware cell linesIVIS Imaging Systems

      7. Volume :
        5
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        B16-F10-luc2, B16F10-luc2, IVIS
      12. Abstract :
        The evidence that EMILIN1 (Elastic Microfibril Interface Located proteIN) deficiency in Emilin1(-/-) mice caused dermal and epidermal hyperproliferation and an abnormal lymphatic phenotype prompted us to hypothesize the involvement of this extracellular matrix component in tumor development and in lymphatic metastasis. Using the 12-dimethylbenz(alpha)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) two-stage model of skin carcinogenesis, we found that Emilin1(-/-) mice presented an accelerated formation, a higher incidence, and the development of a larger number of tumors compared with their wild-type littermates. EMILIN1-negative tumors showed more Ki67-positive proliferating cells and higher levels of pErk1/2. In these tumors, PTEN expression was lower. Emilin1(-/-) mice displayed enhanced lymphangiogenesis both in the tumor and in the sentinel lymph nodes. Accordingly, tumor growth and lymph node metastasis of transplanted syngenic tumors were also increased in Emilin1(-/-) mice. In vitro transmigration assays through lymphatic endothelial cells showed that EMILIN1 deficiency greatly facilitated tumor cell trafficking. Overall, these data established that EMILIN1 exerts a protective role in tumor growth, in tumor lymphatic vessel formation, as well as in metastatic spread to lymph nodes and reinforced the importance of its presence in the microenvironment to determine the tumor phenotype.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22827975
      14. Call Number :
        PKI @ kd.modi @ 9
      15. Serial :
        10483
      1. Author :
        Hensley, H. H.; Roder, N. A.; O'Brien, S. W.; Bickel, L. E.; Xiao, F.; Litwin, S.; Connolly, D. C.
      2. Title :
        Combined in vivo molecular and anatomic imaging for detection of ovarian carcinoma-associated protease activity and integrin expression in mice
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Neoplasia
      6. Products :

        ProSenseAnnexin VivoIVIS Imaging SystemsIntegriSenseMMPSenseFMT Imaging Systems

      7. Volume :
        14
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        ProSense, IntegriSense, MMPSense, Annexin-Vivo, Annexin vivo, IVIS, Animals; Antineoplastic Agents/administration & dosage/pharmacology; Carcinoma/*diagnosis/*metabolism/pathology; Cathepsins/metabolism; Cell Line, Tumor; Disease Progression; Female; Fluorescent Dyes/chemistry/metabolism; Integrin alphaVbeta3/metabolism; Integrins/genetics/*metabolism; Magnetic Resonance Imaging; Matrix Metalloproteinases/metabolism; Mice; Mice, Transgenic; *Molecular Imaging; Ovarian Neoplasms/*diagnosis/drug therapy/*metabolism; Peptide Hydrolases/*metabolism; Protein Binding; Tumor Burden/drug effects
      12. Abstract :
        Most patients with epithelial ovarian cancer (EOC) experience drug-resistant disease recurrence. Identification of new treatments is a high priority, and preclinical studies in mouse models of EOC may expedite this goal. We previously developed methods for magnetic resonance imaging (MRI) for tumor detection and quantification in a transgenic mouse model of EOC. The goal of this study was to determine whether three-dimensional (3D) fluorescence molecular tomography (FMT) and fluorescent molecular imaging probes could be effectively used for in vivo detection of ovarian tumors and response to therapy. Ovarian tumor-bearing TgMISIIR-TAg mice injected with fluorescent probes were subjected to MRI and FMT. Tumor-specific probe retention was identified in vivo by alignment of the 3D data sets, confirmed by ex vivo fluorescent imaging and correlated with histopathologic findings. Mice were treated with standard chemotherapy, and changes in fluorescent probe binding were detected by MRI and FMT. Ovarian tumors were detected using probes specific for cathepsin proteases, matrix metalloproteinases (MMPs), and integrin alpha(v)beta(3). Cathepsin and integrin alpha(v)beta(3) probe activation and retention correlated strongly with tumor volume. MMP probe activation was readily detected in tumors but correlated less strongly with tumor volume. Tumor regression associated with response to therapy was detected and quantified by serial MRI and FMT. These results demonstrate the feasibility and sensitivity of FMT for detection and quantification of tumor-associated biologic targets in ovarian tumors and support the translational utility of molecular imaging to assess functional response to therapy in mouse models of EOC.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22787427
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10425
      1. Author :
        Tanaka, M.; Mroz, P.; Dai, T.; Huang, L.; Morimoto, Y.; Kinoshita, M.; Yoshihara, Y.; Nemoto, K.; Shinomiya, N.; Seki, S.; Hamblin, M. R.
      2. Title :
        Photodynamic therapy can induce a protective innate immune response against murine bacterial arthritis via neutrophil accumulation
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        PLoS One
      6. Products :

