187 results on '"Verrijp, K."'
Search Results
2. Pseudobudding: ruptured glands do not represent true tumor buds.
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Haddad, T.S., Dobbelsteen, L. van den, Ozturk, Sonay Kus, Geene, R., Nijman, I.J., Verrijp, K., Jamieson, N.B., Wood, C., Lent-van Vliet, S. van, Reuvers, Luuk, Achouiti, Soumia, Rutgers, N., Brouwer, N.P.M., Simmer, F., Zlobec, I., Lugli, A., Nagtegaal, I.D., Haddad, T.S., Dobbelsteen, L. van den, Ozturk, Sonay Kus, Geene, R., Nijman, I.J., Verrijp, K., Jamieson, N.B., Wood, C., Lent-van Vliet, S. van, Reuvers, Luuk, Achouiti, Soumia, Rutgers, N., Brouwer, N.P.M., Simmer, F., Zlobec, I., Lugli, A., and Nagtegaal, I.D.
- Abstract
01 september 2023, Contains fulltext : 296134.pdf (Publisher’s version ) (Open Access), Tumor budding (TB) is a strong biomarker of poor prognosis in colorectal cancer and other solid cancers. TB is defined as isolated single cancer cells or clusters of up to four cancer cells at the invasive tumor front. In areas with a large inflammatory response at the invasive front, single cells and cell clusters surrounding fragmented glands are observed appearing like TB. Occurrence of these small groups is referred to as pseudobudding (PsB), which arises due to external influences such as inflammation and glandular disruption. Using a combination of orthogonal approaches, we show that there are clear biological differences between TB and PsB. TB is representative of active invasion by presenting features of epithelial-mesenchymal transition and exhibiting increased deposition of extracellular matrix within the surrounding tumor microenvironment (TME), whereas PsB represents a reactive response to heavy inflammation where increased levels of granulocytes within the surrounding TME are observed. Our study provides evidence that areas with a strong inflammatory reaction should be avoided in the routine diagnostic assessment of TB. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
- Published
- 2023
3. Multiplex Immunohistochemical Analysis of the Spatial Immune Cell Landscape of the Tumor Microenvironment.
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Gorris, M.A.J., Martynova, E., Sweep, M.W.D., Hoorn, I.A.E. van der, Sultan, S., Claassens, M.J.D.E., Woude, L.L. van der, Verrijp, K., Figdor, C.G., Textor, J.C., Vries, I.J.M. de, Gorris, M.A.J., Martynova, E., Sweep, M.W.D., Hoorn, I.A.E. van der, Sultan, S., Claassens, M.J.D.E., Woude, L.L. van der, Verrijp, K., Figdor, C.G., Textor, J.C., and Vries, I.J.M. de
- Abstract
Contains fulltext : 295926.pdf (Publisher’s version ) (Closed access), The immune cell landscape of the tumor microenvironment potentially contains information for the discovery of prognostic and predictive biomarkers. Multiplex immunohistochemistry is a valuable tool to visualize and identify different types of immune cells in tumor tissues while retaining its spatial information. Here we provide detailed protocols to analyze lymphocyte, myeloid, and dendritic cell populations in tissue sections. Starting from cutting formalin-fixed paraffin-embedded sections, automatic multiplex staining procedures on an automated platform, scanning of the slides on a multispectral imaging microscope, to the analysis of images using an in-house-developed machine learning algorithm ImmuNet. These protocols can be applied to a variety of tumor specimens by simply switching tumor markers to analyze immune cells in different compartments of the sample (tumor versus invasive margin) and apply nearest-neighbor analysis. This analysis is not limited to tumor samples but can also be applied to other (non-)pathogenic tissues. Improvements to the equipment and workflow over the past few years have significantly shortened throughput times, which facilitates the future application of this procedure in the diagnostic setting.
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- 2023
4. Direct In Vivo Activation of T Cells with Nanosized Immunofilaments Inhibits Tumor Growth and Metastasis.
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Weiss, L., Weiden, J., Dolen, Y., Grad, E.M., Dinther, E.A.W. van, Schluck, M., Eggermont, L.J., Mierlo, G. van, Gileadi, U., Bartoló-Ibars, A., Raavé, R., Gorris, M.A.J., Maassen, L., Verrijp, K., Valente, M.C.P., Deplancke, B., Verdoes, M., Benitez-Ribas, D., Heskamp, S., Spriel, A.B. van, Figdor, C.G., Hammink, R., Weiss, L., Weiden, J., Dolen, Y., Grad, E.M., Dinther, E.A.W. van, Schluck, M., Eggermont, L.J., Mierlo, G. van, Gileadi, U., Bartoló-Ibars, A., Raavé, R., Gorris, M.A.J., Maassen, L., Verrijp, K., Valente, M.C.P., Deplancke, B., Verdoes, M., Benitez-Ribas, D., Heskamp, S., Spriel, A.B. van, Figdor, C.G., and Hammink, R.
- Abstract
Contains fulltext : 294765.pdf (Publisher’s version ) (Open Access), Adoptive T cell therapy has successfully been implemented for the treatment of cancer. Nevertheless, ex vivo expansion of T cells by artificial antigen-presenting cells (aAPCs) remains cumbersome and can compromise T cell functionality, thereby limiting their therapeutic potential. We propose a radically different approach aimed at direct expansion of T cells in vivo, thereby omitting the need for large-scale ex vivo T cell production. We engineered nanosized immunofilaments (IFs), with a soluble semiflexible polyisocyanopeptide backbone that presents peptide-loaded major histocompatibility complexes and costimulatory molecules multivalently. IFs readily activated and expanded antigen-specific T cells like natural APCs, as evidenced by transcriptomic analyses of T cells. Upon intravenous injection, IFs reach the spleen and lymph nodes and induce antigen-specific T cell responses in vivo. Moreover, IFs display strong antitumor efficacy resulting in inhibition of the formation of melanoma metastases and reduction of primary tumor growth in synergy with immune checkpoint blockade. In conclusion, nanosized IFs represent a powerful modular platform for direct activation and expansion of antigen-specific T cells in vivo, which can greatly contribute to cancer immunotherapy.
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- 2023
5. Paired primary and metastatic lesions of patients with ipilimumab-treated melanoma: high variation in lymphocyte infiltration and HLA-ABC expression whereas tumor mutational load is similar and correlates with clinical outcome
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Gorris, M.A.J., Woude, L.L. van der, Kroeze, L., Bol, K.F., Verrijp, K., Amir, A., Meek, J.M., Textor, J.C., Figdor, C.G., Vries, I.J.M. de, Gorris, M.A.J., Woude, L.L. van der, Kroeze, L., Bol, K.F., Verrijp, K., Amir, A., Meek, J.M., Textor, J.C., Figdor, C.G., and Vries, I.J.M. de
- Abstract
Contains fulltext : 250263.pdf (Publisher’s version ) (Open Access)
- Published
- 2022
6. Immunological and Genomic Analysis Reveals Clinically Relevant Distinctions between Angiosarcoma Subgroups
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Ravensteijn, S.G. van, Versleijen-Jonkers, Y.M.H., Hillebrandt-Roeffen, M.H.S., Weidema, M.E., Nederkoorn, M.J.L., Bol, K.F., Gorris, M.A.J., Verrijp, K., Kroeze, L., Bitter, T.J.J. de, Voer, R.M. de, Flucke, U.E., Desar, I.M.E., Ravensteijn, S.G. van, Versleijen-Jonkers, Y.M.H., Hillebrandt-Roeffen, M.H.S., Weidema, M.E., Nederkoorn, M.J.L., Bol, K.F., Gorris, M.A.J., Verrijp, K., Kroeze, L., Bitter, T.J.J. de, Voer, R.M. de, Flucke, U.E., and Desar, I.M.E.
- Abstract
Item does not contain fulltext
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- 2022
7. Tumor microenvironment shows an immunological abscopal effect in patients with NSCLC treated with pembrolizumab-radiotherapy combination
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Woude, L.L. van der, Gorris, M.A.J., Wortel, I.M.N., Creemers, J.H.A., Verrijp, K., Monkhorst, Kim, Grunberg, K., Heuvel, M.M. van den, Textor, J.C., Figdor, C.G., Piet, B., Theelen, Willemijn S.M.E., Vries, I.J.M. de, Woude, L.L. van der, Gorris, M.A.J., Wortel, I.M.N., Creemers, J.H.A., Verrijp, K., Monkhorst, Kim, Grunberg, K., Heuvel, M.M. van den, Textor, J.C., Figdor, C.G., Piet, B., Theelen, Willemijn S.M.E., and Vries, I.J.M. de
- Abstract
Contains fulltext : 283861.pdf (Publisher’s version ) (Open Access)
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- 2022
8. Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis
- Author
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Küsters, B, Kats, G, Roodink, I, Verrijp, K, Wesseling, P, Ruiter, D J, de Waal, R M W, and Leenders, W P J
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- 2007
- Full Text
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9. The tumour microenvironment shapes dendritic cell plasticity in a human organotypic melanoma culture
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Blasio, S. Di, Wigcheren, G.F. van, Becker, A., Duffelen, A. van, Gorris, M.A., Verrijp, K., Stefanini, I., Bakker, G.J., Bloemendal, M., Halilovic, A., Vasaturo, A., Bakdash, G., Hato, S.V., Wilt, J.H.W. de, Schalkwijk, J., Vries, I.J.M. de, Textor, J.C., Bogaard, E.H.J. van den, Tazzari, M., Figdor, C.G., Blasio, S. Di, Wigcheren, G.F. van, Becker, A., Duffelen, A. van, Gorris, M.A., Verrijp, K., Stefanini, I., Bakker, G.J., Bloemendal, M., Halilovic, A., Vasaturo, A., Bakdash, G., Hato, S.V., Wilt, J.H.W. de, Schalkwijk, J., Vries, I.J.M. de, Textor, J.C., Bogaard, E.H.J. van den, Tazzari, M., and Figdor, C.G.
