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      1. Author :
        Mumprecht, V.; Honer, M.; Vigl, B.; Proulx, S. T.; Trachsel, E.; Kaspar, M.; Banziger-Tobler, N. E.; Schibli, R.; Neri, D.; Detmar, M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Cancer Res
      6. Products :
      7. Volume :
        70
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals, B16-F10-luc2, B16F10-luc2; Antibodies, Monoclonal/diagnostic use/immunology; *Diagnostic Imaging; Female; Fluorodeoxyglucose F18/diagnostic use; Glycoproteins/*immunology; Humans; Inflammation/*complications/immunology/pathology; Iodine Radioisotopes/diagnostic use/pharmacokinetics; Luminescent Measurements; Lymph Nodes/immunology/pathology/*radionuclide imaging; *Lymphangiogenesis; Lymphatic Metastasis; Melanoma, Experimental/*complications/immunology/pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; *Positron-Emission Tomography; Prognosis; Radiopharmaceuticals/diagnostic use; Skin/metabolism; Tissue Distribution; Vascular Endothelial Growth Factor C/metabolism; Vascular Endothelial Growth Factor Receptor-3/immunology
      12. Abstract :
        Metastasis to regional lymph nodes (LN) is a prognostic indicator for cancer progression. There is a great demand for sensitive and noninvasive methods to detect metastasis to LNs. Whereas conventional in vivo imaging approaches have focused on the detection of cancer cells, lymphangiogenesis within tumor-draining LNs might be the earliest sign of metastasis. In mouse models of LN lymphangiogenesis, we found that systemically injected antibodies to lymphatic epitopes accumulated in the lymphatic vasculature in tissues and LNs. Using a (124)I-labeled antibody against the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), we imaged, for the first time, inflammation- and tumor-draining LNs with expanded lymphatic networks in vivo by positron emission tomography (PET). Anti-LYVE-1 immuno-PET enabled visualization of lymphatic vessel expansion in LNs bearing metastases that were not detected by [(18)F]fluorodeoxyglucose-PET, which is clinically applied to detect cancer metastases. Immuno-PET with lymphatic-specific antibodies may open up new avenues for the early detection of metastasis, and the images obtained might be used as biomarkers for the progression of diseases associated with lymphangiogenesis.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20978206
      14. Call Number :
        PKI @ kd.modi @ 2
      15. Serial :
        10349
      1. Author :
        Proulx, S. T.; Luciani, P.; Derzsi, S.; Rinderknecht, M.; Mumprecht, V.; Leroux, J. C.; Detmar, M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Cancer Res
      6. Products :
      7. Volume :
        70
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals, B16-F10-luc2, B16F10-luc2; Coloring Agents/administration & dosage/*diagnostic use; Indocyanine Green/administration & dosage/*diagnostic use; Injections, Intradermal; Liposomes/administration & dosage; Lymphatic Metastasis; Lymphatic Vessels/metabolism/*pathology; Melanoma, Experimental/blood supply/metabolism/*pathology; Mice; Mice, Inbred C57BL; Vascular Endothelial Growth Factor C/biosynthesis
      12. Abstract :
        Lymphatic vessels play a major role in cancer progression and in postsurgical lymphedema, and several new therapeutic approaches targeting lymphatics are currently being developed. Thus, there is a critical need for quantitative imaging methods to measure lymphatic flow. Indocyanine green (ICG) has been used for optical imaging of the lymphatic system, but it is unstable in solution and may rapidly enter venous capillaries after local injection. We developed a novel liposomal formulation of ICG (LP-ICG), resulting in vastly improved stability in solution and an increased fluorescence signal with a shift toward longer wavelength absorption and emission. When injected intradermally to mice, LP-ICG was specifically taken up by lymphatic vessels and allowed improved visualization of deep lymph nodes. In a genetic mouse model of lymphatic dysfunction, injection of LP-ICG showed no enhancement of draining lymph nodes and slower clearance from the injection site. In mice bearing B16 luciferase-expressing melanomas expressing vascular endothelial growth factor-C (VEGF-C), sequential near-IR imaging of intradermally injected LP-ICG enabled quantification of lymphatic flow. Increased flow through draining lymph nodes was observed in mice bearing VEGF-C-expressing tumors without metastases, whereas a decreased flow pattern was seen in mice with a higher lymph node tumor burden. This new method will likely facilitate quantitative studies of lymphatic function in preclinical investigations and may also have potential for imaging of lymphedema or improved sentinel lymph detection in cancer.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20823159
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10350
      1. Author :
        Nguyen, V. H.; Kim, H. S.; Ha, J. M.; Hong, Y.; Choy, H. E.; Min, J. J.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Cancer Res
      6. Products :
      7. Volume :
        70
