Working Group

Angiogenesis

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Group Leader:
PD Dr. med. Thomas Hawighorst

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Functional analysis of the lymphatic system in normal and diseased tissue

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Although the lymphatic vasculature plays important roles in the metastatic spread of malignant tumors, studies of the lymphatic system have been hindered by the lack of specific lymphatic markers and growth factors. The recently identified hyaluronan (HA) receptor LYVE-1 is largely restricted to lymphatic endothelial cells. Since HA is a key mediator of tumor cell migration, we wish to analyze the role of LYVE-1 in tumor progression and metastasis. To this end we will perform mouse xenotransplantation studies using MDA-MB-435 breast cancer cells transfected to overexpress soluble LYVE-1 proteins. Beside the knowledge of the structural components of the lymphatic vessels, we are also pursuing to establishing a genetic mouse model overexpressing hrGFP under the control of the LYVE-1 promoter. In addition to the characterization of a specific lymphatic vessel promoter, this mouse model will enable us to create tissue specific transgenic as well as (Cre-lox) knockout mice. These tools will without any doubt lead to further exciting and relevant research in the field of cancer metastasis.

Funding:

• Deutsche Forschungsgemeinschaft HA 2898/2-1 (SPP 1069 "Angiogenesis")

• Deutsche Forschungsgemeinschaft HA 2898/4-1

• Deutsche Forschungsgemeinschaft HA 2898/4-2

Publications:

• Streit M, Riccardi L, Velasco P, Brown LF, Hawighorst T, Bornstein P, Detmar M. Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis. Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14888-93

• Streit M, Velasco P, Riccardi L, Spencer L, Brown LF, Janes L, Lange-Asschenfeldt B, Yano K, Hawighorst T, Iruela-Arispe L, Detmar M. Thrombospondin-1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice. EMBO J. 2000 Jul 3;19(13):3272-82.

• Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med. 2001 Feb;7(2):192-8.

• Hawighorst T, Velasco P, Streit M, Hong YK, Kyriakides TR, Brown LF, Bornstein P, Detmar M. Thrombospondin-2 plays a protective role in multistep carcinogenesis: a novel host anti-tumor defense mechanism. EMBO J. 2001 Jun 1;20(11):2631-40.

• Skobe M, Hamberg LM, Hawighorst T, Schirner M, Wolf GL, Alitalo K, Detmar M. Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am J Pathol. 2001 Sep;159(3):893-903.

• Lange-Asschenfeldt B, Velasco P, Streit M, Hawighorst T, Pike SE, Tosato G, Detmar M. The angiogenesis inhibitor vasostatin does not impair wound healing at tumor-inhibiting doses. J Invest Dermatol. 2001 Nov;117(5):1036-41.

• Streit M, Stephen AE, Hawighorst T, Matsuda K, Lange-Asschenfeldt B, Brown LF, Vacanti JP, Detmar M. Systemic inhibition of tumor growth and angiogenesis by thrombospondin-2 using cell-based antiangiogenic gene therapy. Cancer Res. 2002 Apr 1;62(7):2004-12.

• Hawighorst T, Skobe M, Streit M, Hong YK, Velasco P, Brown LF, Riccardi L, Lange-Asschenfeldt B, Detmar M. Activation of the tie2 receptor by angiopoietin-1 enhances tumor vessel maturation and impairs squamous cell carcinoma growth. Am J Pathol. 2002 Apr;160(4):1381-92

• Hawighorst T, Oura H, Streit M, Janes L, Nguyen L, Brown LF, Oliver G, Jackson DG, Detmar M. Thrombospondin-1 selectively inhibits early-stage carcinogenesis and angiogenesis but not tumor lymphangiogenesis and lymphatic metastasis in transgenic mice. Oncogene. 2002 Nov 14;21(52):7945-56.

• Hawighorst T. Angiogenese, Lymphangiogenese und Tumorprogression. Zentralbl Gynakol. 2002 Nov;124(11):497-505

• Yee KO, Streit M, Hawighorst T, Detmar M, Lawler J. Expression of the type-1 repeats of thrombospondin-1 inhibits tumor growth through activation of transforming growth factor-beta. Am J Pathol. 2004 Aug;165(2):541-52.

• Wilting J, Hawighorst T, Hecht M, Christ B, Papoutsi M (2005) Development of lymphatic vessels: tumour lymphangiogenesis and lymphatic invasion. Curr Med Chem. 2005;12(26):3043-53.

• Hawighorst T, Hussein F, Stein W, Gründker C, Emons G (2008) Anti-Angiogenese: Von der präklinischen Forschung zur klinischen Anwendung. Geburtshilfe und Frauenheilkunde 68(4):397-403

• Hawighorst T, Stein W, Gründker C, Emons G (2010) Angiogenese in Reproduktionsmedizin und gynäkologischer Onkologie. Der Gynäkologe 43:595-60

• Koch M, Hussein F, Woeste A, Gründker C, Frontzek K, Emons G, Hawighorst T (2011) CD36 mediated activation of endothelial cell apoptosis by an N-terminal recombinant fragment of thrombospondin-2 inhibits breast cancer growth and metastasis in vivo. Breast Cancer Research and Treatment 128(2):337-346