- Abstract
Contains fulltext : 220729.pdf (publisher's version ) (Open Access), The tumour microenvironment (TME) forms a major obstacle in effective cancer treatment and for clinical success of immunotherapy. Conventional co-cultures have shed light onto multiple aspects of cancer immunobiology, but they are limited by the lack of physiological complexity. We develop a human organotypic skin melanoma culture (OMC) that allows real-time study of host-malignant cell interactions within a multicellular tissue architecture. By co-culturing decellularized dermis with keratinocytes, fibroblasts and immune cells in the presence of melanoma cells, we generate a reconstructed TME that closely resembles tumour growth as observed in human lesions and supports cell survival and function. We demonstrate that the OMC is suitable and outperforms conventional 2D co-cultures for the study of TME-imprinting mechanisms. Within the OMC, we observe the tumour-driven conversion of cDC2s into CD14(+) DCs, characterized by an immunosuppressive phenotype. The OMC provides a valuable approach to study how a TME affects the immune system.
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- 2020
10. Proliferating cells in HIV and pamidronate-associated collapsing focal segmental glomerulosclerosis are parietal epithelial cells
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Dijkman, H BPM, Weening, J J, Smeets, B, Verrijp, K CN, van Kuppevelt, T H, Assmann, K KJM, Steenbergen, E J, and Wetzels, J FM
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- 2006
11. Isocitrate dehydrogenase 1-mutated human gliomas depend on lactate and glutamate to alleviate metabolic stress
- Author
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Lenting, K., Khurshed, M., Peeters, T.H., Heuvel, C.N.A.M. van den, Lith, S.A.M. van, Bitter, T.J.J. de, Hendriks, W.J.A.J., Span, P.N., Molenaar, R.J., Botman, D., Verrijp, K., Heerschap, A., Laan, M. ter, Kusters, B., Ewijk, A. van, Huynen, M.A., Noorden, C.J.F. van, Leenders, W.P.J., Lenting, K., Khurshed, M., Peeters, T.H., Heuvel, C.N.A.M. van den, Lith, S.A.M. van, Bitter, T.J.J. de, Hendriks, W.J.A.J., Span, P.N., Molenaar, R.J., Botman, D., Verrijp, K., Heerschap, A., Laan, M. ter, Kusters, B., Ewijk, A. van, Huynen, M.A., Noorden, C.J.F. van, and Leenders, W.P.J.
- Abstract
Contains fulltext : 202248.pdf (publisher's version ) (Closed access), Diffuse gliomas often carry point mutations in isocitrate dehydrogenase ( IDH1(mut)), resulting in metabolic stress. Although IDH(mut) gliomas are difficult to culture in vitro, they thrive in the brain via diffuse infiltration, suggesting brain-specific tumor-stroma interactions that can compensate for IDH-1 deficits. To elucidate the metabolic adjustments in clinical IDH(mut) gliomas that contribute to their malignancy, we applied a recently developed method of targeted quantitative RNA next-generation sequencing to 66 clinical gliomas and relevant orthotopic glioma xenografts, with and without the endogenous IDH-1(R132H) mutation. Datasets were analyzed in R using Manhattan plots to calculate distance between expression profiles, Ward's method to perform unsupervised agglomerative clustering, and the Mann Whitney U test and Fisher's exact tests for supervised group analyses. The significance of transcriptome data was investigated by protein analysis, in situ enzymatic activity mapping, and in vivo magnetic resonance spectroscopy of orthotopic IDH1(mut)- and IDH(wt)-glioma xenografts. Gene set enrichment analyses of clinical IDH1(mut) gliomas strongly suggest a role for catabolism of lactate and the neurotransmitter glutamate, whereas, in IDH(wt) gliomas, processing of glucose and glutamine are the predominant metabolic pathways. Further evidence of the differential metabolic activity in these cancers comes from in situ enzymatic mapping studies and preclinical in vivo magnetic resonance spectroscopy imaging. Our data support an evolutionary model in which IDH(mut) glioma cells exist in symbiosis with supportive neuronal cells and astrocytes as suppliers of glutamate and lactate, possibly explaining the diffuse nature of these cancers. The dependency on glutamate and lactate opens the way for novel approaches in the treatment of IDH(mut) gliomas.-Lenting, K., Khurshed, M., Peeters, T. H., van den Heuvel, C. N. A. M., van Lith, S. A. M., de Bitter, T., Hendriks, W.
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- 2019
12. The Importance of Wall Apposition in Flow Diverters
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Aquarius, R.J., Korte, A.M. de, Smits, D.J., Gounis, M.J., Verrijp, K., Driessen, L.M., Leenders, W.P.J., Vries, J. de, Aquarius, R.J., Korte, A.M. de, Smits, D.J., Gounis, M.J., Verrijp, K., Driessen, L.M., Leenders, W.P.J., and Vries, J. de
- Abstract
Item does not contain fulltext
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- 2019
13. Selective MET Kinase Inhibition in MET-Dependent Glioma Models Alters Gene Expression and Induces Tumor Plasticity
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Heuvel, C.N.A.M. van den, Navis, A.C., Bitter, T.J.J. de, Amiri, H., Verrijp, K., Heerschap, A., Rex, K., Dussault, I., Caenepeel, S., Coxon, A., Span, P.N., Wesseling, P., Hendriks, W.J.A.J., Leenders, W.P.J., Heuvel, C.N.A.M. van den, Navis, A.C., Bitter, T.J.J. de, Amiri, H., Verrijp, K., Heerschap, A., Rex, K., Dussault, I., Caenepeel, S., Coxon, A., Span, P.N., Wesseling, P., Hendriks, W.J.A.J., and Leenders, W.P.J.
- Abstract
Contains fulltext : 181795.pdf (publisher's version ) (Closed access), The receptor tyrosine kinase (RTK) MET represents a promising tumor target in a subset of glioblastomas. Most RTK inhibitors available in the clinic today, including those inhibiting MET, affect multiple targets simultaneously. Previously, it was demonstrated that treatment with cabozantinib (MET/VEGFR2/RET inhibitor) prolonged survival of mice carrying orthotopic patient-derived xenografts (PDX) of the MET-addicted glioblastoma model E98, yet did not prevent development of recurrent and cabozantinib-resistant tumors. To exclude VEGFR2 inhibition-inflicted blood-brain barrier normalization and diminished tumor distribution of the drug, we have now investigated the effects of the novel MET-selective inhibitor Compound A in the orthotopic E98 xenograft model. In vitro, Compound A proved a highly potent inhibitor of proliferation of MET-addicted cell lines. In line with its target selectivity, Compound A did not restore the leaky blood-brain barrier and was more effective than cabozantinib in inhibiting MET phosphorylation in vivo Compound A treatment significantly prolonged survival of mice carrying E98 tumor xenografts, but did not prevent eventual progression. Contrasting in vitro results, the Compound A-treated xenografts displayed high levels of AKT phosphorylation despite the absence of phosphorylated MET. Profiling by RNA sequencing showed that in vivo transcriptomes differed significantly from those in control xenografts.Implications: Collectively, these findings demonstrate the plasticity of paracrine growth factor receptor signaling in vivo and urge for prudency with in vitro drug-testing strategies to validate monotherapies. Mol Cancer Res; 15(11); 1587-97. (c)2017 AACR.
- Published
- 2017
14. Development of the tumor vascular bed in response to hypoxia-induced VEGF-A differs from that in tumors with constitutive VEGF-A expression
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Roodink, I., Laak, J.A.W.M. van der, Kusters, B., Wesseling, P., Verrijp, K., Waal, R.M.W. de, and Leenders, W.P.J.
- Subjects
Chemical and physical biology [NCMLS 7] ,Tumor microenvironment [UMCN 1.3] ,Growth and differentiation [NCMLS 3] ,Translational research [ONCOL 3] ,Tissue engineering and pathology [NCMLS 3] ,Functional Neurogenomics [DCN 2] - Abstract
Contains fulltext : 50529.pdf (Publisher’s version ) (Open Access) Tumors arise initially as avascular masses in which central hypoxia induces expression of vascular endothelial growth factor-A (VEGF-A) and subsequently tumor vascularization. However, VEGF-A can also be constitutively expressed as a result of genetic events. VEGF-A is alternatively spliced to yield at least 6 different isoforms. Of these, VEGF-A(121) is freely diffusible whereas basically charged domains in the larger isoforms confer affinity for cell surface or extracellular matrix components. We previously reported that in a mouse brain metastasis model of human melanoma, VEGF-A(121) induced a qualitatively different tumor vascular phenotype than VEGF-A(165) and VEGF-A(189): in contrast to the latter ones, and VEGF-A(121) did not induce a neovascular bed but rather led to leakage and dilatation of preexistent brain vessels. Here, we correlate vascular phenotypes with spatial VEGF-A expression profiles in clinical brain tumors (low grade gliomas; n = 6, melanoma metastases; n = 4, adenocarcinoma metastases; n = 4, glioblastoma multiforme; n = 3, sarcoma metastasis; n = 1, renal cell carcinoma metastasis; n = 1). We show that tumors that constitutively express VEGF-A present with different vascular beds than tumors in which VEGF-A is expressed as a response to central hypoxia. This phenotypic difference is consistent with a model where in tumors with constitutive VEGF-A expression, all isoforms exert their effects on vasculature, resulting in a classical angiogenic phenotype. In tumors where only central parts express hypoxia-induced VEGF-A, the larger angiogenic isoforms are retained by extracellular matrix, leaving only freely diffusible VEGF-A(121) to exert its dilatation effects on distant vessels.
- Published
- 2006
15. Elevated levels of polymorphonuclear myeloid-derived suppressor cells in patients with glioblastoma highly express S100A8/9 and arginase and suppress T cell function
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Gielen, P.R., Schulte, B.M., Kers-Rebel, E.D., Verrijp, K., Bossman, S.A., Laan, M. ter, Wesseling, P., Adema, G.J., Gielen, P.R., Schulte, B.M., Kers-Rebel, E.D., Verrijp, K., Bossman, S.A., Laan, M. ter, Wesseling, P., and Adema, G.J.
