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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 130627
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 01.05.2010 - 30.04.2013
Approved amount 755'000.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Pharmacology, Pharmacy

Keywords (7)

angiogenesis; lymphangiogenesis; inflammation; cancer metastasis; VEGF; Cancer; Metastasis

Lay Summary (English)

Lead
Lay summary
Our previous studies have identified vascular endothelial growth factor-A (VEGF-A) as a molecule of central importance for normal, inflammation-associated and cancer-associated blood vessel formation (angiogenesis) in the skin. We also found that VEGF-A may induce lymphatic vessel growth (lymphangiogenesis). Importantly, increased production of VEGF-A in the skin leads to chronic inflammatory skin lesions that resemble the human skin disease psoriasis. We have also identified a critical role of VEGF-C (acting through its receptor VEGFR3) in the induction of tumor lymphangiogenesis and lymph node metastasis.We now propose experiments to test our specific hypotheses: (1) that VEGF-A induces and maintains skin inflammation through specific receptor interactions and mediators that might serve as new therapeutic targets, whereas VEGF-C-mediated lymphatic activation might inhibit inflammation, (2) that VEGFR3, in addition to its role in promoting lymphangiogenesis and lymph node metastasis, also promotes primary cancer growth, angiogenesis and organ metastasis, and (3) that cancer-activated lymphatic vessels in primary tumors and in tumor-draining lymph nodes show activation of specific genes that are different from those genes that are activated in inflammation. These genes and their products might serve as novel tools for detection of cancer metastasis in patients. Understanding the mechanisms of lymphatic vessel and blood vessel activation will be the basis for developing novel therapeutic strategies to treat inflammatory diseases and cancer.Therefore, we will pursue the following experimental approach:Aim 1: Define the importance of VEGF-A versus VEGF-C for skin inflammation.Aim 2: Define the role of VEGF receptor-3 activation in skin tumor growth, angiogenesis, lymphangiogenesis and lymph node versus organ metastasis.Aim 3: Identify the molecular mechanisms that are responsible for tumor-induced lymphangiogenesis and lymph node lymphangiogenesis, as compared to inflammation-induced lymphangiogenesis, using isolation of specific cell types from cancers and from inflamed tissues, followed by determination of their gene activities.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Dynamics of lymphatic regeneration and flow patterns after lymph node dissection
Blum KS, Proulx ST, Luciani P, Leroux J-C, Detmar M (2013), Dynamics of lymphatic regeneration and flow patterns after lymph node dissection, in Breast Cancer Research and Treatment, 139(1), 81-86.
Endocan is upregulated on tumor vessels in invasive bladder cancer where it mediates VEGF-A-induced angiogenesis
Roudnicky F, Poyet C, Wild P, Krampitz S, Negrini F, Huggenberger R, Rogler A, Stöhr R, Hartmann A, Provenzano M, Otto VI, Detmar M (2013), Endocan is upregulated on tumor vessels in invasive bladder cancer where it mediates VEGF-A-induced angiogenesis, in Cancer Research, 73(3), 1097-1106.
An important role of blood and lymphatic vessels in inflammation and allergy.
Zgraggen Silvana, Ochsenbein Alexandra M, Detmar Michael (2013), An important role of blood and lymphatic vessels in inflammation and allergy., in Journal of allergy, 2013, 672381-672381.
Blockade of VEGF receptor-3 aggravates inflammatory bowel disease and lymphatic vessel enlargement.
Jurisic G, Sundberg JP, Detmar M (2013), Blockade of VEGF receptor-3 aggravates inflammatory bowel disease and lymphatic vessel enlargement., in Inflamm Bowel Dis, 19, 1983-1989.
VEGF-C and VEGF-D blockade inhibits inflammatory skin carcinogenesis
Alitalo A, Proulx S, Karaman S, Aebischer D, Martino S, Jost S, Schneider M, Bry M, Detmar M (2013), VEGF-C and VEGF-D blockade inhibits inflammatory skin carcinogenesis, in Cancer Research, 73, 4212-4221.
Non-invasive dynamic near-infrared imaging and quantification of vascular leakage in vivo
Proulx ST, Luciani P, Alitalo A, Mumprecht V, Christiansen AJ, Huggenberger R, Leroux J-C, Detmar M (2013), Non-invasive dynamic near-infrared imaging and quantification of vascular leakage in vivo, in Angiogenesis, 16, 525-540.
