Citation Details

Journal Article

Animals; Antigen Presentation; Antigens, Neoplasm; B16-F10-luc-G5 cells; Bioware; B-Lymphocytes; Cell Adhesion; Cell Line, Tumor; Cell Movement; dendritic cells; Female; Lectins, C-Type; Lymphatic Metastasis; Lymphatic System; Macrophages; Male; Mannose-Binding Lectins; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Cell Surface; T-Lymphocytes

Macrophage mannose receptor (MR) participates in pathogen recognition, clearance of endogenous serum glycoproteins, and antigen presentation. MR is also present on lymphatic vessels, where its function is unknown. Here we show that migration of lymphocytes from the skin into the draining lymph nodes through the afferent lymphatics is reduced in MR-deficient mice, while the structure of lymphatic vasculature remains normal in these animals. Moreover, in a tumor model the primary tumors grow significantly bigger in MR(-/-) mice than in the wild-type (WT) controls, whereas the regional lymph node metastases are markedly smaller. Adhesion of both normal lymphocytes and tumor cells to lymphatic vessels is significantly decreased in MR-deficient mice. The ability of macrophages to present tumor antigens is indistinguishable between the 2 genotypes. Thus, MR on lymphatic endothelial cells is involved in leukocyte trafficking and contributes to the metastatic behavior of cancer cells. Blocking of MR may provide a new approach to controlling inflammation and cancer metastasis by targeting the lymphatic vasculature.

Journal Article

Cancer; flank tumor; In vivo; MMPSense 750; ProSense 680; tomography; VisEn FMT

<AbstractText Label=“BACKGROUND” NlmCategory=“BACKGROUND”>The possibility that μ opioid agonists can influence cancer recurrence is a subject of recent interest. Epidemiologic studies suggested that there were differences in cancer recurrence in breast and prostate cancer contingent on anesthetic regimens. In this study, we identify a possible mechanism for these epidemiologic findings on the basis of μ opioid receptor (MOR) regulation of Lewis lung carcinoma (LLC) tumorigenicity in cell and animal models.</AbstractText> <AbstractText Label=“METHODS” NlmCategory=“METHODS”>We used human lung tissue and human non-small cell lung cancer (NSCLC) cell lines and evaluated MOR expression using immunoblot and immunohistochemical analysis. LLC cells were treated with the peripheral opioid antagonist methylnaltrexone (MNTX) or MOR shRNA and evaluated for proliferation, invasion, and soft agar colony formation in vitro and primary tumor growth and lung metastasis in C57BL/6 and MOR knockout mice using VisEn fluorescence mediated tomography imaging and immunohistochemical analysis.</AbstractText> <AbstractText Label=“RESULTS” NlmCategory=“RESULTS”>We provide several lines of evidence that the MOR may be a potential target for lung cancer, a disease with high mortality and few treatment options. We first observed that there is ~5- to 10-fold increase in MOR expression in lung samples from patients with NSCLC and in several human NSCLC cell lines. The MOR agonists morphine and [d-Ala(2), N-MePhe(4), Gly-ol]-enkephalin (DAMGO) increased in vitro LLC cell growth. Treatment with MNTX or silencing MOR expression inhibited LLC invasion and anchorage-independent growth by 50%-80%. Injection of MOR silenced LLC lead to a ~65% reduction in mouse lung metastasis. In addition, MOR knockout mice do not develop significant tumors when injected with LLC in comparison with wild-type controls. Finally, continuous infusion of the peripheral opioid antagonist MNTX attenuates primary LLC tumor growth and reduces lung metastasis.</AbstractText> <AbstractText Label=“CONCLUSIONS” NlmCategory=“CONCLUSIONS”>Taken together, our data suggest a possible direct effect of opiates on lung cancer progression, and provide a plausible explanation for the epidemiologic findings. Our observations further suggest a possible therapeutic role for opioid antagonists.</AbstractText>

Journal Article

AngioSense, Animals; Blood Vessels/embryology/*physiology; Chromosomes, Artificial, Bacterial; Embryo, Mammalian; Endothelial Cells/cytology/metabolism; Endothelium, Vascular/cytology/embryology/metabolism; Female; Founder Effect; Gene Expression Regulation, Developmental; Genes, Reporter; Mice; *Mice, Transgenic; Microscopy, Fluorescence; Morphogenesis/physiology; *Neovascularization, Pathologic; *Neovascularization, Physiologic; Retina/embryology/*physiology; Vascular Endothelial Growth Factor A/genetics/metabolism; Vascular Endothelial Growth Factor Receptor-1/genetics/*metabolism; Vascular Endothelial Growth Factor Receptor-2/genetics/metabolism

Blood vessel development and network patterning are controlled by several signaling molecules, including VEGF, FGF, TGF-ss, and Ang-1,2. Among these, the role of VEGF-A signaling in vessel morphogenesis is best understood. The biological activity of VEGF-A depends on its reaction with specific receptors Flt1 and Flk1. Roles of VEGF-A signaling in endothelial cell proliferation, migration, survival, vascular permeability, and induction of tip cell filopodia have been reported. In this study, we have generated Flt1-tdsRed BAC transgenic (Tg) mice to monitor Flt1 gene expression during vascular development. We show that tdsRed fluorescence is observed within blood vessels of adult mice and embryos, indicative of retinal angiogenesis and tumor angiogenesis. Flt1 expression recapitulated by Flt1-tdsRed BAC Tg mice overlapped well with Flk1, while Flt1 was expressed more abundantly in endothelial cells of large blood vessels such as dorsal aorta and presumptive stalk cells in retina, providing a unique model to study blood vessel development.

Journal Article

molecular imaging; myocardial infarction; inflammation; FMT; fluorescent molecular tomography; in vivo imaging

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Journal Article

FMT; in vivo imaging; ProSense

Fluorescent molecular tomographic (FMT) imaging can noninvasively monitor molecular function in living animals using specific fluorescent probes. However, macroscopic imaging methods such as FMT generally exhibit low anatomical details. To overcome this, we report a quantitative technique to image both structure and function by combining FMT and magnetic resonance (MR) imaging. We show that FMT-MR imaging can produce three-dimensional, multimodal images of living mouse brains allowing for serial monitoring of tumor morphology and protease activity. Combined FMT-MR tumor imaging provides a unique in vivo diagnostic parameter, protease activity concentration (PAC), which reflects histological changes in tumors and is significantly altered by systemic chemotherapy. Alterations in this diagnostic parameter are detectable early after chemotherapy and correlate with subsequent tumor growth, predicting tumor response to chemotherapy. Our results reveal that combined FMT-MR imaging of fluorescent molecular probes could be valuable for brain tumor drug development and other neurological and somatic imaging applications.