- Abstract
Contains fulltext : 167769.pdf (publisher's version ) (Closed access), BACKGROUND: Gliomas are primary brain tumors that are associated with a poor prognosis. The introduction of new treatment modalities (including immunotherapy) for these neoplasms in the last 3 decades has resulted in only limited improvement in survival. Gliomas are known to create an immunosuppressive microenvironment that hampers the efficacy of (immuno)therapy. One component of this immunosuppressive environment is the myeloid-derived suppressor cell (MDSC). METHODS: We set out to analyze the presence and activation state of MDSCs in blood (n = 41) and tumor (n = 20) of glioma patients by measuring S100A8/9 and arginase using flow cytometry and qPCR. Inhibition of T cell proliferation and cytokine production after stimulation with anti-CD3/anti-CD28 coated beads was used to measure in vitro MDSC suppression capacity. RESULTS: We report a trend toward a tumor grade-dependent increase of both monocytic (M-) and polymorphonuclear (PMN-) MDSC subpopulations in the blood of patients with glioma. M-MDSCs of glioma patients have increased levels of intracellular S100A8/9 compared with M-MDSCs in healthy controls (HCs). Glioma patients also have increased S100A8/9 serum levels, which correlates with increased arginase activity in serum. PMN-MDSCs in both blood and tumor tissue demonstrated high expression of arginase. Furthermore, we assessed blood-derived PMN-MDSC function and showed that these cells have potent T cell suppressive function in vitro. CONCLUSIONS: These data indicate a tumor grade-dependent increase of MDSCs in the blood of patients with a glioma. These MDSCs exhibit an increased activation state compared with MDSCs in HCs, independent of tumor grade.
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- 2016
16. Identification of a novel inactivating mutation in Isocitrate Dehydrogenase 1 (IDH1-R314C) in a high grade astrocytoma
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Lith, S.A.M. van, Navis, A.C., Lenting, K., Verrijp, K., Schepens, J.T.G., Hendriks, W.J.A.J., Schubert, N.A., Venselaar, H., Wevers, R.A., Rooij, A.J. van, Wesseling, P., Molenaar, R.J., Noorden, C.J.F. van, Pusch, S., Tops, B., Leenders, W.P.J., Lith, S.A.M. van, Navis, A.C., Lenting, K., Verrijp, K., Schepens, J.T.G., Hendriks, W.J.A.J., Schubert, N.A., Venselaar, H., Wevers, R.A., Rooij, A.J. van, Wesseling, P., Molenaar, R.J., Noorden, C.J.F. van, Pusch, S., Tops, B., and Leenders, W.P.J.
- Abstract
Contains fulltext : 167864.pdf (publisher's version ) (Open Access), The majority of low-grade and secondary high-grade gliomas carry heterozygous hotspot mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or the mitochondrial variant IDH2. These mutations mostly involve Arg132 in IDH1, and Arg172 or Arg140 in IDH2. Whereas IDHs convert isocitrate to alpha-ketoglutarate (alpha-KG) with simultaneous reduction of NADP(+) to NADPH, these IDH mutants reduce alpha-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of alpha-KG-dependent enzymes that are involved in metabolism and epigenetic regulation. However, much less is known about the implications of the metabolic stress, imposed by decreased alpha-KG and NADPH production, for tumor biology. We here present a novel heterozygous IDH1 mutation, IDH1(R314C), which was identified by targeted next generation sequencing of a high grade glioma from which a mouse xenograft model and a cell line were generated. IDH1(R314C) lacks isocitrate-to-alpha-KG conversion activity due to reduced affinity for NADP(+), and differs from the IDH1(R132) mutants in that it does not produce D-2-HG. Because IDH1(R314C) is defective in producing alpha-KG and NADPH, without concomitant production of the D-2-HG, it represents a valuable tool to study the effects of IDH1-dysfunction on cellular metabolism in the absence of this oncometabolite.
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- 2016
17. Comprehensive protein tyrosine phosphatase mRNA profiling identifies new regulators in the progression of glioma
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Bourgonje, A.M., Verrijp, K., Schepens, J.T.G., Navis, A.C., Piepers, J.A., Palmen, C.B., Eijnden, M. van den, Huijsduijnen, R. Hooft van, Wesseling, P., Leenders, W.P.J., Hendriks, W.J.A.J., Bourgonje, A.M., Verrijp, K., Schepens, J.T.G., Navis, A.C., Piepers, J.A., Palmen, C.B., Eijnden, M. van den, Huijsduijnen, R. Hooft van, Wesseling, P., Leenders, W.P.J., and Hendriks, W.J.A.J.
- Abstract
Contains fulltext : 170209.pdf (publisher's version ) (Open Access), The infiltrative behavior of diffuse gliomas severely reduces therapeutic potential of surgical resection and radiotherapy, and urges for the identification of new drug-targets affecting glioma growth and migration. To address the potential role of protein tyrosine phosphatases (PTPs), we performed mRNA expression profiling for 91 of the 109 known human PTP genes on a series of clinical diffuse glioma samples of different grades and compared our findings with in silico knowledge from REMBRANDT and TCGA databases. Overall PTP family expression levels appeared independent of characteristic genetic aberrations associated with lower grade or high grade gliomas. Notably, seven PTP genes (DUSP26, MTMR4, PTEN, PTPRM, PTPRN2, PTPRT and PTPRZ1) were differentially expressed between grade II-III gliomas and (grade IV) glioblastomas. For DUSP26, PTEN, PTPRM and PTPRT, lower expression levels correlated with poor prognosis, and overexpression of DUSP26 or PTPRT in E98 glioblastoma cells reduced tumorigenicity. Our study represents the first in-depth analysis of PTP family expression in diffuse glioma subtypes and warrants further investigations into PTP-dependent signaling events as new entry points for improved therapy.
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- 2016
18. Differential effects of vascular endothelial growth factor A isoforms in a mouse brain metastasis model of human melanoma
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Kusters, B., Waal, Rmw, P. Wesseling, Verrijp, K., Maass, C., Heerschap, A., Barentsz, Jo, Sweep, F., Ruiter, Dj, and Leenders, Wpj
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Tumor microenvironment [UMCN 1.3] ,Endocrinology and reproduction [UMCN 5.2] ,Functional Imaging [UMCN 1.1] - Abstract
Item does not contain fulltext We reported previously that vascular endothelial growth factor isoform A (VEGF-A) expression by Mel57 human melanoma cells led to tumor progression in a murine brain metastasis model in an angiogenesis-independent fashion by dilation of co-opted, pre-existing vessels and concomitant enhanced blood supply (B. Kusters et al., Cancer Res., 62: 341-345, 2002). Here, we compare the activities of the 121, 165, and 189 VEGF-A isoforms in this model by transfecting Mel57 cells with the respective cDNAs and by injecting the resulting stably transfected cell lines in the internal carotid arteries of nude mice (n = 10 for each isoform). Although the three isoforms had similar potency to induce endothelial cell proliferation, VEGF(121) expression did not result in sprouting angiogenesis but rather led to extensive vasodilation and increased permeability of pre-existing, predominantly peritumoral vessels. Sometimes, proliferating endothelial cells accumulated in vessel lumina, giving these a microvascular, glomeruloid, proliferation-like appearance. Expression of VEGF(165) or VEGF(189) was associated with induction of an intratumoral neovascular bed. In VEGF(165)-expressing tumors, daughter endothelial cells were distributed among newly formed vessels that were extensively dilated. This also occurred in VEGF(189) tumors, but there, vasodilation was less pronounced. Using contrast-enhanced magnetic resonance imaging, the different vascular phenotypes were visualized on characteristic radiological images. VEGF(165) expression was the most unfavorable of the three. Mice carrying VEGF(165) tumors became moribund earlier than those carrying VEGF(121)-expressing tumors (16 +/- 4 days versus 22 +/- 3 days). Our data demonstrate that VEGF-A isoforms differ in angiogenic properties that can be visualized by contrast-enhanced magnetic resonance imaging.
- Published
- 2003
19. Increase in both CD14-positive and CD15-positive myeloid-derived suppressor cell subpopulations in the blood of patients with glioma but predominance of CD15-positive myeloid-derived suppressor cells in glioma tissue
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Gielen, P.R., Schulte, B.M., Rebel, E.D., Verrijp, K., Petersen-Baltussen, H.M., Laan, M. ter, Wesseling, P., Adema, G.J., Gielen, P.R., Schulte, B.M., Rebel, E.D., Verrijp, K., Petersen-Baltussen, H.M., Laan, M. ter, Wesseling, P., and Adema, G.J.
- Abstract
Contains fulltext : 153143.pdf (publisher's version ) (Closed access), Myeloid-derived suppressor cells (MDSCs), defined as CD33-positive major histocompatibility complex class II-negative cells, are increased in a variety of human tumors and are associated with immunosuppression. Myeloid-derived suppressor cells can be further subdivided into CD14-positive monocytic MDSC and CD15-positive granulocytic MDSC (polymorphonuclear MDSC) subpopulations. Here we analyzed MDSC subsets in the blood and tumor tissue of patients with glioma, including the most malignant variant, glioblastoma multiforme (GBM). CD33-positive major histocompatibility complex class II-negative MDSCs in blood from 21 patients with glioma and 12 healthy individuals were phenotyped and quantified by flow cytometry. Myeloid populations of the monocytic MDSC and polymorphonuclear MDSC phenotypes were both significantly increased in the blood of patients with GBM versus healthy controls. The myeloid activation markers CD80 and PD-L1 could not be detected on either of these MDSC subsets; CD124, CD86, and CD40 were detected at similar levels on MDSCs in patients with glioma and healthy donors. By contrast, in tumor cell suspensions, the MDSC population consisted almost exclusively of CD15-positive cells. Immunohistochemistry confirmed infiltration of CD15-positive major histocompatibility complex class II-negative cells in glioma tissue samples. These data support a role for cells with an MDSC phenotype in the blood and tumor microenvironment of patients with GBM.