        Bioware bacteria

      7. Volume :
        7
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen31, Xen 31, MRSA, S. aureus, IVIS, Bioluminescence, Animals; Arthritis, Infectious/*drug therapy/immunology/microbiology; *Immunity, Innate; Methicillin-Resistant Staphylococcus aureus/isolation & purification; Methylene Blue/therapeutic use; Mice; Neutrophils/*immunology; *Photochemotherapy; Photosensitizing Agents/therapeutic use
      12. Abstract :
        BACKGROUND: Local microbial infections induced by multiple-drug-resistant bacteria in the orthopedic field can be intractable, therefore development of new therapeutic modalities is needed. Photodynamic therapy (PDT) is a promising alternative modality to antibiotics for intractable microbial infections, and we recently reported that PDT has the potential to accumulate neutrophils into the infected site which leads to resolution of the infection. PDT for cancer has long been known to be able to stimulate the innate and adaptive arms of the immune system. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, a murine methicillin-resistant Staphylococcus aureus (MRSA) arthritis model using bioluminescent MRSA and polystyrene microparticles was established, and both the therapeutic (Th-PDT) and preventive (Pre-PDT) effects of PDT using methylene blue as photosensitizer were examined. Although Th-PDT could not demonstrate direct bacterial killing, neutrophils were accumulated into the infectious joint space after PDT and MRSA arthritis was reduced. With the preconditioning Pre-PDT regimen, neutrophils were quickly accumulated into the joint immediately after bacterial inoculation and bacterial growth was suppressed and the establishment of infection was inhibited. CONCLUSIONS/SIGNIFICANCE: This is the first demonstration of a protective innate immune response against a bacterial pathogen produced by PDT.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22761911
      14. Call Number :
        PKI @ kd.modi @ 10
      15. Serial :
        10557
      1. Author :
        Vujanovic, L.; Ballard, W.; Thorne, S. H.; Vujanovic, N. L.; Butterfield, L. H.
      2. Title :
        Adenovirus-engineered human dendritic cells induce natural killer cell chemotaxis via CXCL8/IL-8 and CXCL10/IP-10
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Oncoimmunology
      6. Products :

