Showing papers by "Michael Detmar published in 2006"
TL;DR: Scientific advances have provided surprising evidence that malignant tumors can directly promote lymphangiogenesis and lymphatic metastasis, and that lymphatic vessels play a major role in cutaneous inflammation and in the cutaneous response to UVB irradiation.
239 citations
TL;DR: Tumor lymphangiogenesis actively contributes to cancer dissemination, that blockade of lymphatic vessel growth might inhibit tumor metastasis to LN, and that the extent of tumor‐associated lymphang iogenesis could serve as a novel, prognostic parameter for the metastatic risk of human cancers are suggested.
Abstract: The extent of lymph node (LN) metastasis is a major determinant for the staging and the prognosis of most human malignancies and often guides therapeutic decisions. Although the clinical significance of LN involvement is well documented, little has been known about the molecular mechanisms that promote tumor spread via lymphatic vessels to sentinel and distal LN and beyond. However, recent discoveries have identified novel lymphatic-specific markers, and the newly discovered lymphangiogenesis factors vascular endothelial growth factor-C (VEGF-C) and VEGF-D were found to promote tumor-associated lymphatic vessel growth in mouse tumor models, leading to enhanced tumor spread to sentinel LN. Our recent findings indicate that VEGF-A also acts as a potent tumor lymphangiogenesis factor that promotes lymphatic tumor spread. VEGF-A overexpressing primary tumors induced sentinel LN lymphangiogenesis even before metastasizing and maintained their lymphangiogenic activity after metastasis to draining LN. Our recent studies showed that primary human melanomas that later metastasized were characterized by increased lymphangiogenesis and that the degree of tumor lymphangiogenesis can serve as a novel predictor of LN metastasis and overall patient survival, independently of tumor thickness. Tumor lymphangiogenesis also significantly predicted the presence of sentinel LN metastases at the time of surgical excision of the primary melanoma. Together, these findings suggest that tumor lymphangiogenesis actively contributes to cancer dissemination, that blockade of lymphatic vessel growth might inhibit tumor metastasis to LN, and that the extent of tumor-associated lymphangiogenesis could serve as a novel, prognostic parameter for the metastatic risk of human cancers.
213 citations
TL;DR: The Vascular endothelial growth factor-C (VEGF-C) and VEGF-D were the first specific lymphangiogenesis factors identified, acting predominantly via VEG receptor-3 (VEGFR-3) that is expressed by lymphatic endothelial cells as mentioned in this paper.
Abstract: Tumor metastasis to sentinel lymph nodes represents the first step of tumor dissemination in most human cancers and serves as a major prognostic indicator for disease progression. Recent studies have revealed that tumors can actively induce the formation of lymphatic vessels, and that tumor lymphangiogenesis is correlated with lymph node metastasis in experimental cancer models and in several types of human cancers. Metastatic tumor cells may continue to promote lymphatic vessel growth even after their metastasis to sentinel lymph nodes, likely promoting further cancer spread. Vascular endothelial growth factor-C (VEGF-C) and VEGF-D were the first specific lymphangiogenesis factors identified, acting predominantly via VEGF receptor-3 (VEGFR-3) that is expressed by lymphatic endothelial cells, and a large number of clinical studies have shown a correlation between tumor expression of VEGF-C or VEGF-D and lymph node metastasis. VEGFR-3 activation promotes lymphatic endothelial cell proliferation, migration, and survival via the extracellular signal-regulated kinase 1/2, the phosphatidylinositol 3-kinase/AKT, and the c-Jun NH 2 -terminal kinase 1/2 pathways. Additional tumor lymphangiogenesis factors have been recently identified, including VEGF-A. Importantly, blockade of the VEGFR-3 pathway by specific antibodies, by soluble receptor constructs, and by small molecule kinase inhibitors efficiently inhibits experimental tumor lymphangiogenesis and metastasis and might also represent a novel therapeutic avenue for the treatment of human cancers.