- Published
- 2015
20. Nanobody-functionalized polymersomes for tumor-vessel targeting
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Debets, M.F., Leenders, W.P.J., Verrijp, K., Zonjee, M., Meeuwissen, S.A., Otte-Holler, I., and Hest, J.C.M. van
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Translational research Renal disorder [ONCOL 3] ,Translational research [ONCOL 3] ,Bio-Organic Chemistry ,Translational research Tissue engineering and pathology [ONCOL 3] - Abstract
Item does not contain fulltext Targeted carrier systems (e.g., liposomes or nanoparticles) are used to specifically deliver drugs to a site of interest. Site-direction can be achieved by attachment of targeting molecules, such as peptides, DNA/RNA, or antibodies, to the surface of the carrier. Here, the formation of polymersomes with tumor-targeting potential is described. A single-domain antibody (A12) that specifically targets PlexinD1 (a transmembrane protein overexpressed in tumor vasculature) is equipped with an azide-functionality using expressed protein ligation. This azide-containing A12 can subsequently be attached to BCN-functionalized polymersomes using a strain-promoted azide alkyne cycloaddition, thereby forming polymersomes with tumor-targeting potential.
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- 2013
21. Increased mitochondrial activity in a novel IDH1-R132H mutant human oligodendroglioma xenograft model: in situ detection of 2-HG and alpha-KG
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Navis, A.C., Niclou, S.P., Fack, F., Stieber, D., Lith, S. van, Verrijp, K., Wright, A., Stauber, J., Tops, B., Otte-Holler, I., Wevers, R.A., Rooij, A. van, Pusch, S., Deimling, A. Von, Tigchelaar, W., Noorden, C.J.F. van, Wesseling, P., and Leenders, W.P.J.
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Genomic disorders and inherited multi-system disorders [IGMD 3] ,Translational research Renal disorder [ONCOL 3] ,Translational research [ONCOL 3] ,Glycostation disorders [IGMD 4] ,Glycostation disorders [DCN PAC - Perception action and control IGMD 4] ,DCN NN - Brain networks and neuronal communication ,Translational research Tissue engineering and pathology [ONCOL 3] - Abstract
Contains fulltext : 125973.pdf (Publisher’s version ) (Open Access) BACKGROUND: Point mutations in genes encoding NADP+-dependent isocitrate dehydrogenases (especially IDH1) are common in lower grade diffuse gliomas and secondary glioblastomas and occur early during tumor development. The contribution of these mutations to gliomagenesis is not completely understood and research is hampered by the lack of relevant tumor models. We previously described the development of the patient-derived high-grade oligodendroglioma xenograft model E478 that carries the commonly occurring IDH1-R132H mutation. We here report on the analyses of E478 xenografts at the genetic, histologic and metabolic level. RESULTS: LC-MS and in situ mass spectrometric imaging by LESA-nano ESI-FTICR revealed high levels of the proposed oncometabolite D-2-hydroxyglutarate (D-2HG), the product of enzymatic conversion of alpha-ketoglutarate (alpha-KG) by IDH1-R132H, in the tumor but not in surrounding brain parenchyma. alpha-KG levels and total NADP+-dependent IDH activity were similar in IDH1-mutant and -wildtype xenografts, demonstrating that IDH1-mutated cancer cells maintain alpha-KG levels. Interestingly, IDH1-mutant tumor cells in vivo present with high densities of mitochondria and increased levels of mitochondrial activity as compared to IDH1-wildtype xenografts. It is not yet clear whether this altered mitochondrial activity is a driver or a consequence of tumorigenesis. CONCLUSIONS: The oligodendroglioma model presented here is a valuable model for further functional elucidation of the effects of IDH1 mutations on tumor metabolism and may aid in the rational development of novel therapeutic strategies for the large subgroup of gliomas carrying IDH1 mutations.
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- 2013
22. Intracellular and extracellular domains of protein tyrosine phosphatase PTPRZ-B differentially regulate glioma cell growth and motility
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Bourgonje, A.M., Navis, A.C., Schepens, J.T.G., Verrijp, K., Hovestad, L., Hilhorst, R., Harroch, S., Wesseling, P., Leenders, W.P.J., Hendriks, W.J.A.J., Bourgonje, A.M., Navis, A.C., Schepens, J.T.G., Verrijp, K., Hovestad, L., Hilhorst, R., Harroch, S., Wesseling, P., Leenders, W.P.J., and Hendriks, W.J.A.J.
- Abstract
Item does not contain fulltext, Gliomas are primary brain tumors for which surgical resection and radiotherapy is difficult because of the diffuse infiltrative growth of the tumor into the brain parenchyma. For development of alternative, drug-based, therapies more insight in the molecular processes that steer this typical growth and morphodynamic behavior of glioma cells is needed. Protein tyrosine phosphatase PTPRZ-B is a transmembrane signaling molecule that is found to be strongly up-regulated in glioma specimens. We assessed the contribution of PTPRZ-B protein domains to tumor cell growth and migration, via lentiviral knock-down and over-expression using clinically relevant glioma xenografts and their derived cell models. PTPRZ-B knock-down resulted in reduced migration and proliferation of glioma cells in vitro and also inhibited tumor growth in vivo. Interestingly, expression of only the PTPRZ-B extracellular segment was sufficient to rescue the in vitro migratory phenotype that resulted from PTPRZ-B knock-down. In contrast, PTPRZ-B knock-down effects on proliferation could be reverted only after re-expression of PTPRZ-B variants that contained its C-terminal PDZ binding domain. Thus, distinct domains of PTPRZ-B are differentially required for migration and proliferation of glioma cells, respectively. PTPRZ-B signaling pathways therefore represent attractive therapeutic entry points to combat these tumors.
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- 2014
23. Glutamate as chemotactic fuel for diffuse glioma cells: Are they glutamate suckers?
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Lith, S.A.M. van, Navis, A.C., Verrijp, K., Niclou, S.P., Bjerkvig, R., Wesseling, P., Tops, B., Molenaar, R., Noorden, C.J.F. van, Leenders, W.P.J., Lith, S.A.M. van, Navis, A.C., Verrijp, K., Niclou, S.P., Bjerkvig, R., Wesseling, P., Tops, B., Molenaar, R., Noorden, C.J.F. van, and Leenders, W.P.J.
- Abstract
Item does not contain fulltext, Diffuse gliomas comprise a group of primary brain tumors that originate from glial (precursor) cells and present as a variety of malignancy grades which have in common that they grow by diffuse infiltration. This phenotype complicates treatment enormously as it precludes curative surgery and radiotherapy. Furthermore, diffusely infiltrating glioma cells often hide behind a functional blood-brain barrier, hampering delivery of systemically administered therapeutic and diagnostic compounds to the tumor cells. The present review addresses the biological mechanisms that underlie the diffuse infiltrative phenotype, knowledge of which may improve treatment strategies for this disastrous tumor type. The invasive phenotype is specific for glioma: most other brain tumor types, both primary and metastatic, grow as delineated lesions. Differences between the genetic make-up of glioma and that of other tumor types may therefore help to unravel molecular pathways, involved in diffuse infiltrative growth. One such difference concerns mutations in the NADP+-dependent isocitrate dehydrogenase (IDH1 and IDH2) genes, which occur in >80% of cases of low grade glioma and secondary glioblastoma. In this review we present a novel hypothesis which links IDH1 and IDH2 mutations to glutamate metabolism, possibly explaining the specific biological behavior of diffuse glioma.
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- 2014
24. Circulating tumour tissue fragments in patients with pulmonary metastasis of clear cell renal cell carcinoma
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Ugurlu, G., Roodink, I., Weijert, M.C.A. de, Tiemessen, D.M., Maass, C.N., Verrijp, K., Laak, J.A.W.M. van der, Waal, R.M.W. de, Mulders, P.F.A., Oosterwijk, E., and Leenders, W.P.J.
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Chemical and physical biology [NCMLS 7] ,Immune Regulation [NCMLS 2] ,Translational research [ONCOL 3] - Abstract
Contains fulltext : 79867.pdf (Publisher’s version ) (Open Access) Tumour metastasis is the result of a complex sequence of events, including migration of tumour cells through stroma, proteolytic degradation of stromal and vessel wall elements, intravasation, transport through the circulation, extravasation and outgrowth at compatible sites in the body (the 'seed and soil' hypothesis). However, the high incidence of metastasis from various tumour types in liver and lung may be explained by a stochastic process as well, based on the anatomical relationship of the primary tumour with the circulation and mechanical entrapment of metastatic tumour cells in capillary beds. We previously reported that constitutive VEGF-A expression in tumour xenografts facilitates this type of metastatic seeding by promoting shedding of multicellular tumour tissue fragments, surrounded by vessel wall elements, into the circulation. After transport through the vena cava, such fragments may be trapped in pulmonary arteries, allowing them to expand to symptomatic lesions. Here we tested whether this process has clinical relevance for clear cell renal cell carcinoma (ccRCC), a prototype tumour in the sense of high constitutive VEGF-A expression. To this end we collected and analysed outflow samples from the renal vein, directly after tumour nephrectomy, in 42 patients diagnosed with ccRCC. Tumour fragments in venous outflow were observed in 33% of ccRCC patients and correlated with the synchronous presence or metachronous development of pulmonary metastases (p < 0.001, Fisher's exact test). In patients with tumours that, in retrospect, were not of the VEGF-A-expressing clear cell type, tumour fragments were never observed in the renal outflow. These data suggest that, in ccRCC, a VEGF-A-induced phenotype promotes a release of tumour cell clusters into the circulation that may contribute to pulmonary metastasis.
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- 2009
25. Deficiency of Dol-P-Man Synthase Subunit DPM3 Bridges the Congenital Disorders of Glycosylation with the Dystroglycanopathies
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Lefeber, D.J. Schönberger, J. Morava, E. Guillard, M. Huyben, K.M. Verrijp, K. Grafakou, O. Evangeliou, A. Preijers, F.W. Manta, P. Yildiz, J. Grünewald, S. Spilioti, M. van den Elzen, C. Klein, D. Hess, D. Ashida, H. Hofsteenge, J. Maeda, Y. van den Heuvel, L. Lammens, M. Lehle, L. Wevers, R.A.