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen26, Xen 26, Salmonella typhumurium, Animals; Blotting, Western; Cell Line, Tumor; Diagnostic Imaging/methods; Gene Therapy/*methods; Genetic Engineering/*methods; Genetic Vectors/*therapeutic use; Humans; Male; Mice; Mice, Inbred BALB C; Neoplasms/*therapy; Perforin/*genetics/therapeutic use; Promoter Regions, Genetic; Salmonella typhimurium/*genetics; bcl-Associated Death Protein/genetics
      12. Abstract :
        Tumor-targeting bacteria have been studied in terms of their ability to visualize the infection pathway (through imaging probes) or to carry therapeutic molecules to tumors. To integrate these monitoring and therapeutic functions, we engineered attenuated Salmonella typhimurium defective in guanosine 5'-diphosphate-3'-diphosphate synthesis to carry cytotoxic proteins (cytolysin A) and express reporter genes. We successfully visualized the therapeutic process with these engineered bacteria in mice and found that they often mediated complete tumor (CT-26) eradication on cytotoxic gene induction. Furthermore, treatment with the engineered bacteria markedly suppressed metastatic tumor growth.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20028866
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10560
      1. Author :
        Huang, Yujie; Song, Nan; Ding, Yanping; Yuan, Shaopeng; Li, Xuhui; Cai, Hongchen; Shi, Hubing; Luo, Yongzhang
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
        69
      8. Issue :
        19
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Angiopoietin-2; Animals; Bioware; Breast Neoplasms; Capillary Permeability; Female; Gene Expression; Humans; Lung; Lung Neoplasms; Matrix Metalloproteinase 10; Matrix Metalloproteinase 3; MDA-MB-231-D3H1 cells; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Nude; RNA Interference; Up-Regulation
      12. Abstract :
        Before metastasis, certain organs have already been influenced by primary tumors. However, the exact alterations and regulatory mechanisms of the premetastatic organs remain poorly understood. Here, we report that, in the premetastatic stage, angiopoietin 2 (Angpt2), matrix metalloproteinase (MMP) 3, and MMP10 are up-regulated in the lung by primary B16/F10 tumor, which leads to the increased permeability of pulmonary vasculatures and extravasation of circulating tumor cells. Subsequent studies show that Angpt2, MMP3, and MMP10 have a synergistic effect on disrupting vascular integrity in both in vitro and in vivo models. Lentivirus-based in vivo RNA interference of Angpt2, MMP3, and MMP10 attenuates the pulmonary vascular permeability and suppresses the infiltration of myeloid cells in the premetastatic lung. Moreover, knocking down these factors significantly inhibits the spontaneous lung metastasis in the model by orthotopic implantation of MDA-MB-231-Luc-D3H1 cells in nude mice. Further investigations reveal that the malignancy of tumor cells is positively correlated with their capabilities to induce the expression of Angpt2, MMP3, and MMP10. Luciferase reporter assay and chromatin immunoprecipitation assay also suggest that transforming growth factor-beta1 and tumor necrosis factor-alpha signaling are involved in the regulation of these premetastatic factors. Our study shows that pulmonary vascular destabilization in the premetastatic phase promotes the extravasation of tumor cells and facilitates lung metastasis, which may provide potential targets for clinical prevention of metastasis.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19773447
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8989
      1. Author :
        Marttila-Ichihara, Fumiko; Auvinen, Kaisa; Elima, Kati; Jalkanen, Sirpa; Salmi, Marko
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
        69
      8. Issue :
        19
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Amine Oxidase (Copper-Containing); Animals; Antigens, CD11b; B16-F10-luc-G5 cells; Bioware; Cell Adhesion Molecules; Cell Growth Processes; Female; Lymphoma; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Cells; Neovascularization, Pathologic; Oxidoreductases; Receptors, Chemokine
      12. Abstract :
        Cancer growth is regulated by several nonmalignant cell types, such as leukocytes and endothelial cells, which reside in the stroma of the tumor. Vascular adhesion protein-1 (VAP-1) is an amine oxidase enzyme that is expressed on the surface of endothelial cells. It supports leukocyte traffic into inflamed tissues, but nothing is known about its possible role in cancer biology in vivo. Here, we report that B16 melanoma and EL-4 lymphoma remain smaller in VAP-1-deficient mice than in wild-type controls. We found an unexpected defect in tumor angiogenesis in the absence of VAP-1. VAP-1 also selectively enhanced the recruitment of Gr-1+CD11b+ myeloid cells into the tumors. Generation of mice expressing enzymatically inactive VAP-1 showed that the oxidase activity of VAP-1 was necessary to support neoangiogenesis, myeloid cell recruitment, and tumor growth in vivo. These data describe VAP-1 as the first adhesion molecule known to be involved in the recruitment of Gr-1+CD11b+ myeloid cells into tumors. They also suggest that VAP-1 is a potential new tool for immunotherapy of tumors that could be exploited to reduce tumor burden by controlling the traffic of Gr-1+CD11b+ myeloid cells.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19789345