        VivoTagIVIS Imaging Systems

      7. Volume :
        1
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        VivoTag, IVIS, Vivotag
      12. Abstract :
        Recombinant adenovirus-engineered dendritic cells (Ad.DC) are potent vaccines for induction of anti-viral and anti-cancer T cell immunity. The effectiveness of Ad.DC vaccines may depend on the newly described ability of Ad.DC to crosstalk with natural killer (NK) cells via cell-to-cell contact, and to mediate activation, polarization and bridging of innate and adaptive immunity. For this interaction to occur in vivo, Ad.DC must be able to attract NK cells from surrounding tissues or peripheral blood. We developed a novel live mouse imaging system-based NK-cell migration test, and demonstrated for the first time that human Ad.DC induced directional migration of human NK cells across subcutaneous tissues, indicating that Ad.DC-NK cell contact and interaction could occur in vivo. We examined the mechanism of Ad.DC-induced migration of NK cells in vitro and in vivo. Ad.DC produced multiple chemokines previously reported to recruit NK cells, including immunoregulatory CXCL10/IP-10 and proinflammatory CXCL8/IL-8. In vitro chemotaxis experiments utilizing neutralizing antibodies and recombinant human chemokines showed that CXCL10/IP-10 and CXCL8/IL-8 were critical for Ad.DC-mediated recruitment of CD56(hi)CD16(-) and CD56(lo)CD16(+) NK cells, respectively. The importance of CXCL8/IL-8 was further demonstrated in vivo. Pretreatment of mice with the neutralizing anti-CXCL8/IL-8 antibody led to significant inhibition of Ad.DC-induced migration of NK cells in vivo. These data show that Ad.DC can recruit spatially distant NK cells toward a vaccine site via specific chemokines. Therefore, an Ad.DC vaccine can likely induce interaction with endogenous NK cells via transmembrane mediators, and consequently mediate Th1 polarization and amplification of immune functions in vivo.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22754763
      14. Call Number :
        PKI @ kd.modi @ 4
      15. Serial :
        10570
      1. Author :
        Pickert, G.; Lim, H. Y.; Weigert, A.; Haussler, A.; Myrczek, T.; Waldner, M.; Labocha, S.; Ferreiros, N.; Geisslinger, G.; Lotsch, J.; Becker, C.; Brune, B.; Tegeder, I.
      2. Title :
        Inhibition of GTP cyclohydrolase attenuates tumor growth by reducing angiogenesis and M2-like polarization of tumor associated macrophages
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Int J Cancer
      6. Products :

        IntegriSense

      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense
      12. Abstract :
        GTP cyclohydrolase (GCH1) is the key-enzyme to produce the essential enzyme cofactor, tetrahydrobiopterin. The byproduct, neopterin is increased in advanced human cancer and used as cancer-biomarker, suggesting that pathologically increased GCH1 activity may promote tumor growth. We found that inhibition or silencing of GCH1 reduced tumor cell proliferation and survival and the tube formation of human umbilical vein endothelial cells, which upon hypoxia increased GCH1 and endothelial NOS expression, the latter prevented by inhibition of GCH1. In nude mice xenografted with HT29-Luc colon cancer cells GCH1 inhibition reduced tumor growth and angiogenesis, determined by in vivo luciferase and near-infrared imaging of newly formed blood vessels. The treatment with the GCH1 inhibitor shifted the phenotype of tumor associated macrophages from the proangiogenic M2 towards M1, accompanied with a shift of plasma chemokine profiles towards tumor-attacking chemokines including CXCL10 and RANTES. GCH1 expression was increased in mouse AOM/DSS-induced colon tumors and in high grade human colon and skin cancer and oppositely, the growth of GCH1-deficient HT29-Luc tumor cells in mice was strongly reduced. The data suggest that GCH1 inhibition reduces tumor growth by (i) direct killing of tumor cells, (ii) by inhibiting angiogenesis, and (iii) by enhancing the antitumoral immune response.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22753274
      14. Call Number :
        PKI @ kd.modi @ 17
      15. Serial :
        10377
      1. Author :
        Yun, M.; Pan, S.; Jiang, S. N.; Nguyen, V. H.; Park, S. H.; Jung, C. H.; Kim, H. S.; Min, J. J.; Choy, H. E.; Hong, Y.
      2. Title :
        Effect of Salmonella treatment on an implanted tumor (CT26) in a mouse model
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Microbiol
      6. Products :