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carbohydrates (lipids) - Abstract
Alpha-dystroglycanopathies such as Walker Warburg syndrome represent an important subgroup of the muscular dystrophies that have been related to defective O-mannosylation of alpha-dystroglycan. In many patients, the underlying genetic etiology remains unsolved. Isolated muscular dystrophy has not been described in the congenital disorders of glycosylation (CDG) caused by N-linked protein glycosylation defects. Here, we present a genetic N-glycosylation disorder with muscular dystrophy in the group of CDG type I. Extensive biochemical investigations revealed a strongly reduced dolichol-phosphate-mannose (Dol-P-Man) synthase activity. Sequencing of the three DPM subunits and complementation of DPM3-deficient CHO2.38 cells showed a pathogenic p.L85S missense mutation in the strongly conserved coiled-coil domain of DPM3 that tethers catalytic DPM1 to the ER membrane. Cotransfection experiments in CHO cells showed a reduced binding capacity of DPM3(L85S) for DPM1. Investigation of the four Dol-P-Man-dependent glycosylation pathways in the ER revealed strongly reduced O-mannosylation of alpha-dystroglycan in a muscle biopsy, thereby explaining the clinical phenotype of muscular dystrophy. This mild Dol-P-Man biosynthesis defect due to DPM3 mutations is a cause for alpha-dystroglycanopathy, thereby bridging the congenital disorders of glycosylation with the dystroglycanopathies. © 2009 The American Society of Human Genetics.
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- 2009
26. Effects of Dual Targeting of Tumor Cells and Stroma in Human Glioblastoma Xenografts with a Tyrosine Kinase Inhibitor against c-MET and VEGFR2
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Navis, A.C., Bourgonje, A.M., Wesseling, P., Wright, A., Hendriks, W.J.A.J., Verrijp, K., Laak, J.A.W.M. van der, Heerschap, A., Leenders, W.P.J., Navis, A.C., Bourgonje, A.M., Wesseling, P., Wright, A., Hendriks, W.J.A.J., Verrijp, K., Laak, J.A.W.M. van der, Heerschap, A., and Leenders, W.P.J.
- Abstract
Contains fulltext : 118357.pdf (publisher's version ) (Open Access), Anti-angiogenic treatment of glioblastoma with Vascular Endothelial Growth Factor (VEGF)- or VEGF Receptor 2 (VEGFR2) inhibitors normalizes tumor vessels, resulting in a profound radiologic response and improved quality of life. This approach however does not halt tumor progression by diffuse infiltration, as this phenotype is less angiogenesis dependent. Combined inhibition of angiogenesis and diffuse infiltrative growth would therefore be a more effective treatment approach in these tumors. The HGF/c-MET axis is important in both angiogenesis and cell migration in several tumor types including glioma. We therefore analyzed the effects of the c-MET- and VEGFR2 tyrosine kinase inhibitor cabozantinib (XL184, Exelixis) on c-MET positive orthotopic E98 glioblastoma xenografts, which routinely present with angiogenesis-dependent areas of tumor growth, as well as diffuse infiltrative growth. In cultures of E98 cells, cabozantinib effectively inhibited c-MET phosphorylation, concomitant with inhibitory effects on AKT and ERK1/2 phosphorylation, and cell proliferation and migration. VEGFR2 activation in endothelial cells was also effectively inhibited . Treatment of BALB/c nu/nu mice carrying orthotopic E98 xenografts resulted in a significant increase in overall survival. Cabozantinib effectively inhibited angiogenesis, resulting in increased hypoxia in angiogenesis-dependent tumor areas, and induced vessel normalization. Yet, tumors ultimately escaped cabozantinib therapy by diffuse infiltrative outgrowth via vessel co-option. Of importance, in contrast to the results from experiments, blockade of c-MET activation was incomplete, possibly due to multiple factors including restoration of the blood-brain barrier resulting from cabozantinib-induced VEGFR2 inhibition. In conclusion, cabozantinib is a promising therapy for c-MET positive glioma, but improving delivery of the drug to the tumor and/or the surrounding tissue may be needed for full activity.
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- 2013
27. MC13-0035 Generation and (genetic) characterization of pre-clinical glioma models for “targeted therapies”
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Tops, B., primary, Navis, A., additional, Van Raaij, A., additional, Verrijp, K., additional, Petersen-Baltussen, H., additional, Laan, M. Ter, additional, Wesseling, P., additional, and Leenders, W., additional
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- 2013
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28. Vascular endothelial growth factor-A(165) induces progression of melanoma brain metastases without induction of sprouting angiogenesis
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Kusters, B., Leenders, W.P.J., Wesseling, P., Smits, D., Verrijp, K., Ruiter, D.J., Peters, J.P.W., Kogel, A.J. van der, and Waal, R.M.W. de
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Tumor pathology ,Tumor pathologie ,Experimentele radiotherapie en neuro-oncologie ,Experimental radiotherapy and neuro-oncology - Abstract
Item does not contain fulltext We investigated the mechanisms of vascularization in a brain metastases model of malignant melanoma. Parenchymal metastases expressing little vascular endothelial growth factor-A (VEGF-A) co-opted the preexistent brain vasculature, leading to an infiltrative phenotype. Metastases of the human melanoma cell line Mel57, engineered to express recombinant VEGF-A(165), showed accelerated growth in a combined expansive and infiltrative pattern with marked central necrosis. This difference in growth profile was accompanied by dilation of co-opted intra- and peritumoral vessels with concomitant induction of vascular permeability. Our data show that modulation of preexistent vasculature can contribute to malignant progression without induction of sprouting angiogenesis.
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- 2002
29. Autosomal Recessive Dilated Cardiomyopathy due to DOLK Mutations Results from Abnormal Dystroglycan O-Mannosylation.
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Lefeber, D.J., Brouwer, A.P.M. de, Morava, E., Riemersma, M., Schuurs-Hoeijmakers, J.H.M., Absmanner, B., Verrijp, K., Akker, W.M.R. van den, Huijben, K., Steenbergen, G.C., Reeuwijk, J. van, Jozwiak, A., Zucker, N., Lorber, A., Lammens, M.M.Y., Knopf, C., Bokhoven, H. van, Grunewald, S., Lehle, L., Kapusta, L., Mandel, H., Wevers, R.A., Lefeber, D.J., Brouwer, A.P.M. de, Morava, E., Riemersma, M., Schuurs-Hoeijmakers, J.H.M., Absmanner, B., Verrijp, K., Akker, W.M.R. van den, Huijben, K., Steenbergen, G.C., Reeuwijk, J. van, Jozwiak, A., Zucker, N., Lorber, A., Lammens, M.M.Y., Knopf, C., Bokhoven, H. van, Grunewald, S., Lehle, L., Kapusta, L., Mandel, H., and Wevers, R.A.
- Abstract
Contains fulltext : 96663.pdf (publisher's version ) (Open Access)
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- 2011
30. Mild muscular features in tenascin-x knockout mice, a model of ehlers-danlos syndrome
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Voermans, N.C., Verrijp, K., Eshuis, L., Balemans, M.C.M., Egging, D.F., Sterrenburg, E., Rooij, I.A.L.M. van, Laak, J.A.W.M. van der, Schalkwijk, J., Maarel, S. van der, Lammens, M.M.Y., Engelen, B.G.M. van, Voermans, N.C., Verrijp, K., Eshuis, L., Balemans, M.C.M., Egging, D.F., Sterrenburg, E., Rooij, I.A.L.M. van, Laak, J.A.W.M. van der, Schalkwijk, J., Maarel, S. van der, Lammens, M.M.Y., and Engelen, B.G.M. van
- Abstract
Contains fulltext : 97113.pdf (Publisher’s version ) (Open Access), INTRODUCTION: Tenascin-X (TNX) is an extracellular matrix (ECM) glycoprotein, the absence of which in humans leads to a recessive form of Ehlers-Danlos syndrome (EDS), a group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. A mouse model of TNX-deficient type EDS has been used to characterize the dermatological, orthopedic, and obstetrical features. The growing insight in the clinical overlap between myopathies and inherited connective tissue disorders asks for a study of the muscular characteristics of inherited connective tissue diseases. Therefore, this study aims to define the muscular phenotype of TNX knockout (KO) mice. MATERIALS AND METHODS: We performed a comprehensive study on the muscular phenotype of these TNX KO mice, consisting of standardized clinical assessment, muscle histology, and gene expression profiling of muscle tissue. Furthermore, peripheral nerve composition was studied by histology and electron microscopy. RESULTS: The main findings are the presence of mild muscle weakness, mild myopathic features on histology, and functional upregulation of genes encoding proteins involved in ECM degradation and synthesis. Additionally, sciatic nerve samples showed mildly reduced collagen fibril density of endoneurium. DISCUSSION: The muscular phenotype of TNX KO mice consists of mild muscle weakness with histological signs of myopathy and of increased turnover of the ECM in muscle. Furthermore, mildly reduced diameter of myelinated fibers and reduction of collagen fibril density of endoneurium may correspond with polyneuropathy in TNX-deficient EDS patients. This comprehensive assessment can serve as a starting point for further investigations on neuromuscular function in TNX KO mice.
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- 2011
31. Urinary dopamine in aromatic L-amino acid decarboxylase deficiency: the unsolved paradox.
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Wassenberg, T., Willemsen, M.H., Geurtz, P.B., Lammens, M.M.Y., Verrijp, K., Wilmer, M.J.G., Lee, W.T., Wevers, R.A., Verbeek, M.M., Wassenberg, T., Willemsen, M.H., Geurtz, P.B., Lammens, M.M.Y., Verrijp, K., Wilmer, M.J.G., Lee, W.T., Wevers, R.A., and Verbeek, M.M.