131 citations
TL;DR: It is reported that peripheral blood mononuclear cells (PBMCs) and epidermal keratinocytes (KC) from patients with psoriasis demonstrate differential, genotype-dependent, regulation of VEGF.
113 citations
TL;DR: These findings identify lymphatic vessels as novel targets for UVB-induced cutaneous photodamage and suggest that VEGF-A mediates impairment of lymphatic vessel function, thereby contributing to the adverse effects of UVB irradiation on the skin.
Abstract: UVB irradiation of the skin induces erythema, epidermal hyperplasia, vascular hyperpermeability, and edema formation. Previous studies have revealed that the cutaneous blood vasculature plays a critical role in the mediation of photodamage. In contrast, the role of lymphatic vessels, which play an essential role in the maintenance of tissue fluid balance, in the response to UVB irradiation has remained unknown. We report here that both acute and chronic UVB irradiation of murine skin results in prominent enlargement of lymphatic vessels. Surprisingly, these enlarged lymphatic vessels were functionally impaired and hyperpermeable, as detected by intravital lymphangiography. The expression levels of vascular endothelial growth factor (VEGF)-A but not of the known lymphangiogenesis factors VEGF-C or VEGF-D, were enhanced in UVB-irradiated epidermis. Targeted overexpression of VEGF-A in the epidermis of transgenic mice led to increased enlargement and leakage of lymphatic vessels after acute UVB irradiation, whereas systemic blockade of VEGF-A signaling largely prevented lymphatic vessel abnormalities and photodamage induced by UVB. Together, these findings identify lymphatic vessels as novel targets for UVB-induced cutaneous photodamage and suggest that VEGF-A mediates impairment of lymphatic vessel function, thereby contributing to the adverse effects of UVB irradiation on the skin.
100 citations
75 citations
TL;DR: The results reveal, for the first time, that ES cells can differentiate into lymphatic endothelial cells, and they identify the EB assay as a powerful new tool to dissect the molecular mechanisms that control lymphatic vessel formation.
64 citations
Johns Hopkins University1, New York University2, Georgia Regents University3, Katholieke Universiteit Leuven4, Temple University5, Harvard University6, University of New Mexico7, University of Vienna8, ETH Zurich9, Genentech10, Wayne State University11, University College London12, University of Florida13, Heidelberg University14, University of Southern California15, Hebrew University of Jerusalem16, University of Michigan17, Cincinnati Children's Hospital Medical Center18, University of California, San Francisco19, Technion – Israel Institute of Technology20, University of Wisconsin-Madison21, University of Texas Southwestern Medical Center22, Northwestern University23, University of Würzburg24, Regeneron25
TL;DR: The First ARVO/Pfizer Ophthalmics Institute meeting was held Friday and Saturday, April 29 and 30, 2005, in Fort Lauderdale, Florida, in conjunction with the 2005 ARVO Annual Meeting.
Abstract: The First ARVO/Pfizer Ophthalmics Institute meeting was held Friday and Saturday, April 29 and 30, 2005, in Fort Lauderdale, Florida, in conjunction with the 2005 ARVO Annual Meeting. The Institute meeting was funded by The ARVO Foundation for Eye Research through a grant from Pfizer Ophthalmics. The goal of the Institute is to develop strategies to improve research and clinical care in areas of ophthalmology related to preventable vision loss and blindness. The specific topic and organizer were selected by an independent selection committee which reviewed proposals received through an open call for proposals related to angiogenesis, neovascularization, and vasoproliferation. The proposal organizer solicited an international, interdisciplinary panel of expert speakers that comprised the First ARVO/Pfizer Ophthalmics Institute Working Group. One outcome of the Institute is publication of the research presented and discussions that followed to share possible new opportunities for research with the vision community and its partners in other disciplines.
46 citations
TL;DR: This issue of Immunity is provided the first evidence that remodeling of the lymphatic network within LNs and in peripheral tissues enhances DC migration after immunization and that this process depends on the presence of B cells within the LN.