        Bioware bacteria

      7. Volume :
        50
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen26, Xen 26, Salmonella typhumurium, Animals; Biological Therapy/*methods; Colonic Neoplasms/chemistry/*therapy; Disease Models, Animal; Electrophoresis, Gel, Two-Dimensional; Male; Mass Spectrometry; Mice; Mice, Inbred BALB C; Proteome/analysis; Salmonella typhimurium/*growth & development/*pathogenicity
      12. Abstract :
        The use of bacteria has contributed to recent advances in targeted cancer therapy especially for its tumor-specific accumulation and proliferation. In this study, we investigated the molecular events following bacterial therapy using an attenuated Salmonella Typhimurium defective in ppGpp synthesis (DeltappGpp), by analyzing those proteins differentially expressed in tumor tissues from treated and untreated mice. CT26 murine colon cancer cells were implanted in BALB/c mice and allowed to form tumors. The tumor-bearing mice were treated with the attenuated Salmonella Typhimurium. Tumor tissues were analyzed by 2D-PAGE. Fourteen differentially expressed proteins were identified by mass spectrometry. The analysis revealed that cytoskeletal components, including vimentin, drebrin-like protein, and tropomyosin-alpha 3, were decreased while serum proteins related to heme or iron metabolism, including transferrin, hemopexin, and haptoglobin were increased. Subsequent studies revealed that the decrease in cytoskeletal components occurred at the transcriptional level and that the increase in heme and iron metabolism proteins occurred in liver. Most interestingly, the same pattern of increased expression of transferrin, hemopexin, and haptoglobin was observed following radiotherapy at the dosage of 14 Gy.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22752915
      14. Call Number :
        PKI @ kd.modi @ 3
      15. Serial :
        10561
      1. Author :
        Noberini, R.; Koolpe, M.; Lamberto, I.; Pasquale, E. B.
      2. Title :
        Inhibition of Eph receptor-ephrin ligand interaction by tea polyphenols
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Pharmacol Res
      6. Products :

        Bioware cell linesIVIS Imaging Systems

      7. Volume :
        66
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, B16-F10-luc-G5, B16F10-luc-G5, B16-F10-luc, B16F10-luc, Animals; COS Cells; Catechin/analogs & derivatives/chemistry/pharmacology; Cell Line; Cercopithecus aethiops; Ephrins/*metabolism; Mice; Polyphenols/*chemistry/*pharmacology; Protein Binding/drug effects; Protein Interaction Maps/*drug effects; Receptor, EphA4/antagonists & inhibitors/metabolism; Receptors, Eph Family/antagonists & inhibitors/*metabolism; Signal Transduction/drug effects; Small Molecule Libraries/chemistry/pharmacology; Tea/*chemistry
      12. Abstract :
        Tea contains a variety of bioactive chemicals, such as catechins and other polyphenols. These compounds are thought to be responsible for the health benefits of tea consumption by affecting the function of many cellular targets, not all of which have been identified. In a high-throughput screen for small molecule antagonists of the EphA4 receptor tyrosine kinase, we identified five tea polyphenols that substantially inhibit EphA4 binding to a synthetic peptide ligand. Further characterization of theaflavin monogallates from black tea and epigallocatechin-3,5-digallate from green tea revealed that these compounds at low micromolar concentrations also inhibit binding of the natural ephrin ligands to EphA4 and several other Eph receptors in in vitro assays. The compounds behave as competitive EphA4 antagonists, and their inhibitory activity is affected by amino acid mutations within the ephrin binding pocket of EphA4. In contrast, the major green tea catechin, epigallocatechin-3-gallate (EGCG), does not appear to be an effective Eph receptor antagonist. In cell culture assays, theaflavin monogallates and epigallocatechin-3,5-digallate inhibit ephrin-induced tyrosine phosphorylation (activation) of Eph receptors and endothelial capillary-like tube formation. However, the wider spectrum of Eph receptors affected by the tea derivatives in cells suggests additional mechanisms of inhibition besides interfering with ephrin binding. These results show that tea polyphenols derived from both black and green tea can suppress the biological activities of Eph receptors. Thus, the Eph receptor tyrosine kinase family represents an important class of targets for tea-derived phytochemicals.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22750215
      14. Call Number :
        PKI @ kd.modi @ 17
      15. Serial :
        10533
      1. Author :
        Zhang, Z.; Hu, Z.; Gupta, J.; Krimmel, J. D.; Gerseny, H. M.; Berg, A. F.; Robbins, J. S.; Du, H.; Prabhakar, B.; Seth, P.
      2. Title :
        Intravenous administration of adenoviruses targeting transforming growth factor beta signaling inhibits established bone metastases in 4T1 mouse mammary tumor model in an immunocompetent syngeneic host
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Cancer Gene Ther
      6. Products :

