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      1. Author :
        M van Eekelen; LS Sasportas; R Kasmieh; S Yip; J-L Figueiredo; DN Louis; R Weissleder; K Shah
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Oncogene
      6. Products :
      7. Volume :
        29
      8. Issue :
        22
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        brain tumor; glioma; human neural stem cells; TSP-1; endothelial cells; angiogenesis; in vivo imaging
      12. Abstract :
        Novel therapeutic agents combined with innovative modes of delivery and non-invasive imaging of drug delivery, pharmacokinetics and efficacy are crucial in developing effective clinical anticancer therapies. In this study, we have created and characterized multiple novel variants of anti-angiogenic protein thrombospondin (aaTSP-1) that comprises unique regions of three type-I-repeats of TSP-1 and used engineered human neural stem cells (hNSC) to provide sustained on-site delivery of secretable aaTSP-1 to tumor-vasculature. We show that hNSC-aaTSP-1 has anti-angiogenic effect on human brain and dermal microvascular endothelial cells co-cultured with established glioma cells and CD133+ glioma-initiating cells. Using human glioma cells and hNSC engineered with different combinations of fluorescent and bioluminescent marker proteins and employing multi-modality imaging techniques, we show that aaTSP-1 targets the vascular-component of gliomas and a single administration of hNSC-aaTSP-1 markedly reduces tumor vessel-density that results in inhibition of tumor-progression and increased survival in mice bearing highly malignant human gliomas. We also show that therapeutic hNSC do not proliferate and remain in an un-differentiated state in the brains of glioma-bearing mice. This study provides a platform for accelerated development of future cell-based therapies for cancer.
      13. URL :
        http://www.nature.com/onc/journal/v29/n22/abs/onc201075a.html
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4492
      1. Author :
        Thobe, M N; Gurusamy, D; Pathrose, P; Waltz, S E
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Oncogene
      6. Products :
      7. Volume :
        29
      8. Issue :
        2
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antigens, CD31; Bioware; Blotting, Western; Cell Line; Cell Line, Tumor; Cell Movement; Chemokine CXCL1; Chemokine CXCL5; Chemokines; Endothelial Cells; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Interleukin-8; Male; Mice; Mice, Nude; Neoplasms, Experimental; Neovascularization, Pathologic; NF-kappa B; PC-3M-luc2; Prostatic Neoplasms; Receptor Protein-Tyrosine Kinases; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Transplantation, Heterologous
      12. Abstract :
        Overexpression of the Ron receptor tyrosine kinase has recently been shown in a wide variety of human cancers. However, no studies have examined Ron receptor expression or function during prostate tumorigenesis. In this study we report that Ron is highly expressed in human prostate adenocarcinoma and metastatic lymph nodes when compared with normal prostate or benign prostate hyperplasia. Furthermore, we show that Ron is overexpressed in PC-3 and DU145 prostate cancer cell lines, and that the levels of angiogenic chemokines produced by prostate cancer cells positively correlate with Ron expression. The knockdown of Ron in PC-3 or DU145 cells results in a significant decrease in angiogenic chemokine production and is associated with a decreased activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Moreover, exogenous overexpression of Ron in LNCaP cells is sufficient to induce a significant increase in angiogenic chemokines that can be abrogated by inhibition of NF-kappaB signaling. Given that the function of angiogenic chemokines is important in the development of new blood vessels, we also examined the ability of Ron to modulate endothelial cell migration. Our data show that knockdown of Ron in prostate cancer cells results in significantly less endothelial cell chemotaxis when compared with Ron-expressing cells in vitro as well as in reduced tumor growth and decreased microvessel density after orthotopic transplantation into the prostate in vivo. In total, our data suggest that the Ron receptor is important in modulating prostate tumor growth by modulating angiogenic chemokine production and subsequent endothelial cell recruitment.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19838218
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8943
      1. Author :
        Zhang, H; Fagan, D H; Zeng, X; Freeman, K T; Sachdev, D; Yee, D
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Oncogene