- Abstract
1 december 2010, Contains fulltext : 87540.pdf (publisher's version ) (Closed access), INTRODUCTION: In aromatic L-amino acid decarboxylase (AADC) deficiency, a neurotransmitter biosynthesis defect, paradoxical normal or increased levels of urinary dopamine have been reported. Genotype/phenotype correlations or alternative metabolic pathways may explain this remarkable finding, but were never studied systematically. METHODS: We studied the mutational spectrum and urinary dopamine levels in 20 patients with AADC-deficiency. Experimental procedures were designed to test for alternative metabolic pathways of dopamine production, which included alternative substrates (tyramine and 3-methoxytyrosine) and alternative enzymes (tyrosinase and CYP2D6). RESULTS/DISCUSSION: In 85% of the patients the finding of normal or increased urinary levels of dopamine was confirmed, but a relation with AADC genotype could not be identified. Renal microsomes containing CYP2D were able to convert tyramine into dopamine (3.0 nmol/min/g protein) but because of low plasma levels of tyramine this is an unlikely explanation for urinary dopamine excretion in AADC-deficiency. No evidence was found for the production of dopamine from 3-methoxytyrosine. Tyrosinase was not expressed in human kidney. CONCLUSION: Normal or increased levels of urinary dopamine are found in the majority of AADC-deficient patients. This finding can neither be explained by genotype/phenotype correlations nor by alternative metabolic pathways, although small amounts of dopamine may be formed via tyramine hydroxylation by renal CYP2D6. CYP2D6-mediated conversion of tyramine into dopamine might be an interesting target for the development of new therapeutic strategies in AADC-deficiency.
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- 2010
32. Isolation of targeting nanobodies against co-opted tumor vasculature.
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Roodink, I., Franssen, M., Zuidscherwoude, M.C.M., Verrijp, K., Donk, T. van der, Raats, J., Leenders, W.P.J., Roodink, I., Franssen, M., Zuidscherwoude, M.C.M., Verrijp, K., Donk, T. van der, Raats, J., and Leenders, W.P.J.
- Abstract
1 januari 2010, Contains fulltext : 87890.pdf (publisher's version ) (Closed access), Tumor vasculature is in general highly heterogeneous. This characteristic is most prominent in high-grade gliomas, which present with areas of angiogenic growth, next to large areas of diffuse infiltrative growth in which tumor cells thrive on pre-existent brain vasculature. This limits the effectiveness of anti-angiogenic compounds as these will not affect more matured and co-opted vessels. Therefore, additional destruction of existing tumor vasculature may be a promising alternative avenue to effectively deprive tumors from blood. This approach requires the identification of novel tumor vascular targeting agents, which have broad tumor vessel specificities, ie are not restricted to newly formed vessels. Here, we describe the generation of a phage library displaying nanobodies that were cloned from lymphocytes of a Llama which had been immunized with clinical glioma tissue. In vivo biopanning with this library in the orthotopic glioma xenograft models E98 and E434 resulted in the selection of various nanobodies which specifically recognized glioma vessels in corresponding glioma xenografts. Importantly, also nanobodies were isolated which discriminated incorporated pre-existent vessels in highly infiltrative cerebral E434 xenografts from normal brain vessels. Our results suggest that the generation of nanobody-displaying immune phage libraries and subsequent in vivo biopanning in appropriate animal models is a promising approach for the identification of novel vascular targeting agents.
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- 2010
33. Tumor accumulation of radiolabeled bevacizumab due to targeting of cell- and matrix-associated VEGF-A isoforms.
- Author
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Stollman, T.H., Scheer, M.G.W., Franssen, G.M., Verrijp, K., Oyen, W.J.G., Ruers, T.J.M., Leenders, W.P.J., Boerman, O.C., Stollman, T.H., Scheer, M.G.W., Franssen, G.M., Verrijp, K., Oyen, W.J.G., Ruers, T.J.M., Leenders, W.P.J., and Boerman, O.C.
- Abstract
Contains fulltext : 81037.pdf (publisher's version ) (Open Access), PURPOSE: Vascular endothelial growth factor-A (VEGF-A) is one of the most important factors inducing angiogenesis in tumors. Nine splice-variant isoforms of VEGF-A have been identified, each having different properties. Recently, we showed that radiolabeled anti-VEGF monoclonal antibody, bevacizumab, accumulates specifically in VEGF-A expressing tumors. In this study, we investigated in a nude mouse model which VEGF-isoforms are responsible for tumor accretion. MATERIALS AND METHODS: The humanized anti-VEGF-A antibody, A.4.6.1. (bevacizumab), was radiolabeled with In-111. The originally VEGF-negative Mel57 tumor was transfected with different VEGF isoforms (VEGF-121, VEGF-165, and VEGF-189). The obtained melanoma xenografts specifically expressing different VEGF-isoforms were used in mice. The bevacizumab uptake was examined in biodistribution studies and by gamma-camera imaging. RESULTS: The tumor cell line expressing VEGF-121 did not show specific uptake, most likely as a result of the fact that this isoform is freely diffusible. Tumors expressing VEGF-165 and -189 were clearly visualized by using gamma-camera imaging. CONCLUSION: The accumulation of radiolabeled bevacizumab in the tumor is due to interaction with VEGF-A isoforms that are associated with the tumor cell surface and/or the extracellular matrix. Scintigraphic imaging of the expression of these VEGF isoforms may thus be useful to predict response to angiogenic therapy.
- Published
- 2009
34. Plexin D1 is ubiquitously expressed on tumor vessels and tumor cells in solid malignancies.
- Author
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Roodink, I., Verrijp, K., Raats, J., Leenders, W.P.J., Roodink, I., Verrijp, K., Raats, J., and Leenders, W.P.J.
- Abstract
Contains fulltext : 79501.pdf (publisher's version ) (Open Access), BACKGROUND: Plexin D1 is expressed on both tumor-associated endothelium and malignant cells in a number of clinical brain tumors. Recently we demonstrated that Plexin D1 expression is correlated with tumor invasion level and metastasis in a human melanoma progression series. The objective of this study was to examine whether Plexin D1 might be clinically useful as a pan-tumor vessel and pan-tumor cell target in solid tumors. METHODS: We examined Plexin D1 expression in clinical solid tumors (n = 77) of different origin, a selection of pre-malignant lesions (n = 29) and a variety of non-tumor related tissues (n = 52) by immunohistochemistry. Signals were verified in a selection of tissues via mRNA in situ hybridization. RESULTS: Plexin D1 is abundantly expressed on both activated established tumor vasculature and malignant cells in the majority of primary and metastatic clinical tumors, as well as on macrophages and fibroblasts. Importantly, in non-tumor related tissues Plexin D1 expression is restricted to a subset of, presumably activated, fibroblasts and macrophages. CONCLUSION: We demonstrate that Plexin D1 is in general ubiquitously expressed in tumor but not normal vasculature, as well as in malignant cells in a wide range of human tissues. This expression profile highlights Plexin D1 as a potentially valuable therapeutic target in clinical solid tumors, enabling simultaneous targeting of different tumor compartments.
- Published
- 2009
35. Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies.
- Author
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Lefeber, D.J., Schonberger, J., Morava, E., Guillard, M., Huyben, C.M.L.C., Verrijp, K., Grafakou, O., Evangeliou, A., Preijers, F.W.M.B., Manta, P., Yildiz, J., Grunewald, S., Spilioti, M., Elzen, C. van den, Klein, D., Hess, D., Ashida, H., Hofsteenge, J., Maeda, Y., Heuvel, L.P.W.J. van den, Lammens, M.M.Y., Lehle, L., Wevers, R.A., Lefeber, D.J., Schonberger, J., Morava, E., Guillard, M., Huyben, C.M.L.C., Verrijp, K., Grafakou, O., Evangeliou, A., Preijers, F.W.M.B., Manta, P., Yildiz, J., Grunewald, S., Spilioti, M., Elzen, C. van den, Klein, D., Hess, D., Ashida, H., Hofsteenge, J., Maeda, Y., Heuvel, L.P.W.J. van den, Lammens, M.M.Y., Lehle, L., and Wevers, R.A.
- Abstract
Contains fulltext : 80044.pdf (publisher's version ) (Closed access), Alpha-dystroglycanopathies such as Walker Warburg syndrome represent an important subgroup of the muscular dystrophies that have been related to defective O-mannosylation of alpha-dystroglycan. In many patients, the underlying genetic etiology remains unsolved. Isolated muscular dystrophy has not been described in the congenital disorders of glycosylation (CDG) caused by N-linked protein glycosylation defects. Here, we present a genetic N-glycosylation disorder with muscular dystrophy in the group of CDG type I. Extensive biochemical investigations revealed a strongly reduced dolichol-phosphate-mannose (Dol-P-Man) synthase activity. Sequencing of the three DPM subunits and complementation of DPM3-deficient CHO2.38 cells showed a pathogenic p.L85S missense mutation in the strongly conserved coiled-coil domain of DPM3 that tethers catalytic DPM1 to the ER membrane. Cotransfection experiments in CHO cells showed a reduced binding capacity of DPM3(L85S) for DPM1. Investigation of the four Dol-P-Man-dependent glycosylation pathways in the ER revealed strongly reduced O-mannosylation of alpha-dystroglycan in a muscle biopsy, thereby explaining the clinical phenotype of muscular dystrophy. This mild Dol-P-Man biosynthesis defect due to DPM3 mutations is a cause for alpha-dystroglycanopathy, thereby bridging the congenital disorders of glycosylation with the dystroglycanopathies.
- Published
- 2009
36. Skeletal muscle ultrasound: correlation between fibrous tissue and echo intensity.
- Author
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Pillen, S., Tak, R.O., Zwarts, M.J., Lammens, M.M.Y., Verrijp, K., Arts, I.M.P., Laak, J.A.W.M. van der, Hoogerbrugge, P.M., Engelen, B.G.M. van, Verrips, A., Pillen, S., Tak, R.O., Zwarts, M.J., Lammens, M.M.Y., Verrijp, K., Arts, I.M.P., Laak, J.A.W.M. van der, Hoogerbrugge, P.M., Engelen, B.G.M. van, and Verrips, A.
- Abstract
Contains fulltext : 81544.pdf (Publisher’s version ) (Open Access), In this study, we examined the correlation between muscle ultrasound and muscle structure. Echo intensity (EI) of 14 muscles of two golden retriever muscular dystrophy dogs was correlated to the percentage interstitial fibrous tissue and fat in muscle biopsy. A significant correlation between interstitial fibrous tissue and EI was found (r = 0.87; p < 0.001). The separate influence of interstitial fat on muscle EI could not be established as only little fat was present. We conclude that fibrous tissue causes increased muscle EI. The high correlation between interstitial fibrous tissue and EI makes ultrasound a reliable method to determine severity of structural muscle changes.
