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Molecular mechanisms of angiogenesis and lymphangiogenesis in inflammation and cancer progression

English title Molecular mechanisms of angiogenesis and lymphangiogenesis in inflammation and cancer progression
Applicant Detmar Michael
Number 147087
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pharmazeutische Wissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Experimental Cancer Research
Start/End 01.05.2013 - 30.04.2016
Approved amount 793'880.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Pathophysiology

Keywords (5)

Cancer Stem Cells; Inflammation; Angiogenesis; Lymphangiogenesis; Cancer metastasis

Lay Summary (German)

Lead
Blutgefässe und Lymphgefässe spielen eine wichtige Rolle bei der Ausbreitung von Tumorzellen im Körper und bei entzündlichen Erkrankungen. Das Ziel unserer Untersuchungen ist die weitere Aufklärung der Mechanismen, die zur Aktivierung von Blutgefässen und Lymphgefässen führen, und die Entwicklung von neuen Behandlungsansätzen für Tumorerkrankungen und Entzündungskrankheiten.
Lay summary

In unseren vorangehenden Untersuchungen konnten wir zeigen, das der Wachstumsfaktor VEGF-A (vaskulärer Endothelzell-Wachstumsfaktor-A) eine zentrale Rolle in der Neubildung von Blutgefässen und Lymphgefässen bei Entzündungskrankheiten und Tumorerkrankungen spielt. Ebenfalls konnten wir den Wachstumsfaktor VEGF-C als einen wichtigen Faktor identifizieren, der das Wachstum der Lymphgefässe in malignen Tumoren und in Lymphknoten anregt und somit die Tumorabsiedlung fördert. Hierbei spielen sogenannte Makrophagen und Krebs-Stammzellen eine wichtige Rolle. Unsere Studien konnten einige der Moleküle identifizieren, welche wahrscheinlich die Wirkung von VEGF-A in der Entzündungsreaktion vermitteln, und wir fanden überraschenderweise, dass die Behandlung mit einem gentechnisch hergestellten VEGF-C Protein sowohl akute als auch chronische Entzündungen der Haut zu hemmen vermag.

In zukünftigen Studien werden wir nun Experimente durchführen um folgende Hypothesen untersuchen:

  1. Definierte Moleküle vermiteln die entzündlichen Effekte von VEGF-A, einschliesslich MMP12 und Thrombin, und können somit als Zielstrukturen für neue Behandlungsmöglichkeiten dienen.
  2. Behandlung mit einem gentechnisch veränderten VEGF-C Protein kann Entzündungskrankheiten lindern.
  3. Das Zusammenspiel von Lymphgefässzellen und Makrophagen bewirkt das Wachstum von Lymphgefässen in Lymphknoten während der Tumorausbreitung und bei Entzündungskrankheiten, mit Bedeutung für neue Therapieansätze.
  4. Aktivierte Lymphgefässe fördern das Ueberleben und die Ausbreitung von Krebsstammzellen beim Melanom und Brustkrebs.

Die Aufklärung der Mechanismen, die Lymphgefässe und Blutgefässe aktivieren, wird die Vorausetzungen für die Entwicklung neuer Behandlungsansätze für Entzündungskrankheiten und Tumorerkrankungen schaffen.

Direct link to Lay Summary Last update: 06.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
DeepCAGE transcriptomics identify HOXD10 as transcription factor regulating lymphatic endothelial responses to VEGF-C.
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, 186767.
Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells
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.
In vivo visualization and quantification of collecting lymphatic vessel contractility using near-infrared imaging
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.
Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice
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.
Tumor lymphangiogenesis and new drug development
Dieterich Lothar C., Detmar Michael (2016), Tumor lymphangiogenesis and new drug development, in Advanced Drug Delivery Reviews, 99, 148-160.
A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules
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.
A Transgenic Prox1-Cre-tdTomato Reporter Mouse for Lymphatic Vessel Research
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.
Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet
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.
Characterization of macrophage - cancer cell crosstalk in estrogen receptor positive and triple-negative breast cancer
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.
Decline of lymphatic vessel density and function in murine skin during aging
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.
DeepCAGE Transcriptomics Reveal an Important Role of the Transcription Factor MAFB in the Lymphatic Endothelium
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.
G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer
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.
Walking the Line: A Fibronectin Fiber-Guided Assay to Probe Early Steps of (Lymph)angiogenesis
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.
An Important Role of the SDF-1/CXCR4 Axis in Chronic Skin Inflammation
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.
Chronic high-fat diet impairs collecting lymphatic vessel function in mice
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.
Lymphatic vessels - new targets for the treatment of inflammatory diseases
Dieterich Lothar C., Seidel Catharina D., Detmar Michael (2014), Lymphatic vessels - new targets for the treatment of inflammatory diseases, in Angiogenesis, 17, 359-371.
Mechanisms of lymphatic metastasis
Karaman Sinem, Detmar Michael (2014), Mechanisms of lymphatic metastasis, in The Journal of Clinical Investigation, 124(3), 922-928.
The role of neuropilin-1/semaphorin 3A signaling in lymphatic vessel development and maturation
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.

Collaboration

Group / person Country
Types of collaboration
Prof. Tatjana Petrova/University of Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Friedemann Kiefer/Max Planck Institute Münster Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Kari Alitalo, University of Helsinki Finland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Donald McDonald/UCSF United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Guillermo Oliver/St. Jude's Childrens' Hospital United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Jean-Christophe Leroux Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Lu Chen/University of California Berkeley United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Gordon Research Conference: Lymphatics Talk 20.03.2016 Ventura, CA, United States of America Detmar Michael;
Gordon Research Conference: Lymphatics Poster 19.03.2016 Ventura, CA, United States of America Seidel Catharina;
6th Cancer Network Zurich Retreat Poster 12.04.2015 Emmeten, Switzerland Seidel Catharina;
5th Cancer Biology Student Retreat Poster 12.02.2014 Filzbach, Switzerland Seidel Catharina;


Awards

Title Year
Michael Detmar was elected as a member of the German National Academy of Sciences Leopoldina. 2015
Poster prize, 5th Student Retreat, Cancer Biology PhD Program, Feb 2014 2014

Associated projects

Number Title Start Funding scheme
130627 Molecular mechanisms of angiogenesis and lymphangiogenesis in inflammation and cancer progression 01.05.2010 Project funding (Div. I-III)
166490 The role of lymphatic vessels in cancer progression 01.05.2016 Project funding (Div. I-III)

Abstract

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.
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