      6. Products :
      7. Volume :
        29
      8. Issue :
        17
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Cell Line, Tumor; Cell Proliferation; Female; Humans; Insulin; Lung Neoplasms; Lymphangiogenesis; MDA-MB-231-D3H1 cells; Mice; Neoplasm Metastasis; Neoplasms, Experimental; Neovascularization, Pathologic; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptor, Insulin; RNA, Small Interfering; Vascular Endothelial Growth Factor A
      12. Abstract :
        Insulin receptor (IR) and the type I IGF receptor (IGF1R) are structurally and functionally related. The function of IGF1R in cancer has been well documented and anti-IGF1R strategies to treat cancer have shown initial positive results. However, the role of IR in tumor biology, independent of IGF1R, is less clear. To address this issue, short hairpin RNA (shRNA) was used to specifically downregulate IR in two cancer cell lines, LCC6 and T47D. Cells with reduced IR showed reduced insulin-stimulated Akt activation, without affecting IGF1R activation. Cells with reduced IR formed fewer colonies in anchorage-independent conditions. LCC6 IR shRNA xenograft tumors in mice had reduced growth, angiogenesis and lymphangiogensis when compared with LCC6 wild-type cells. Accordingly, LCC6 IR shRNA clones produced less hypoxia-inducible factor-1alpha, vascular endothelial growth factor (VEGF)-A and VEGF-D. Furthermore, LCC6 IR shRNA cells formed fewer pulmonary metastases when compared with LCC6 wild-type cells. Using in vivo luciferase imaging, we have shown that LCC6 IR shRNA cells have less seeding and colonization potential in the lung and liver of mice than LCC6 cells. In conclusion, downregulation of IR inhibited cancer cell proliferation, angiogenesis, lymphangiogenesis and metastasis. Our data argue that IR should also be targeted in cancer therapy.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20154728
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8986
      1. Author :
        Yigit, M. V.; Ghosh, S. K.; Kumar, M.; Petkova, V.; Kavishwar, A.; Moore, A.; Medarova, Z.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Oncogene
      6. Products :
      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        MDA-MB-231-luc-D3H2Ln, D3H2Ln, Bioware, IVIS
      12. Abstract :
        Metastases, and not the primary tumor from which they originate, are the main reason for mortality from carcinoma. Although the molecular mechanisms behind metastasis are poorly understood, it is clear that epigenetic dysregulation at the level of microRNA expression is a key characteristic of the metastatic process that can be exploited for therapy. Here, we describe an miRNA-targeted therapeutic approach for the prevention and arrest of lymph node metastasis. Therapy relies on the inhibition of the pro-metastatic microRNA-10b. It is delivered to primary and lymph node metastatic tumor cells using an imaging-capable nanodrug that is designed to specifically home to these tissues. Treatment of invasive human breast tumor cells (MDA-MB-231) with the nanodrug in vitro downregulates miR-10b and abolishes the invasion and migration of the tumor cells. After intravenous delivery to mice bearing orthotopic MDA-MB-231-luc-D3H2LN tumors, the nanodrug accumulates in the primary tumor and lymph nodes. When treatment is initiated before metastasis to lymph nodes, metastasis is prevented. Treatment after the formation of lymph node metastases arrests the metastatic process without a concomitant effect on primary tumor growth raising the possibility of a context-dependent variation in miR-10b breast oncogenesis.Oncogene advance online publication, 14 May 2012; doi:10.1038/onc.2012.173.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22580603
      14. Call Number :
        PKI @ kd.modi @ 9
      15. Serial :
        10505
      1. Author :
        Vujanovic, L.; Ballard, W.; Thorne, S. H.; Vujanovic, N. L.; Butterfield, L. H.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Oncoimmunology
      6. Products :
      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 :
        Guo, K.; Tang, J. P.; Jie, L.; Al-Aidaroos, A. Q.; Hong, C. W.; Tan, C. P.; Park, J. E.; Varghese, L.; Feng, Z.; Zhou, J.; Chng, W. J.; Zeng, Q.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Oncotarget
      6. Products :
      7. Volume :
        3
