Cancer Stem Cells; Inflammation; Angiogenesis; Lymphangiogenesis; Cancer metastasis
Klein S Dieterich LC Mathelier A Chong C Sliwa-Primorac A Hong YK Shin JW ...Detmar M (2016), DeepCAGE transcriptomics identify HOXD10 as transcription factor regulating lymphatic endothelial responses to VEGF-C., in Cell Reports
Ochsenbein A. M., Karaman S., Proulx S. T., Berchtold M., Jurisic G., Stoeckli E. T., Detmar M. (2016), Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells, in Development
, 143(4), 589-594.
Chong Chloé, Scholkmann Felix, Bachmann Samia B., Luciani Paola, Leroux Jean-Christophe, Detmar Michael, Proulx Steven T. (2016), In vivo visualization and quantification of collecting lymphatic vessel contractility using near-infrared imaging, in Scientific Reports
, 6, 22930-22930.
Escobedo Noelia, Proulx Steven T., Karaman Sinem, Dillard Miriam E., Johnson Nicole, Detmar Michael, Oliver Guillermo (2016), Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice, in JCI Insight
, 1(2), e85096.
Dieterich Lothar C., Detmar Michael (2016), Tumor lymphangiogenesis and new drug development, in Advanced Drug Delivery Reviews
, 99, 148-160.
Aspelund Aleksanteri, Antila Salli, Proulx Steven T., Karlsen Tine Veronica, Karaman Sinem, Detmar Michael, Wiig Helge, Alitalo Kari (2015), A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules, in The Journal of Experimental Medicine
, 212(7), 991-999.
Bianchi Roberta, Teijeira Alvaro, Proulx Steven T., Christiansen Ailsa J., Seidel Catharina D., Rülicke Thomas, Mäkinen Taija, Hägerling René, Halin Cornelia, Detmar Michael (2015), A Transgenic Prox1-Cre-tdTomato Reporter Mouse for Lymphatic Vessel Research, in PLOS ONE
, 10(4), e0122976-e0122976.
Karaman Sinem, Hollmén Maija, Robciuc Marius R., Alitalo Annamari, Nurmi Harri, Morf Bettina, Buschle Dorina, Alkan H. Furkan, Ochsenbein Alexandra M., Alitalo Kari, Wolfrum Christian, Detmar Michael (2015), Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet, in Molecular Metabolism
, 4(2), 93-105.
Hollmén Maija, Roudnicky Filip, Karaman Sinem, Detmar Michael (2015), Characterization of macrophage - cancer cell crosstalk in estrogen receptor positive and triple-negative breast cancer, in Scientific Reports
, 5, 9188-9188.
Karaman Sinem, Buschle Dorina, Luciani Paola, Leroux Jean-Christophe, Detmar Michael, Proulx Steven T. (2015), Decline of lymphatic vessel density and function in murine skin during aging, in Angiogenesis
, 18(4), 489-498.
Dieterich Lothar C., Klein Sarah, Mathelier Anthony, Sliwa-Primorac Adriana, Ma Qiaoli, Hong Young-Kwon, Shin Jay W., Hamada Michito, Lizio Marina, Itoh Masayoshi, Kawaji Hideya, Lassmann Timo, Daub Carsten O., Arner Erik, Carninci Piero, Hayashizaki Yoshihide, Forrest Alistair R.R., Wasserman Wyeth W., Detmar Michael (2015), DeepCAGE Transcriptomics Reveal an Important Role of the Transcription Factor MAFB in the Lymphatic Endothelium, in Cell Reports
, 13(7), 1493-1504.
Hollmén Maija, Karaman Sinem, Schwager Simon, Lisibach Angela, Christiansen Ailsa J., Maksimow Mikael, Varga Zsuzsanna, Jalkanen Sirpa, Detmar Michael (2015), G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer, in OncoImmunology
, 5(3), e1115177-e1115177.
Mitsi Maria, Schulz Martin Michael Peter, Gousopoulos Epameinondas, Ochsenbein Alexandra Michaela, Detmar Michael, Vogel Viola (2015), Walking the Line: A Fibronectin Fiber-Guided Assay to Probe Early Steps of (Lymph)angiogenesis, in PLOS ONE
, 10(12), e0145210-e0145210.
Zgraggen Silvana, Huggenberger Reto, Kerl Katrin, Detmar Michael (2014), An Important Role of the SDF-1/CXCR4 Axis in Chronic Skin Inflammation, in PLoS ONE
, 9(4), e93665-e93665.
Blum Katrin S., Karaman Sinem, Proulx Steven T., Ochsenbein Alexandra M. (2014), Chronic high-fat diet impairs collecting lymphatic vessel function in mice, in Detmar, Michael
, 9(4), e94713.
Dieterich Lothar C., Seidel Catharina D., Detmar Michael (2014), Lymphatic vessels - new targets for the treatment of inflammatory diseases, in Angiogenesis
, 17, 359-371.
Karaman Sinem, Detmar Michael (2014), Mechanisms of lymphatic metastasis, in The Journal of Clinical Investigation
, 124(3), 922-928.
Ochsenbein Alexandra M., Karaman Sinem, Jurisic Giorgia, Detmar Michael (2014), The role of neuropilin-1/semaphorin 3A signaling in lymphatic vessel development and maturation, in F. Kiefer and S. Schulte-Merker (eds.) (ed.), Springer, Wien, 143-152.
Our previous studies have identified vascular endothelial growth factor-A (VEGF-A) as a cytokine of central importance for normal, inflammatory and neoplastic skin angiogenesis that also induces lymphatic vessel growth. We have also identified a critical role of VEGF-C in the induction of tumor lymphangiogenesis, lymph node lymphangiogenesis and lymph node metastasis. Our recent studies have identified several candidate molecules that might mediate the effects of VEGF-A in inflammation, and they surprisingly also revealed that genetic overexpression of VEGF-C or treatment with a recombinant VEGF-C protein potently inhibited both acute and chronic skin inflammation. Furthermore, we found evidence that macrophages play an important role in mediating lymph node lymphangiogenesis, a process of crucial importance for cancer metastasis and for chronic inflammation. Finally, our recent studies have identified an unanticipated role of lymphatic vessels in promoting the stemness of cancer stem cells - with important implications for the generation of lymph node metastases and the clinically observed phenomenon of "in-transit" metastases. We now propose experiments to test our specific hypotheses: (1) that specific molecules mediate the proinflammatory effects of VEGF-A, including MMP12 and thrombin, and that they might serve as new therapeutic targets; (2) that specific delivery of a mutated VEGF-C protein, that only activates VEGF receptor-3, inhibits inflammation; (3) that specific molecular and cellular interactions between macrophages and lymphatic endothelium mediate tumor-induced and inflammation-induced lymph node remodeling and lymph node lymphangiogenesis, with important therapeutic implications; and (4) that tumor-activated lymphatic vessels promote the survival and metastasis of melanoma and breast cancer stem cells. Understanding the mechanisms of lymphatic and blood vessel activation, and their interaction with macrophages and cancer stem cells, will be the basis for developing novel therapeutic strategies to treat inflammation and cancer.