26 citations
Patent•
30 Mar 2006
TL;DR: In this article, methods and compositions for the modulation of hepatocyte growth factor activity to regulate lymphatic vessel development and function are provided. And methods and composition for the monitoring and treatment of skin disorders, lymphedema, and metastatic cancers are disclosed.
Abstract: Provided are methods and compositions for the modulation of hepatocyte growth factor activity to regulate lymphatic vessel development and function. Methods and composition for the monitoring and treatment of skin disorders, lymphedema, and metastatic cancers are disclosed. Also described are methods of identifying inhibitors of hepatocyte growth factor dependent lymphangiogenesis.
13 citations
01 Jan 2006
TL;DR: The Vascular endothelial growth factor-C (VEGF-C) and VEGF-D were the first specific lymphangiogenesis factors identified, acting predominantly via VEG- receptor-3 (VEGFR-3) that is expressed by lymphatic endothelial cells, and a large number of clinical studies have shown a correlation between tumor expression of VEGFs and lymph node metastasis.
Abstract: Tumor metastasis to sentinel lymph nodes represents the first step of tumor dissemination in most human cancers and serves as a major prognostic indicator for disease progression. Recent studies have revealed that tumors can actively induce the formation of lymphatic ves- sels, and that tumor lymphangiogenesis is correlated with lymph node metastasis in experi- mental cancer models and in several types of human cancers. Metastatic tumor cells may continue to promote lymphatic vessel growth even after their metastasis to sentinel lymph nodes, likely promoting further cancer spread. Vascular endothelial growth factor-C (VEGF-C) and VEGF-D were the first specific lymphangiogenesis factors identified, acting predominantly via VEGF receptor-3 (VEGFR-3) that is expressed by lymphatic endothelial cells, and a large number of clinical studies have shown a correlation between tumor expression of VEGF-C or VEGF-D and lymph node metastasis. VEGFR-3 activation promotes lymphatic endothelial cell proliferation, migration, and survival via the extracellular signal-regulated kinase 1/2, the phos- phatidylinositol 3-kinase/AKT, and the c-Jun NH2-terminal kinase 1/2 pathways. Additional tumor lymphangiogenesis factors have been recently identified, including VEGF-A. Importantly, blockade of the VEGFR-3 pathway by specific antibodies, by soluble receptor constructs, and by small molecule kinase inhibitors efficiently inhibits experimental tumor lymphangiogenesis and metastasis and might also represent a novel therapeutic avenue for the treatment of human cancers.
Patent•
30 Mar 2006
Patent•
30 Mar 2006
TL;DR: In this paper, methods and compositions for the modulation of hepatocyte growth factor activity to regulate lymphatic vessel development and function are provided. And methods for identifying inhibitors of growth factor dependent lymphangiogenesis are also described.
Abstract: Provided are methods and compositions for the modulation of hepatocyte growth factor activity to regulate lymphatic vessel development and function. Methods and composition for the monitoring and treatment of skin disorders, lymphedema, and metastatic cancers are disclosed. Also described are methods for identifying inhibitors of hepatocyte growth factor dependent lymphangiogenesis.
Patent•
30 Mar 2006
TL;DR: In this article, a procedure for the identification and identification of inhibitors of the facteur de croissance of the cellule hepatique dependant on the lymphangiogenese is presented.
Abstract: L'invention concerne des procedes et des compositions de modulation de l'activite du facteur de croissance de la cellule hepatique permettant de reguler le developpement et le fonctionnement des vaisseaux lymphatiques. L'invention concerne egalement des procedes et une composition destines a la surveillance et au traitement de troubles cutanes, de lymphoedemes et de cancers metastatiques. L'invention concerne enfin des procedes d'identification d'inhibiteurs du facteur de croissance de la cellule hepatique dependant de la lymphangiogenese.