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  • 1
    Online Resource
    Online Resource
    Aggressive primary cutaneous B‐cell lymphomas show increased Angiopoietin‐2‐induced angiogenesis
    Wiley ; 2015
    In:  Experimental Dermatology Vol. 24, No. 6 ( 2015-06), p. 424-429
    Details
    In: Experimental Dermatology, Wiley, Vol. 24, No. 6 ( 2015-06), p. 424-429
    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 CD 20 and CD 31. 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/ CD 34 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.
    Type of Medium: Online Resource
    ISSN: 0906-6705 , 1600-0625
    URL: Issue
    URL: Article
    DOI: 10.1111/exd.2015.24.issue-6
    DOI: 10.1111/exd.12688
    RVK:
    XA 42446
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 2026228-0
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  • 2
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    Online Resource
    An Inducible Hepatocellular Carcinoma Model for Preclinical Evaluation of Antiangiogenic Therapy in Adult Mice
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 15 ( 2014-08-01), p. 4157-4169
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    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 15 ( 2014-08-01), p. 4157-4169
    Abstract: The limited availability of experimental tumor models that faithfully mimic the progression of human tumors and their response to therapy remains a major bottleneck to the clinical translation and application of novel therapeutic principles. To address this challenge in hepatocellular carcinoma (HCC), one of the deadliest and most common cancers in the world, we developed and validated an inducible model of hepatocarcinogenesis in adult mice. Tumorigenesis was triggered by intravenous adenoviral delivery of Cre recombinase in transgenic mice expressing the hepatocyte-specific albumin promoter, a loxP-flanked stop cassette, and the SV40 large T-antigen (iAST). Cre recombinase–mediated excision of the stop cassette led to a transient viral hepatitis and resulted in multinodular tumorigenesis within 5 to 8 weeks. Tumor nodules with histologic characteristics of human HCC established a functional vasculature by cooption, remodeling, and angiogenic expansion of the preexisting sinusoidal liver vasculature with increasing signs of vascular immaturity during tumor progression. Treatment of mice with sorafenib rapidly resulted in the induction of vascular regression, inhibition of tumor growth, and enhanced overall survival. Vascular regression was characterized by loss of endothelial cells leaving behind avascular type IV collagen–positive empty sleeves with remaining pericytes. Sorafenib treatment led to transcriptional changes of Igf1, Id1, and cMet over time, which may reflect the emergence of potential escape mechanisms. Taken together, our results established the iAST model of inducible hepatocarcinogenesis as a robust and versatile preclinical model to study HCC progression and validate novel therapies. Cancer Res; 74(15); 4157–69. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-13-2311
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
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    Online Resource
    Tumor Cell–Derived Angiopoietin-2 Promotes Metastasis in Melanoma
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 12 ( 2020-06-15), p. 2586-2598
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 12 ( 2020-06-15), p. 2586-2598
    Abstract: The angiopoietin (Angpt)–TIE signaling pathway controls vascular maturation and maintains the quiescent phenotype of resting vasculature. The contextual agonistic and antagonistic Tie2 ligand ANGPT2 is believed to be exclusively produced by endothelial cells, disrupting constitutive ANGPT1–TIE2 signaling to destabilize the microvasculature during pathologic disorders like inflammation and cancer. However, scattered reports have also portrayed tumor cells as a source of ANGPT2. Employing ISH-based detection of ANGPT2, we found strong tumor cell expression of ANGPT2 in a subset of patients with melanoma. Comparative analysis of biopsies revealed a higher fraction of ANGPT2-expressing tumor cells in metastatic versus primary sites. Tumor cell–expressed Angpt2 was dispensable for primary tumor growth, yet in-depth analysis of primary tumors revealed enhanced intratumoral necrosis upon silencing of tumor cell Angpt2 expression in the absence of significant immune and vascular alterations. Global transcriptional profiling of Angpt2-deficient tumor cells identified perturbations in redox homeostasis and an increased response to cellular oxidative stress. Ultrastructural analyses illustrated a significant increase of dysfunctional mitochondria in Angpt2-silenced tumor cells, thereby resulting in enhanced reactive oxygen species (ROS) production and downstream MAPK stress signaling. Functionally, enhanced ROS in Angpt2-silenced tumor cells reduced colonization potential in vitro and in vivo. Taken together, these findings uncover the hitherto unappreciated role of tumor cell–expressed ANGPT2 as an autocrine-positive regulator of metastatic colonization and validate ANGPT2 as a therapeutic target for a well-defined subset of patients with melanoma. Significance: This study reveals that tumor cells can be a source of ANGPT2 in the tumor microenvironment and that tumor cell-derived ANGPT2 augments metastatic colonization by protecting tumor cells from oxidative stress.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-19-2660
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
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    Online Resource
    Endothelial transdifferentiation in hepatocellular carcinoma: loss of Stabilin‐2 expression in peri‐tumourous liver correlates with increased survival
    Wiley ; 2013
    In:  Liver International Vol. 33, No. 9 ( 2013-10), p. 1428-1440
    Details
    In: Liver International, Wiley, Vol. 33, No. 9 ( 2013-10), p. 1428-1440
    Abstract: Hepatocellular carcinoma ( HCC ) is a malignant tumour that is characterized by extensive vascular remodelling and responsiveness to treatment with the anti‐angiogenic multikinase inhibitor sorafenib. The aim was to study endothelial remodelling in HCC . Methods The murine inducible albumin‐ SV 40‐large T‐antigen model and two tissue microarrays ( TMA ) with 295 tumourous and 83 peri‐tumourous samples of 296 patients with HCC were analysed for expression of liver sinusoidal endothelial cell ( LSEC )‐specific marker proteins, stabilin‐1 and stabilin‐2, LYVE ‐1 and CD 32b. Results LSEC marker proteins were sequentially lost during HCC progression in the murine HCC model being absent from tumour nodules larger than 800 μm in diameter. Similarly, the TMA analysis of human HCC s revealed loss of all four marker proteins in the majority of tumourous tissue samples. Preservation of LYVE ‐1 expression showed a significant correlation with low grading (G1). In corresponding peri‐tumourous liver tissue, loss of all marker proteins was seen in a minor proportion of cases (34%) while the majority of cases retained expression of at least one of the marker proteins. Loss of stabilin‐2 expression in peri‐tumourous liver tissue of patients with HCC was significantly less likely to occur (38%) than loss of the other marker proteins (63–95%) and it was associated with significantly longer tumour‐specific ( P  = 0.0523) and overall ( P  = 0.0338) survival. Loss of stabilin‐2 may enhance survival in HCC by preventing endothelial‐tumour cell adhesive interactions and microvascular invasion. Conclusions In summary, endothelial transdifferentiation is a major pathogenic event in HCC development indicating a switch from vessel co‐option/intussusceptive angiogenesis to sprouting angiogenesis.
    Type of Medium: Online Resource
    ISSN: 1478-3223 , 1478-3231
    URL: Issue
    URL: Article
    DOI: 10.1111/liv.2013.33.issue-9
    DOI: 10.1111/liv.12262
    Language: English
    Publisher: Wiley
    Publication Date: 2013
    detail.hit.zdb_id: 2124684-1
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