title: Aggressive primary cutaneous B-cell lymphomas show increased Angiopoietin-2-induced angiogenesis.
abstract: Primary cutaneous large B-cell lymphomas, leg type (PCLBCL/LT) are primary cutaneous B-cell lymphoma (PCBCL) with an intermediate prognosis. Therefore, antracycline-based polychemotherapy combined with rituximab has been recommended as first-line treatment. Yet, despite this regimen, the 5-year survival rate remains 50-66% only. Angiogenesis, the formation of a vascular network, is essential for the pathogenesis of nodal lymphomas. So far, no study has analysed angiogenesis and its key factors in PCLBCL/LT. The present study was aimed at characterizing angiogenesis in PCLBCL/LT to identify the angiogenic molecules as potential therapeutic targets. The intra-tumoral microvessel density (MVD) was assessed by immunohistochemical studies of CD20 and CD31. The MVD was higher in PCLBCL/LT compared with indolent PCBCL. Analyses of open-source microarray data showed correlation between the angiogenic molecule angiopoietin-2 (Ang-2) and pan-endothelial cell markers. ELISA studies determined a shift between Ang-2 and Ang-1 towards Ang-2 in the peripheral blood of PCLBCL/LT patients. Immunofluorescence costainings against the Ang receptor Tie2/angiogenic integrins/CD34 revealed that the vasculature in both aggressive and indolent PCBCL tumors harbours an endothelial cell subpopulation with reduced expression of Tie2. In contrast, the alternative Ang-2 binding partners, angiogenic integrins, are strongly expressed in PCBCL. In line with these findings, downstream targets of Ang-2-integrin signalling, that is phosphorylation of focal adhesion kinase at Tyr397, and sprouting angiogenesis are enhanced in PCLBCL/LT. Our data present Ang-2 as a promising therapeutic target and anti-angiogenic therapy as a new line in treatment of PCLBCL/LT as a hitherto intractable disease.
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Centre Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Teichert
authors.affiliation: Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Centre of Excellence of Dermatology of Baden-Württemberg, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Stumpf
authors.affiliation: Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Centre of Excellence of Dermatology of Baden-Württemberg, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Booken
authors.affiliation: Department of Dermatology, Venereology and Allergy, Julius-Maximilians-University, Würzburg, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Wobser
authors.affiliation: Department of Dermatology, Hospital of Dortmund, Dortmund, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Nashan
authors.affiliation: Department of Dermatology, Fachklinik Hornheide, Münster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hallermann
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Centre Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.|Institute of Pathology, Ruprecht-Karls-University of Heidelberg, Heidelberg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Mogler
authors.affiliation: Department of Dermatology, Venereology and Allergy, Saarland University Hospital, Homburg/Saar, Germany.
authors.forename: Cornelia S L
authors.initials: CS
authors.lastname: Müller
authors.affiliation: Translational Skin Cancer Research, Deutsches Konsortium für Translationale Krebsforschung (DKTK), University Hospital Essen.
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Becker
authors.affiliation: Department of Dermatology, Venereology and Allergy, University of Bochum, Bochum, Germany.
authors.forename: Rose K C
authors.initials: RK
authors.lastname: Moritz
authors.affiliation: Institute of Pathology, Ruprecht-Karls-University of Heidelberg, Heidelberg, Germany.
authors.forename: Mindaugas
authors.initials: M
authors.lastname: Andrulis
authors.affiliation: Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Centre of Excellence of Dermatology of Baden-Württemberg, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Nicolay
authors.affiliation: Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Centre of Excellence of Dermatology of Baden-Württemberg, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.
authors.forename: Sergij
authors.initials: S
authors.lastname: Goerdt
authors.affiliation: Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Centre of Excellence of Dermatology of Baden-Württemberg, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.
authors.forename: Claus-Detlev
authors.initials: CD
authors.lastname: Klemke
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Centre Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.|Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Centre Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.|Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Centre of Excellence of Dermatology of Baden-Württemberg, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Felcht
mesh_terms: D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D006801:Humans; D016023:Integrins / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D055806:Microvessels / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D012878:Skin Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism*
chemical_list: C586513:ANGPT2 protein, human; D042702:Angiopoietin-2; D016023:Integrins; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: Tie2; angiogenesis; angiopoietin; endothelial cell; primary cutaneous B-cell lymphoma; primary cutaneous large B-cell lymphoma, leg type