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8997
      1. Author :
        Francis, K P; Yu, J; Bellinger-Kawahara, C; Joh, D; Hawkinson, M J; Xiao, G; Purchio, T F; Caparon, M G; Lipsitch, M; Contag, P R
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2001
      5. Publication :
        Infection and immunity
      6. Products :
      7. Volume :
        69
      8. Issue :
        5
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Amoxicillin; Animals; Bioware; DNA Transposable Elements; Female; Luminescent Measurements; Lung; Mice; Mice, Inbred BALB C; Nasopharynx; Operon; Promoter Regions, Genetic; pXen-5; Streptococcus pneumoniae; Transformation, Bacterial, Xen10, Xen7
      12. Abstract :
        Animal studies with Streptococcus pneumoniae have provided valuable models for drug development. In order to monitor long-term pneumococcal infections noninvasively in living mice, a novel gram-positive lux transposon cassette, Tn4001 luxABCDE Km(r), that allows random integration of lux genes onto the bacterial chromosome was constructed. The cassette was designed so that the luxABCDE and kanamycin resistance genes were linked to form a single promoterless operon. Bioluminescence and kanamycin resistance only occur in a bacterial cell if this operon has transposed downstream of a promoter on the bacterium's chromosome. S. pneumoniae D39 was transformed with plasmid pAUL-A Tn4001 luxABCDE Km(r), and a number of highly bioluminescent colonies were recovered. Genomic DNA from the brightest D39 strain was used to transform a number of clinical S. pneumoniae isolates, and several of these strains were tested in animal models, including a pneumococcal lung infection model. Strong bioluminescent signals were seen in the lungs of the animals containing these pneumococci, allowing the course and antibiotic treatment of the infections to be readily monitored in real time in the living animals. Recovery of the bacteria from the animals showed that the bioluminescent signal corresponded to the number of CFU and that the lux construct was highly stable even after several days in vivo. We believe that this lux transposon will greatly expand the ability to evaluate drug efficacy against gram-positive bacteria in living animals using bioluminescence.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/11292758
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9027
      1. Author :
        Stan, Silvia D; Hahm, Eun-Ryeong; Warin, Renaud; Singh, Shivendra V
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
        68
      8. Issue :
        18
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Bioware; Breast Neoplasms; Cell Growth Processes; Cell Line, Tumor; Ergosterol; Female; Forkhead Transcription Factors; Humans; MDA-MB-231-D3H1 cells; Membrane Proteins; Mice; Mice, Nude; Proto-Oncogene Proteins; RNA, Small Interfering; Transfection; Withanolides; Xenograft Model Antitumor Assays
      12. Abstract :
        Withaferin A (WA) is derived from the medicinal plant Withania somnifera, which has been safely used for centuries in Indian Ayurvedic medicine for treatment of different ailments. We now show, for the first time, that WA exhibits significant activity against human breast cancer cells in culture and in vivo. The WA treatment decreased viability of MCF-7 (estrogen-responsive) and MDA-MB-231 (estrogen-independent) human breast cancer cells in a concentration-dependent manner. The WA-mediated suppression of breast cancer cell viability correlated with apoptosis induction characterized by DNA condensation, cytoplasmic histone-associated DNA fragmentation, and cleavage of poly-(ADP-ribose)-polymerase. On the other hand, a spontaneously immortalized normal mammary epithelial cell line (MCF-10A) was relatively more resistant to WA-induced apoptosis compared with breast cancer cells. The WA-mediated apoptosis was accompanied by induction of Bim-s and Bim-L in MCF-7 cells and induction of Bim-s and Bim-EL isoforms in MDA-MB-231 cells. The cytoplasmic histone-associated DNA fragmentation resulting from WA exposure was significantly attenuated by knockdown of protein levels of Bim and its transcriptional regulator FOXO3a in both cell lines. Moreover, FOXO3a knockdown conferred marked protection against WA-mediated induction of Bim-s expression. The growth of MDA-MB-231 cells implanted in female nude mice was significantly retarded by 5 weekly i.p. injections of 4 mg WA/kg body weight. The tumors from WA-treated mice exhibited reduced cell proliferation and increased apoptosis compared with tumors from control mice. These results point toward an important role of FOXO3a and Bim in regulation of WA-mediated apoptosis in human breast cancer cells.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18794155
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8990
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