- Published
- 2009
37. Specific imaging of VEGF-A expression with radiolabeled anti-VEGF monoclonal antibody.
- Author
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Stollman, T.H., Scheer, M.G.W., Leenders, W.P.J., Verrijp, K., Soede, A.C., Oyen, W.J.G., Ruers, T.J.M., Boerman, O.C., Stollman, T.H., Scheer, M.G.W., Leenders, W.P.J., Verrijp, K., Soede, A.C., Oyen, W.J.G., Ruers, T.J.M., and Boerman, O.C.
- Abstract
Contains fulltext : 70965.pdf (publisher's version ) (Closed access), Vascular endothelial growth factor-A (VEGF-A) is one of the most important angiogenic factors. Here, we studied in a nude mouse model whether the expression of VEGF-A in a tumor could be imaged with a radiolabeled anti-VEGF antibody. The humanized anti-VEGF-A antibody A.4.6.1. (bevacizumab), which is reactive with all VEGF-A isoforms, was radiolabeled with In-111 or with I-125. The accumulation of the radiolabeled antibodies in VEGF-A expressing tumors (LS174T) in nude mice was examined in biodistribution studies and by gamma camera imaging. The uptake of the In-111-bevacizumab in the tumor at 3 days p.i. was significantly higher than that of I-125-bevacizumab (19.4 +/- 7.0 %ID/g vs. 9.6 +/- 3.3 %ID/g, p = 0.04). Coinjection of an excess unlabeled antibody resulted in a significant decrease in radioactivity concentration in the tumor (<2.9 +/- 1.9 %ID/g, p < 0.005), indicating VEGF-mediated antibody uptake. Highest uptake in the tumor was observed at relatively low antibody protein doses (<3 microg) (20-25 %ID/g). VEGF-A-expressing tumors could be clearly visualized on planar scintigraphic images from 24-hr post injection onwards. In conclusion, VEGF-A expression in tumors can be visualized specifically with radiolabeled anti-VEGF-A-mAb.
- Published
- 2008
38. Delayed intrauterine repair of an experimental spina bifida with a collagen biomatrix.
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Eggink, A.J., Roelofs, L.A.J., Feitz, W.F.J., Wijnen, R.M.H., Lammens, M.M.Y., Mullaart, R.A., Moerkerk, H.T.B. van, Kuppevelt, A.H.M.S.M. van, Crevels, A.J., Verrijp, K., Lotgering, F.K., Berg, P.P. van den, Eggink, A.J., Roelofs, L.A.J., Feitz, W.F.J., Wijnen, R.M.H., Lammens, M.M.Y., Mullaart, R.A., Moerkerk, H.T.B. van, Kuppevelt, A.H.M.S.M. van, Crevels, A.J., Verrijp, K., Lotgering, F.K., and Berg, P.P. van den
- Abstract
Item does not contain fulltext, BACKGROUND/PURPOSE: The aim of the study was to evaluate whether a collagen biomatrix is useful for delayed intrauterine coverage of a surgically created spina bifida in a fetal lamb. METHODS: In 20 fetal lambs, surgery was performed at 72 or 79 days' gestation. In 15 lambs a spina bifida was created surgically. In 8 lambs it was covered with a collagen biomatrix 2 weeks later and in 7 lambs it was left uncovered. Five lambs served as sham operated controls. Neurological examination was performed at 1 week of age and afterwards the lambs were sacrificed for further histological evaluation. RESULTS: None of the 5 surviving lambs with the defect covered showed loss of spinal function and the architecture of the spinal cord was preserved in 4 of the 5 lambs. In the uncovered group, 1 of the 4 surviving lambs had loss of spinal function, 5 lambs were available for histological evaluation and 4 of them showed disturbance of the architecture of the spinal cord. CONCLUSIONS: Collagen biomatrices can be used for intrauterine coverage of an experimental spina bifida and can preserve the architecture of the spinal cord. Neurological outcome is not different between fetuses with their spinal cord covered and fetuses with uncovered cords.
- Published
- 2008
39. Semaphorin 3E expression correlates inversely with Plexin D1 during tumor progression
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Roodink, I., Kats, G., Kempen, L.T.C. Van, Grunberg, M., Maass, C.N., Verrijp, K., Raats, J.M.H., Leenders, W.P.J., Roodink, I., Kats, G., Kempen, L.T.C. Van, Grunberg, M., Maass, C.N., Verrijp, K., Raats, J.M.H., and Leenders, W.P.J.
- Abstract
Item does not contain fulltext
- Published
- 2008
40. Imaging liver metastases of colorectal cancer patients with radiolabelled bevacizumab: Lack of correlation with VEGF-A expression.
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Scheer, M.G.W., Stollman, T.H., Boerman, O.C., Verrijp, K., Sweep, C.G.J., Leenders, W.P.J., Ruers, T.J.M., Oyen, W.J.G., Scheer, M.G.W., Stollman, T.H., Boerman, O.C., Verrijp, K., Sweep, C.G.J., Leenders, W.P.J., Ruers, T.J.M., and Oyen, W.J.G.
- Abstract
Contains fulltext : 69878.pdf (publisher's version ) (Closed access), AIM OF THE STUDY: To investigate the correlation between tumour accumulation of In-111-bevacizumab and VEGF-A expression in patients with colorectal liver metastases. METHODS: Two weeks before resection of the liver metastases 12 patients were intravenously injected with In-111-labelled bevacizumab. Ten minutes and 7 d after injection a whole body scan was acquired. Seven days after the injection, 3D acquisition SPECT of the liver was performed. RESULTS: Enhanced uptake of In-111-bevacizumab in the liver metastases was observed in 9 of the 12 patients. The level of antibody accumulation in these lesions varied considerably. There was no correlation between the level of In-111-antibody accumulation and the level of VEGF-A expression in the tissue as determined by in situ hybridisation and ELISA. CONCLUSIONS: In this study, we investigated the correlation between tumour accumulation of radiolabelled bevacizumab and VEGF-A expression in patients with colorectal liver metastases. No clear-cut correlation between the level of antibody accumulation and expression of VEGF-A was found.
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- 2008
41. Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis.
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Kusters, B., Kats, G., Roodink, I., Verrijp, K., Wesseling, P., Ruiter, D.J., Waal, R.M.W. de, Leenders, W.P.J., Kusters, B., Kats, G., Roodink, I., Verrijp, K., Wesseling, P., Ruiter, D.J., Waal, R.M.W. de, and Leenders, W.P.J.
- Abstract
Contains fulltext : 51895.pdf (publisher's version ) (Closed access), How and why tumors metastasize is still a matter of debate. The assumption is that mutations render tumor cells with a metastatic phenotype, enabling entrance in and transport through lymph or blood vessels. Distant outgrowth is thought to occur only in a suitable microenvironment (the seed and soil hypothesis). However, the anatomical location of most metastases in cancer patients suggests entrapment of tumor cells in the first microcapillary bed that is encountered. We here investigated how vascular endothelial growth factor-A (VEGF-A) attributes to the metastatic process. We describe here that VEGF-A enhances spontaneous metastasis by inducing intravasation of heterogeneous tumor cell clusters, surrounded by vessel wall elements, via an invasion-independent mechanism. These tumor clusters generate metastatic tissue embolisms in pulmonary arteries. Treatment of tumor-bearing mice with the antiangiogenic compound ZD6474 prevented the development of this metastatic phenotype. This work shows that tumors with high constitutive VEGF-A expression metastasize via the formation of tumor emboli and provides an alternative rationale for anti-VEGF-A therapy, namely to inhibit metastasis formation.
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- 2007
42. Proliferating cells in HIV and pamidronate-associated collapsing focal segmental glomerulosclerosis are parietal epithelial cells.
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Dijkman, H.B.P.M., Weening, J.J., Smeets, B., Verrijp, K., Kuppevelt, A.H.M.S.M. van, Assmann, K.K., Steenbergen, E., Wetzels, J.F.M., Dijkman, H.B.P.M., Weening, J.J., Smeets, B., Verrijp, K., Kuppevelt, A.H.M.S.M. van, Assmann, K.K., Steenbergen, E., and Wetzels, J.F.M.
- Abstract
Contains fulltext : 49831.pdf (publisher's version ) (Closed access), Collapsing focal segmental glomerulosclerosis (cFSGS) is characterized by hyperplasia of glomerular epithelial cells. In a mouse model of FSGS and in a patient with recurrent idiopathic FSGS, we identified the proliferating cells as parietal epithelial cells (PECs). In the present study, we have evaluated the origin of the proliferating cells in cFSGS associated with human immunodeficiency virus (HIV) and pamidronate. We performed a detailed study of glomerular lesions in biopsies of two patients with HIV-associated cFSGS and a nephrectomy specimen of a patient with pamidronate-associated cFSGS. Glomeruli were studied by serial sectioning using light and electron microscopy and immunohistochemistry to determine the epithelial cell phenotype. We used Synaptopodin, vascular endothelial growth factor, and CD10 as podocyte markers, CK8 and PAX2 as PEC markers and Ki-67 as marker of cell proliferation. The newly deposited extracellular matrix was characterized using antiheparan sulfate single-chain antibodies. The proliferating cells were negative for the podocyte markers, but stained positive for the PEC markers and the cell proliferation marker Ki-67. The proliferating PAX-2 and CK8 positive cells that covered the capillary tuft were always in continuity with PAX-2/CK8 positive cells lining Bowman's capsule. The matrix deposited by these proliferating cells stained identically to Bowman's capsule. Our study demonstrates that PECs proliferate in HIV and pamidronate-associated cFSGS. Our data do not support the concept of the proliferating, dedifferentiated podocyte.
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- 2006
43. Angiotensin converting enzyme inhibition prevents development of collapsing focal segmental glomerulosclerosis in Thy-1.1 transgenic mice.
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Smeets, B., Steenbergen, M.L.M., Dijkman, H.B.P.M., Verrijp, K., Loeke, N. te, Aten, J., Steenbergen, E., Wetzels, J.F.M., Smeets, B., Steenbergen, M.L.M., Dijkman, H.B.P.M., Verrijp, K., Loeke, N. te, Aten, J., Steenbergen, E., and Wetzels, J.F.M.