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        HCT-116-luc2, IVIS, Bioware, HCT116-luc2, Animals; Antibodies, Monoclonal/*immunology; Antibody-Dependent Cell Cytotoxicity/immunology; Carcinoma, Non-Small-Cell Lung/drug therapy; Carcinoma, Squamous Cell/drug therapy; Cell Line, Tumor; Colorectal Neoplasms/drug therapy; Humans; Immediate-Early Proteins/*immunology; Killer Cells, Natural/*immunology; Lymphocyte Activation/immunology; Melanoma/drug therapy; Mice; Mice, Nude; Mice, SCID; Molecular Targeted Therapy/*methods; Protein Tyrosine Phosphatases/*immunology; Recombinant Fusion Proteins/immunology/pharmacology/therapeutic use
      12. Abstract :
        Antibodies are considered as 'magic bullets' because of their high specificity. It is believed that antibodies are too large to routinely enter the cytosol, thus antibody therapeutic approach has been limited to extracellular or secreted proteins expressed by cancer cells. However, many oncogenic proteins are localized within the cell. To explore the possibility of antibody therapies against intracellular targets, we generated a chimeric antibody targeting the intracellular PRL-3 oncoprotein to assess its antitumor activities in mice. Remarkably, we observed that the PRL-3 chimeric antibody could efficiently and specifically reduce the formation of PRL-3 expressing metastatic tumors. We further found that natural killer (NK) cells were important in mediating the therapeutic effect, which was only observed in a nude mouse model (T-cell deficient), but not in a Severe Combined Immunodeficiency' (scid ) mouse model (B- and T-cell deficient), indicating the anticancer effect also depends on host B-cell activity. Our study involving 377 nude and scid mice suggest that antibodies targeting intracellular proteins can be developed to treat cancer.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22374986
      14. Call Number :
        PKI @ kd.modi @ 3
      15. Serial :
        10497
      1. Author :
        Wen, D.; Qing, L.; Harrison, G.; Golub, E.; Akintoye, S. O.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Oral Dis
      6. Products :
      7. Volume :
        17
      8. Issue :
        N/A
      9. Page Numbers :
        427-32
      10. Research Area :
        N/A
      11. Keywords :
        OsteoSense, Maestro, Animals; Bone Density Conservation Agents/administration & dosage/*pharmacokinetics; Bone and Bones/*metabolism; Calcium/metabolism; Chelating Agents; Decalcification Technique; Diphosphonates/administration & dosage/*pharmacokinetics; Durapatite/metabolism; Edetic Acid; Female; Femur/metabolism; Fibula/metabolism; Fluorescent Dyes/diagnostic use; Fluorometry; Humerus/metabolism; Injections, Intravenous; Mandible/metabolism; Models, Animal; Radius/metabolism; Rats; Rats, Nude; Spectrophotometry, Atomic; Tibia/metabolism; Tissue Distribution; Ulna/metabolism
      12. Abstract :
        OBJECTIVES: Bisphosphonates commonly used to treat osteoporosis, Paget's disease, multiple myeloma, hypercalcemia of malignancy and osteolytic lesions of cancer metastasis have been associated with bisphosphonate-associated jaw osteonecrosis (BJON). The underlying pathogenesis of BJON is unclear, but disproportionate bisphosphonate concentration in the jaw has been proposed as one potential etiological factor. This study tested the hypothesis that skeletal biodistribution of intravenous bisphosphonate is anatomic site-dependent in a rat model system. MATERIALS AND METHODS: Fluorescently labeled pamidronate was injected intravenously in athymic rats of equal weights followed by in vivo whole body fluorimetry, ex vivo optical imaging of oral, axial, and appendicular bones and ethylenediaminetetraacetic acid bone decalcification to assess hydroxyapatite-bound bisphosphonate. RESULTS: Bisphosphonate uptake and bisphosphonate released per unit calcium were similar in oral and appendicular bones but lower than those in axial bones. Hydroxyapatite-bound bisphosphonate liberated by sequential acid decalcification was the highest in oral, relative to axial and appendicular bones (P < 0.05). CONCLUSIONS: This study demonstrates regional differences in uptake and release of bisphosphonate from oral, axial, and appendicular bones of immune deficient rats.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21122034
      14. Call Number :
        PKI @ kd.modi @ 11
      15. Serial :
        10467
      1. Author :
        Luo, Z R; Huang, T; Li, W; Shen, B Z
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Panminerva medica
      6. Products :
      7. Volume :
        52
      8. Issue :
        1
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; B16-F10-luc-G5 cells; Bioware; Diagnostic Imaging; Luminescence; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Molecular Dynamics Simulation
      12. Abstract :