        Bioware cell linesIVIS Imaging Systems

      7. Volume :
        19
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        4T1-luc2, IVIS, Bioluminescence, Adenoviridae/genetics/*metabolism/physiology; Administration, Intravenous; Animals; Bone Neoplasms/secondary/*therapy; Cell Line, Tumor; Female; Humans; Immunocompetence; Luminescent Measurements/methods; Mammary Neoplasms, Experimental/pathology/*therapy; Mice; Mice, Inbred BALB C; Oncolytic Virotherapy/methods; Oncolytic Viruses/genetics/metabolism/physiology; Phosphorylation; Promoter Regions, Genetic; Protein-Serine-Threonine Kinases/genetics/*metabolism; Receptors, Transforming Growth Factor beta/genetics/*metabolism; Signal Transduction; Smad2 Protein/genetics/metabolism; Telomerase/genetics; Transforming Growth Factor beta1/genetics/metabolism; Transplantation, Isogeneic/methods; Tumor Stem Cell Assay/methods; Virus Replication
      12. Abstract :
        We have examined the effect of adenoviruses expressing soluble transforming growth factor receptorII-Fc (sTGFbetaRIIFc) in a 4T1 mouse mammary tumor bone metastasis model using syngeneic BALB/c mice. Infection of 4T1 cells with a non-replicating adenovirus, Ad(E1-).sTbetaRFc, or with two oncolytic adenoviruses, Ad.sTbetaRFc and TAd.sTbetaRFc, expressing sTGFbetaRIIFc (the human TERT promoter drives viral replication in TAd.sTbetaRFc) produced sTGFbetaRIIFc protein. Oncolytic adenoviruses produced viral replication and induced cytotoxicity in 4T1 cells. 4T1 cells were resistant to the cytotoxic effects of TGFbeta-1 (up to 10 ng ml(-1)). However, TGFbeta-1 induced the phosphorylation of SMAD2 and SMAD3, which were inhibited by co-incubation with sTGFbetaRIIFc protein. TGFbeta-1 also induced interleukin-11, a well-known osteolytic factor. Intracardiac injection of 4T1-luc2 cells produced bone metastases by day 4. Intravenous injection of Ad.sTbetaRFc (on days 5 and 7) followed by bioluminescence imaging (BLI) of mice on days 7, 11 and 14 in tumor-bearing mice indicated inhibition of bone metastasis progression (P<0.05). X-ray radiography of mice on day 14 showed a significant reduction of the lesion size by Ad.sTbetaRFc (P<0.01) and TAd.sTbetaRFc (P<0.05). Replication-deficient virus Ad(E1-).sTbetaRFc expressing sTGFbetaRIIFc showed some inhibition of bone metastasis, whereas Ad(E1-).Null was not effective in inhibiting bone metastases. Thus, systemic administration of Ad.sTbetaRFc and TAd.sTbetaRFc can inhibit bone metastasis in the 4T1 mouse mammary tumor model, and can be developed as potential anti-tumor agents for breast cancer.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22744210
      14. Call Number :
        PKI @ kd.modi @ 7
      15. Serial :
        10479
      1. Author :
        Vintonenko, N.; Jais, J. P.; Kassis, N.; Abdelkarim, M.; Perret, G. Y.; Lecouvey, M.; Crepin, M.; Di Benedetto, M.
      2. Title :
        Transcriptome analysis and in vivo activity of fluvastatin versus zoledronic acid in a murine breast cancer metastasis model
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Mol Pharmacol
      6. Products :