Use of a PEG-conjugated bright near-infrared dye for functional imaging of rerouting of tumor lymphatic drainage after sentinel lymph node metastasis.
Proulx SP, Luciani P, Christiansen A, Karaman S, Blum KS, Rinderknecht M, Leroux JC, Detmar M (2013), Use of a PEG-conjugated bright near-infrared dye for functional imaging of rerouting of tumor lymphatic drainage after sentinel lymph node metastasis., in Biomaterials, 34, 5128-5137.
Activation of the epidermal growth factor receptor promotes lymphangiogenesis in the skin.
Marino D, Angehrn Y, Klein S, Riccardi S, Baenziger-Tobler N, Otto VI, Pittelkow M, Detmar M (2013), Activation of the epidermal growth factor receptor promotes lymphangiogenesis in the skin., in Journal of Dermatological Sciences, 144-148.
Molecular mechanisms and imaging of lymphatic metastasis
Proulx ST, Detmar M (2013), Molecular mechanisms and imaging of lymphatic metastasis, in Experimental Cell Research, 117.
Phenotype-based high-content chemical library screening identifies statins as inhibitors of in vivo lymphangiogenesis
Schulz MMP, Reisen F, Zgraggen S, Fischer S, Yuen D, Kang GJ, Chen L, Schneider G, Detmar M (2012), Phenotype-based high-content chemical library screening identifies statins as inhibitors of in vivo lymphangiogenesis, in Proceedings of the National Academy of Sciences of the United States of America, 109(40), E2665-E2674.
Inflammation-Induced Lymph Node Lymphangiogenesis Is Reversible
Mumprecht V, Roudnicky F, Detmar M (2012), Inflammation-Induced Lymph Node Lymphangiogenesis Is Reversible, in AMERICAN JOURNAL OF PATHOLOGY, 180(3), 874-879.
Lymphangiogenesis and Cancer
Christiansen A, Detmar M (2011), Lymphangiogenesis and Cancer, in Genes and Cancer, 2(12), 1146-1158.
The cutaneous vascular system in chronic skin inflammation
Huggenberger R, Detmar M (2011), The cutaneous vascular system in chronic skin inflammation, in Journal of Investigative Dermatology Symposium Proceedings, 15(1), 24-32.
An important role of lymphatic vessel activation in limiting acute inflammation
Huggenberger R, Siddiqui SS, Brander D, Ullmann S, Zimmermann K, Antsiferova M, Werner S, Alitalo K, Detmar M (2011), An important role of lymphatic vessel activation in limiting acute inflammation, in BLOOD, 117(17), 4667-4678.
In vivo Imaging of Inflammation- and Tumor-Induced Lymph Node Lymphangiogenesis by Immuno-Positron Emission Tomography
Mumprecht V, Honer M, Vigl B, Proulx ST, Trachsel E, Kaspar M, Banziger-Tobler NE, Schibli R, Neri D, Detmar M (2010), In vivo Imaging of Inflammation- and Tumor-Induced Lymph Node Lymphangiogenesis by Immuno-Positron Emission Tomography, in CANCER RESEARCH, 70(21), 8842-8851.
An unexpected role of semaphorin3A/neuropilin-1 signaling in lymphatic vessel maturation and valve formation
Jurisic G, Maby-El Hajjami H, Karaman S, Ochsenbein AM, Alitalo A, Siddiqui SS, Ochoa Pereira C, Petrova T, Detmar M, An unexpected role of semaphorin3A/neuropilin-1 signaling in lymphatic vessel maturation and valve formation, in Circulation Research.
Expansion of the lymphatic vasculature in cancer and inflammation: New opportunities for in vivo imaging and drug delivery
Proulx ST, Luciani P, Dieterich LC, Karaman S, Leroux J-C, Detmar M, Expansion of the lymphatic vasculature in cancer and inflammation: New opportunities for in vivo imaging and drug delivery, in Journal of Controlled Release.
Genetic ablation of SOX18 function suppresses tumor lymphangiogenesis and metastasis of melanoma in mice.
Duong Tam, Proulx Steven T, Luciani Paola, Leroux Jean-Christophe, Detmar Michael, Koopman Peter, Francois Mathias, Genetic ablation of SOX18 function suppresses tumor lymphangiogenesis and metastasis of melanoma in mice., in CANCER RESEARCH.
Interaction of tumor cells and lymphatic vessels in cancer progression.
Alitalo A, Detmar M, Interaction of tumor cells and lymphatic vessels in cancer progression., in Oncogene.
The miR-290-295 cluster suppresses autophagic cell death of melanoma cells
Chen Y, Liersch R, Detmar M, The miR-290-295 cluster suppresses autophagic cell death of melanoma cells, in Scientific Reports, 2.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
AACR Annual Meeting 01.03.2012 Chicago, USA
Gordon Research Conference: Angiogenesis 21.08.2011 Newport RI, USA
SID Annual Meeting 04.05.2011 Phoenix AZ, USA