        AIM The aim of this study was to evaluate the veracity and sensitivity of in-vivo imaging system (IVIS) for inspection of tumor dynamic morphology. METHODS Mouse melanoma cells (B16-F10-luc-G5) in 100 mL media were seeded into a 96-well plate by 1:2 serial dilution from 10000 cells (well #1) to 78 cells (well #8). The plate was imaged using IVIS system to evaluate its sensitivity for luminescence. Ten Bablc mice with tumor cells were injected subcutaneously (1 x 10(5) in 100 mL) and tumor luminescence was detected by IVIS at Day 0, Day 3, Day 5, Day 7 and Day 9. RESULTS As few as 78 tumor cells were detectable by IVIS. A strong correlation between number of tumor cells and bioluminescence (R2=0.99) was also demonstrated. Tumor luminescence were observed in all mice by IVIS at all days, and there was significant difference (P<0.01) between each two days from Day 0 to Day 9. Moreover, tumor dynamic morphology could be monitored by IVIS when it is invisible. CONCLUSION Compared with conventional methods, with high veracity and sensitivity, IVIS system should be recommended as an effective method for inspection of tumor dynamic morphology.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20228722
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8995
      1. Author :
        Napp, J.; Mathejczyk, J.E.; Alves, F.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Pediatric Radiology
      6. Products :
      7. Volume :
        41
      8. Issue :
        2
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        AngioSense 680; Cancer; glioblastoma xenograft; mice; tumor vascularization
      12. Abstract :
        To obtain information on the occurrence and location of molecular events as well as to track target-specific probes such as antibodies or peptides, drugs or even cells non-invasively over time, optical imaging (OI) technologies are increasingly applied. Although OI strongly contributes to the advances made in preclinical research, it is so far, with the exception of optical coherence tomography (OCT), only very sparingly applied in clinical settings. Nevertheless, as OI technologies evolve and improve continuously and represent relatively inexpensive and harmful methods, their implementation as clinical tools for the assessment of children disease is increasing. This review focuses on the current preclinical and clinical applications as well as on the future potential of OI in the clinical routine. Herein, we summarize the development of different fluorescence and bioluminescence imaging techniques for microscopic and macroscopic visualization of microstructures and biological processes. In addition, we discuss advantages and limitations of optical probes with distinct mechanisms of target-detection as well as of different bioluminescent reporter systems. Particular attention has been given to the use of near-infrared (NIR) fluorescent probes enabling observation of molecular events in deeper tissue.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21221568
      14. Call Number :
        PKI @ user @ 8559
      15. Serial :
        4796
      1. Author :
        Carlisle, R.; Seymour, L. W.; Coussios, C. C.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Pharm Res
      6. Products :
      7. Volume :
        N/A
      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
      12. Abstract :
        PURPOSE: To improve the delivery of liposomes to tumors using P-selectin glycoprotein ligand 1 (PSGL1) mediated binding to selectin molecules, which are upregulated on tumorassociated endothelium. METHODS: PSGL1 was orientated and presented on the surface of liposomes to achieve optimal selectin binding using a novel streptavidin-protein G linker molecule. Loading of PSGL1 liposomes with luciferin allowed their binding to e-selectin and activated HUVEC to be quantified in vitro and their stability, pharmacokinetics and tumor accumulation to be tested in vivo using murine models. RESULTS: PSGL1 liposomes showed 5-fold (p < 0.05) greater selectin binding than identically formulated control liposomes modified with ligand that did not contain the selectin binding domain. When added to HUVEC, PSGL1 liposomes showed >7-fold (p < 0.001) greater attachment than control liposomes. In in vivo studies PSGL1 liposomes showed similar stability and circulation to control liposomes but demonstrated a >3-fold enhancement in the level of delivery to tumors (p < 0.05). CONCLUSIONS: The technologies and strategies described here may contribute to clinical improvements in the selectivity and efficacy of liposomal drug delivery agents.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22992830
      14. Call Number :
        PKI @ kd.modi @ 19
      15. Serial :
        10529
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