Teichert Martin, Stumpf Christine, Booken Nina, Wobser Marion, Nashan Dorothee, Hallermann Christian, Mogler Carolin, Müller Cornelia S L, Becker Jürgen C, Moritz Rose K C, Andrulis Mindaugas, Nicolay Jan P, Goerdt Sergij, Thomas Markus, Klemke Claus-Detlev, Augustin Hellmut G, Felcht Moritz
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.
Exp Dermatol. 2015 Jun;24(6):424-9. doi: 10.1111/exd.12688. Epub 2015 Apr 16.
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.
原发性皮肤大B细胞淋巴瘤,腿部型(PCLBCL/LT)是预后中等的原发性皮肤B细胞淋巴瘤(PCBCL)。因此,基于蒽环类药物的多药化疗联合利妥昔单抗已被推荐作为一线治疗方案。然而,尽管采用了这种方案,5年生存率仍仅为50%-66%。血管生成,即血管网络的形成,对于淋巴结淋巴瘤的发病机制至关重要。到目前为止,尚无研究分析PCLBCL/LT中的血管生成及其关键因素。本研究旨在对PCLBCL/LT中的血管生成进行特征描述,以确定血管生成分子作为潜在的治疗靶点。通过对CD20和CD31进行免疫组化研究来评估肿瘤内微血管密度(MVD)。与惰性PCBCL相比,PCLBCL/LT中的MVD更高。对开源微阵列数据的分析显示血管生成分子血管生成素-2(Ang-2)与泛内皮细胞标志物之间存在相关性。酶联免疫吸附测定(ELISA)研究确定了PCLBCL/LT患者外周血中Ang-2和Ang-1之间向Ang-2的转变。针对Ang受体Tie2/血管生成整合素/CD34的免疫荧光共染色显示,侵袭性和惰性PCBCL肿瘤中的脉管系统都含有Tie2表达降低的内皮细胞亚群。相比之下,Ang-2的替代结合伙伴血管生成整合素在PCBCL中强烈表达。与这些发现一致,Ang-2-整合素信号的下游靶点,即粘着斑激酶在Tyr397处的磷酸化以及发芽血管生成在PCLBCL/LT中增强。我们的数据表明Ang-2是一个有前景的治疗靶点,抗血管生成治疗作为治疗PCLBCL/LT这种迄今难以治疗疾病的新方法。