- Abstract
Contains fulltext : 36095.pdf (publisher's version ) (Closed access), BACKGROUND: Thy-1.1 transgenic mice develop hypercellular focal and segmental glomerulosclerosis (FSGS) lesions that mimic human collapsing FSGS, in 7 days after injection with anti-Thy-1.1 antibodies. These lesions consist of proliferating parietal epithelial cells (PECs). We questioned whether the angiotensin converting enzyme inhibitor (ACE), captopril, could prevent the development of FSGS and if protection is related to the timing of drug administration. METHODS: First, we compared the effect of captopril treatment with angiotensin II-(ANGII) independent antihypertensive therapy (triple therapy). Second, we tested the effects of captopril administered over four different time intervals: days -7 to 0 (Ca-7>0), days -7 to 7 (Ca-7>7), days 0-7 (Ca0>7) and days 3-7 (Ca3>7) (day 0 being the day of injection of the antibody). Results : In anti-Thy-1.1 injected control (C) mice we observed dedifferentiation and activation of podocytes, reflected by loss of ASD33 and increased expression of desmin, followed by a marked accumulation of PECs forming hypercellular lesions. PECs showed an increased expression of connective tissue growth factor (CTGF). Triple therapy or captorpil pre-treatment (Ca-7>0) had no significant effect on albuminuria or FSGS. In contrast, Ca0>7 and Ca3>7 treatment significantly lowered albuminuria and attenuated development of FSGS. The latter two treatments attenuated loss of ASD33 expression by podocytes but could not prevent increased desmin expression. In addition, these treatments reduced CTGF expression by PECs and prevented PEC proliferation. CONCLUSIONS: ACE inhibition, but not triple therapy, prevents the development of FSGS, suggesting an important role for ANGII. ACE inhibition has a protective effect even when started 3 days after the initial podocyte insult, which is probably related to the ability of ACE-inhibition to block PEC activation and proliferation.
- Published
- 2006
44. Plexin D1 expression is induced on tumor vasculature and tumor cells: a novel target for diagnosis and therapy?
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Roodink, I., Raats, J.M.H., Zwaag, B. van der, Verrijp, K., Kusters, B., Bokhoven, J.H.L.M. van, Linkels, M., Waal, R.M.W. de, Leenders, W.P.J., Roodink, I., Raats, J.M.H., Zwaag, B. van der, Verrijp, K., Kusters, B., Bokhoven, J.H.L.M. van, Linkels, M., Waal, R.M.W. de, and Leenders, W.P.J.
- Abstract
Contains fulltext : 32854.pdf (publisher's version ) (Closed access), We previously reported that during mouse embryogenesis, plexin D1 (plxnD1) is expressed on neuronal and endothelial cells. Endothelial cells gradually loose plxnD1 expression during development. Here we describe, using in situ hybridization, that endothelial plxnD1 expression is regained during tumor angiogenesis in a mouse model of brain metastasis. Importantly, we found PLXND1 expression also in a number of human brain tumors, both of primary and metastatic origin. Apart from the tumor vasculature, abundant expression was also found on tumor cells. Via panning of a phage display library, we isolated two phages that carry single-domain antibodies with specific affinity towards a PLXND1-specific peptide. Immunohistochemistry with these single-domain antibodies on the same tumors that were used for in situ hybridization confirmed PLXND1 expression on the protein level. Furthermore, both these phages and the derived antibodies specifically homed to vessels in brain lesions of angiogenic melanoma in mice after i.v. injection. These results show that PLXND1 is a clinically relevant marker of tumor vasculature that can be targeted via i.v. injections.
- Published
- 2005
45. Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option.
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Leenders, W.P.J., Kusters, B., Verrijp, K., Maass, C.N., Wesseling, P., Heerschap, A., Ruiter, D.J., Ryan, A., Waal, R.M.W. de, Leenders, W.P.J., Kusters, B., Verrijp, K., Maass, C.N., Wesseling, P., Heerschap, A., Ruiter, D.J., Ryan, A., and Waal, R.M.W. de
- Abstract
Contains fulltext : 58165.pdf (publisher's version ) (Closed access), PURPOSE: In the brain, tumors may grow without inducing angiogenesis, via co-option of the dense pre-existent capillary bed. The purpose of this study was to investigate how this phenomenon influences the outcome of antiangiogenic therapy. EXPERIMENTAL DESIGN: Mice carrying brain metastases of the human, highly angiogenic melanoma cell line Mel57-VEGF-A were either or not treated with different dosages of ZD6474, a vascular endothelial growth factor (VEGF) receptor 2 tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor. Effect of treatment was evaluated using contrast-enhanced magnetic resonance imaging (CE- MRI) and (immuno)morphologic analysis. RESULTS: Placebo-treated Mel57-VEGF-A brain metastases evoked an angiogenic response and were highlighted in CE-MRI. After treatment with ZD6474 (100 mg/kg), CE-MRI failed to detect tumors in either prevention or therapeutic treatment regimens. However, (immuno)histologic analysis revealed the presence of numerous, small, nonangiogenic lesions. Treatment with 25 mg/kg ZD6474 also resulted in efficient blockade of vessel formation, but it did not fully inhibit vascular leakage, thereby still allowing visualization in CE-MRI scans. CONCLUSIONS: Our data show that, although angiogenesis can be effectively blocked by ZD6474, in vessel-dense organs this may result in sustained tumor progression via co-option, rather than in tumor dormancy. Importantly, blocking VEGF-A may result in undetectability of tumors in CE-MRI scans, leading to erroneous conclusions about therapeutic efficacy during magnetic resonance imaging follow-up. The maintenance of VEGF-A-induced vessel leakage in the absence of neovascularization at lower ZD6474 doses may be exploited to improve delivery of chemotherapeutic agents in combined treatment regimens of antiangiogenic and chemotherapeutic compounds.
- Published
- 2004
46. Mild Muscular Features in Tenascin-X Knockout Mice, A Model of Ehlers–Danlos Syndrome
- Author
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Voermans, N. C., primary, Verrijp, K., additional, Eshuis, L., additional, Balemans, M. C. M., additional, Egging, D., additional, Sterrenburg, E., additional, van Rooij, I. A. L. M., additional, van der Laak, J. A. W. M., additional, Schalkwijk, J., additional, M van der Maarel, S., additional, Lammens, M., additional, and van Engelen, B. G., additional
- Published
- 2011
- Full Text
- View/download PDF
47. Plasminogen activators, their inhibitors, and urokinase receptor emerge in late stages of melanocytic tumor progression
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Vries, T. J., Paul Quax, Denijn, M., Verrijp, K. N., Verheijen, J. H., Verspaget, H. W., Weidle, U. H., Ruiter, D. J., and Muijen, G. N. P.
- Subjects
Plasminogen Activators ,Plasminogen Inactivators ,Skin Neoplasms ,Humans ,Receptors, Cell Surface ,Tissue Distribution ,RNA, Messenger ,Dysplastic Nevus Syndrome ,Immunohistochemistry ,Melanoma ,In Situ Hybridization ,Research Article ,Receptors, Urokinase Plasminogen Activator - Abstract
Degradation of the extracellular matrix and other tissue barriers by proteases like plasminogen activators (PAs) is a prerequisite for neoplastic growth and metastasis. Recently, we reported that highly metastatic behavior of human melanoma cells in nude mice correlates with urokinase-type PA (u-PA) expression and activity and with PA inhibitor type 1 and 2 (PAI-1, PAI-2) expression. Here we report on the occurrence of components of the PA system in the various stages of human melanoma tumor progression in situ. We studied the protein distribution on freshly frozen lesions of common nevocellular nevi (n = 25), dysplastic (= atypical) nevi (n = 16), early primary melanomas (n = 8), advanced primary melanomas (n = 11), and melanoma metastases (n = 17). Tissue-type PA was present in endothelial cells in all lesions, whereas in metastases it could be detected in tumor cells in a minority of the lesions. u-PA, its receptor, PAI-1, and PAI-2 could not be detected in benign and in early stages but appeared frequently in advanced primary melanoma and melanoma metastasis lesions. u-PA was detected in stromal cells and in tumor cells at the invasive front, the u-PA receptor and PAI-2 in tumor cells, and PAI-1 in the extracellular matrix surrounding tumor cells. Localization of the corresponding messenger RNAs and enzyme activities revealed a similar distribution. We conclude that plasminogen activation is a late event in melanoma tumor progression.
- Published
- 1994
48. Urinary dopamine in aromatic L-amino acid decarboxylase deficiency: The unsolved paradox
- Author
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Wassenberg, T., primary, Willemsen, M.A.A.P., additional, Geurtz, P.B.H., additional, Lammens, M., additional, Verrijp, K., additional, Wilmer, M., additional, Lee, W.T., additional, Wevers, R.A., additional, and Verbeek, M.M., additional
- Published
- 2010
- Full Text
- View/download PDF
49. Delayed Intrauterine Repair of an Experimental Spina Bifida with a Collagen Biomatrix
- Author
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Eggink, A.J., primary, Roelofs, L.A.J., additional, Feitz, W.F.J., additional, Wijnen, R.M.H., additional, Lammens, M.M.Y., additional, Mullaart, R.A., additional, van Moerkerk, H.T.B., additional, van Kuppevelt, T.H., additional, Crevels, A.J., additional, Verrijp, K., additional, Lotgering, F.K., additional, and van den Berg, P.P., additional
- Published
- 2007
- Full Text
- View/download PDF
50. Angiotensin converting enzyme inhibition prevents development of collapsing focal segmental glomerulosclerosis in Thy-1.1 transgenic mice
- Author
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Smeets, B., primary, Steenbergen, M. L. M., additional, Dijkman, H. B. P. M., additional, Verrijp, K. N., additional, te Loeke, N. A. J. M., additional, Aten, J., additional, Steenbergen, E. J., additional, and Wetzels, J. F. M., additional
- Published
- 2006
- Full Text
- View/download PDF
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