angiogenesis; lymphangiogenesis; inflammation; cancer metastasis; VEGF; Cancer; Metastasis
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.
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.
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.
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.
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.
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.
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.
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
Proulx ST, Detmar M (2013), Molecular mechanisms and imaging of lymphatic metastasis, in Experimental Cell Research
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.
Mumprecht V, Roudnicky F, Detmar M (2012), Inflammation-Induced Lymph Node Lymphangiogenesis Is Reversible, in AMERICAN JOURNAL OF PATHOLOGY
, 180(3), 874-879.
Christiansen A, Detmar M (2011), Lymphangiogenesis and Cancer, in Genes and Cancer
, 2(12), 1146-1158.
Huggenberger R, Detmar M (2011), The cutaneous vascular system in chronic skin inflammation, in Journal of Investigative Dermatology Symposium Proceedings
, 15(1), 24-32.
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.
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.
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
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
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
Alitalo A, Detmar M, Interaction of tumor cells and lymphatic vessels in cancer progression., in Oncogene
Chen Y, Liersch R, Detmar M, The miR-290-295 cluster suppresses autophagic cell death of melanoma cells, in Scientific Reports
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.