Self-organised

Title Date Place
EC8 Symposium Zurich 2011 15.06.2011 Zürich

Knowledge transfer events



Self-organised

Title Date Place

Associated projects

Number Title Start Funding scheme
147087 Molecular mechanisms of angiogenesis and lymphangiogenesis in inflammation and cancer progression 01.05.2013 Project funding (Div. I-III)
108207 The function of podoplanin in tumor progression and lymphangiogenesis 01.05.2005 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 may also induce lymphatic vessel growth. After induction of delayed-type hypersensitivity reactions or tape stripping, VEGF-A overexpressing transgenic mice develop chronic inflammatory skin lesions that histologically resemble human psoriasis. We have also identified a critical role of VEGF-C in the induction of tumor lymphangiogenesis, lymph node lymphangiogenesis and lymph node metastasis. We now propose experiments to test our specific hypotheses: (1) that VEGF-A induces and maintains skin inflammation through specific receptor interactions and downstream effectors that might serve as new therapeutic targets, whereas VEGF-C-mediated lymphatic activation might inhibit inflammation, (2) that VEGFR3, in addition to its role in promoting lymphangiogenesis and lymph node metastasis, also enhances primary tumor growth, angiogenesis and organ metastasis, and (3) that tumor-activated lymphatic vessels in primary tumors and in tumor-draining lymph nodes upregulate specific genes that are distinct from those upregulated in inflammation-activated lymphatic vessels and thus might serve as novel biomarkers for in vivo imaging of cancer progression. Understanding the mechanisms of lymphatic and blood vessel activation will be the basis for developing novel therapeutic strategies to treat inflammation and cancer.Aim 1: Define the importance of VEGF-A versus VEGF-C for cutaneous inflammation.1.1. Characterize the provoked, psoriasis-like skin inflammation in VEGF-A transgenic mice.1.2. Determine the anti-inflammatory activity of blockade of VEGF-A-induced downstream signaling using antibodies against all of the known VEGF receptors.1.3. Determine if transgenic expression of VEGF-C inhibits inflammation in VEGF-A transgenic mice.1.4. Identify VEGF-A and VEGF-C target genes involved in skin inflammation in vivo.Aim 2: Define the role of VEGF receptor-3 activation in cutaneous tumor growth, angiogenesis, lymphangiogenesis and lymphatic versus organ metastasis in transgenic and mutant mice. 2.1. Determine the impact of neutralization of the VEGFR3 ligands VEGF-C and VEGF-D, and of genetic inactivation of VEGFR3 signal transduction, on tumor progression, angiogenesis, lymphangiogenesis and lymphatic versus organ metastasis of squamous cell carcinomas chemically induced in transgenic mice with epidermis-targeted expression of a soluble VEGFR3-Fc protein and in Chy mice with inactivating mutations of VEGFR3. Aim 3: Identify the molecular mechanisms that mediate tumor-induced lymphangiogenesis and lymph node lymphangiogenesis, as compared to inflammation-induced lymphangiogenesis, using high-speed cell sorting and transcriptional profiling.3.1. Identify the global transcriptional changes induced in lymphatic vessels of primary melanomas and of lymph nodes draining melanoma cells implanted into the foot pad of mice, as compared with lymphatic vessel changes induced by chronic skin inflammation. 3.2. Determine the in situ expression and the in vitro and in vivo functions of identified candidate genes, using in situ hybridization, loss-of-function and gain-of-function approaches in cultured lymphatic endothelial cells and in melanoma cells.
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