        Bioware cell linesIVIS Imaging Systems

      7. Volume :
        82
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        MDA-MB-231-luc-D3H2Ln, D3H2Ln, IVIS, Breast cancer, Bioware
      12. Abstract :
        Statins and bisphosphonates are two distinct classes of isoprenoid pathway inhibitors targeting downstream enzyme to HMG-CoA reductase (upstream enzyme) and farnesyl-pyrophosphate synthase, respectively. Here, we studied fluvastatin (Fluva) and zoledronate (Zol), representative molecules of each class, respectively. In vivo metastatic potentials of both molecules were assessed. For the first time, we observed a significant reduction in progression of established metastases with Fluva treatment. Treatment with both Zol at 100 mug/kg and Fluva at 15 mg/kg inhibited 80% of the metastasis bioluminescence signal and increased survival of mice. The Zol and Fluva transcriptomic profiles of treated MDA-MB-231 cells revealed analogous patterns of affected genes, but each of them reached with different kinetics. The observable changes in gene expression started after 24 h for Fluva IC(50 72 h) and only after 48 h for Zol IC(50 72 h). To obtain early changes in gene expression of Zol-treated cells, a 3 times higher dose of Zol IC(50 72 h) had to be applied. Combining Fluva and Zol in vivo showed no synergy, but a benefit of several days in survival of mice. This study demonstrated that Zol or Fluva is of potential clinical use for the treatment of established metastasis.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22723339
      14. Call Number :
        PKI @ kd.modi @ 2
      15. Serial :
        10509
      1. Author :
        Chen, J.; Gallo, K. A.
      2. Title :
        MLK3 regulates paxillin phosphorylation in chemokine-mediated breast cancer cell migration and invasion to drive metastasis
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Cancer Res
      6. Products :

        Bioware cell linesIVIS Imaging Systems

      7. Volume :
        72
      8. Issue :
        N/A
      9. Page Numbers :
        4130-40
      10. Research Area :
        N/A
      11. Keywords :
        MDA-MB-231-luc2-tdtomato, IVIS, tdtomato, fluorescent protein, Animals; Breast Neoplasms/enzymology/*metabolism/*pathology; Cell Line, Tumor; Cell Movement/*physiology; Chemokine CXCL12/metabolism; Female; Humans; MAP Kinase Kinase Kinases/*metabolism; MAP Kinase Signaling System; Mice; Mice, Nude; Neoplasm Invasiveness; Paxillin/*metabolism; Phosphorylation
      12. Abstract :
        MLK3 kinase activates multiple mitogen-activated protein kinases and plays a critical role in cancer cell migration and invasion. In the tumor microenvironment, prometastatic factors drive breast cancer invasion and metastasis, but their associated signaling pathways are not well-known. Here, we provide evidence that MLK3 is required for chemokine (CXCL12)-induced invasion of basal breast cancer cells. We found that MLK3 induced robust phosphorylation of the focal adhesion scaffold paxillin on Ser 178 and Tyr 118, which was blocked by silencing or inhibition of MLK3-JNK. Silencing or inhibition of MLK3, inhibition of JNK, or expression of paxillin S178A all led to enhanced Rho activity, indicating that the MLK3-JNK-paxillin axis limits Rho activity to promote focal adhesion turnover and migration. Consistent with this, MLK3 silencing increased focal adhesions and stress fibers in breast cancer cells. MLK3 silencing also decreased the formation of breast cancer lung metastases in vivo, and breast cancer cells derived from mouse lung metastases showed enhanced Ser 178 paxillin phosphorylation. Taken together, our findings suggest that the MLK3-JNK-paxillin signaling axis may represent a potential therapeutic target and/or prognostic marker in breast cancer metastasis.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22700880
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10495
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