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    Keywords: ANGIOGENESIS ; CANCER ; EXPRESSION ; GROWTH ; INVASION ; tumor ; BLOOD ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; IN-VIVO ; THERAPY ; DIAGNOSIS ; imaging ; VOLUME ; NEW-YORK ; TUMORS ; NUCLEAR-MEDICINE ; radiation ; MARKER ; BLOOD-FLOW ; REDUCTION ; blood flow ; FLOW ; HIGH-RESOLUTION MEASUREMENT ; MRI ; TRACER BOLUS PASSAGES ; magnetic resonance ; MAGNETIC-RESONANCE ; molecular imaging ; magnetic resonance imaging ; TARGET ; LESIONS ; RADIATION-THERAPY ; PROSTATE-CANCER ; MARKERS ; PARAMETERS ; BENIGN ; MORPHOLOGY ; PHENOTYPE ; STRATEGIES ; SERIES ; TARGETS ; ABNORMALITIES ; CONTRAST-ENHANCED MRI ; VESSELS ; nuclear medicine ; dynamic MRI ; radiology ; molecular ; review ; RE ; TUMOR-GROWTH ; THERAPIES ; radiation therapy ; LEVEL ; analysis ; NUCLEAR ; technique ; USA ; function ; therapy monitoring ; INTRATUMORAL VASCULATURE ; blood volume ; RESONANCE ; CLINICAL-APPLICATIONS ; ARTERIOVENOUS-MALFORMATIONS ; PHARMACOKINETIC ANALYSIS
    Abstract: The switch to an angiogenic phenotype is an important precondition for tumor growth, invasion and spread. Since newly formed vessels are characterized by structural, functional and molecular abnormalities, they offer promising targets for tumor diagnosis and therapy. Previous studies indicate that MRI is valuable to assess vessel morphology and function. It can be used to distinguish between benign and malignant lesions and to improve delineation of proliferating areas within heterogeneous tumors. In addition, tracer kinetic analysis of contrast-enhanced image series allows the estimation of well-defined physiological parameters such as blood volume, blood flow and vessel permeability. Frequently, changes of these parameters during cytostatic, anti-angiogenic and radiation therapy precede tumor volume reduction. Moreover, target-specific MRI techniques can be used to elucidate the expression of angiogenic markers at the molecular level. This review summarizes strategies for non-invasive characterization of tumor vascularization by functional and molecular MRI, hereby introducing representative preclinical and clinical applications
    Type of Publication: Journal article published
    PubMed ID: 17308924
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  • 4
    Keywords: ALPHA(V)BETA(3), ANGIOGENESIS, BREAST-CANCER, CELL, CELLS, CONTRAST, CONTRAST AGENT, development, DI
    Abstract: Angiogenesis is essential for the development of malignant tumors and provides important targets for tumor diagnosis and therapy. To noninvasively assess the angiogenic profile of tumors, novel alpha(v)beta(3) integrin-targeted ultrasmall superparamagnetic iron oxide particles (USPIOs) were designed and their specific uptake by endothelial cells was evaluated in vitro and in vivo. USPIOs were coated with 3-aminopropyltrimethoxysilane (APTMS) and conjugated with Arg-Gly-Asp (RGD) peptides. Accumulation in human umbilical vein endothelial cells (HUVECs) was evaluated using Prussian blue staining, transmission electron microscopy, magnetic resonance (MR) imaging, and inductively coupled plasma mass spectrometry. Uptake of RGD-USPIO by HUVECs was significantly increased when compared with unlabeled USPIO and could be competitively inhibited by addition of unbound RGD. The ability of the RGD-USPIO to noninvasively distinguish tumors with high (HaCaT-ras-A-5RT3) and lower (A431) area fractions of alpha(v)beta(3) integrin-positive vessels was evaluated using a 1.5-T MR scanner. Indeed, after RGD-USPIO injection, there was a more pronounced decrease in T-2 relaxation times in HaCaT-ras-A5RT3 tumors than in A431 tumors. Furthermore, T-2*-weighted images clearly identified the heterogeneous arrangement of vessels with alpha(v)beta(3) integrins in HaCaT-ras-A-5RT3 tumors by an irregular signal intensity decrease. In contrast, in A431 tumors with predominantly small and uniformly distributed vessels, the signal intensity decreased more homogeneously. In summary, RGD-coupled, APTMS-coated USPIOs efficiently label alpha(v)beta(3) integrins expressed on endothelial cells. Furthermore, these molecular MR imaging probes are capable of distinguishing tumors differing in the degree of alpha(v)beta(3) integrin expression and in their angiogenesis profile even when using a clinical 1.5-T MR scanner
    Type of Publication: Journal article published
    PubMed ID: 17308094
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  • 5
    Keywords: RECEPTOR ; ANGIOGENESIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; GROWTH-FACTOR ; tumor ; TUMOR-CELLS ; CELL ; Germany ; IN-VIVO ; KINASE ; tumor growth ; TYROSINE KINASE ; VIVO ; VOLUME ; TISSUE ; TUMORS ; ACCUMULATION ; LINES ; MICE ; MACROPHAGES ; MR ; bone marrow ; BONE-MARROW ; METASTASIS ; STEM-CELLS ; RECRUITMENT ; OVEREXPRESSION ; TUMOR ANGIOGENESIS ; chemokine ; GLIOMAS ; VEGF ; signaling ; molecular ; ONCOLOGY ; MOLECULAR-BASIS ; RE ; TUMOR-GROWTH ; GLIOMA ; GLIOMA-CELLS ; RECIPIENTS ; BONE-MARROW-CELLS ; chemokines ; FACTOR RECEPTOR-1 ; TUMOR TISSUE ; LEVEL ; USA ; LOSSES ; vascular endothelial growth factor ; bone marrow cells ; BONE ; cancer research ; PROMOTES ; RECONSTITUTION ; ENDOTHELIAL GROWTH ; MARROW ; Myeloid cell ; myeloid cells ; MARROW-CELLS ; FACTOR PIGF ; MONOCYTE ACTIVATION ; PATHOLOGICAL CONDITIONS
    Abstract: Several lines of evidence indicate that Flt-1, a fms-like tyrosine kinase receptor, which binds to vascular endothelial growth factor (VEGF)-A, VFGF-B, and PIGF, is a positive regulator of angiogenesis in the context of tumor growth and metastasis. However, the molecular basis of its action is still not clear. Besides endothelial cells, Flt-1 is also expressed by other different cell types, including myeloid hematopoeitic cells (monocytes and macrophages). To examine the functions of Flt-1 expressed by bone marrow-derived myeloid cells in supporting tumor growth and angiogenesis, Flt-1 tyrosine kinase-deficient (Flt-1 TK-/-) bone marrow cells were transplanted into lethally irradiated syngeneic recipients. After hematopoietic reconstitution, we orthotopically implanted syngeneic wild-type glioma cells or glioma cells overexpressing either VEGF(164) or PIGF-2. Loss of Flt-1 signaling in bone marrow-derived myeloid cells led to a significant decrease in tumor volume and vascularization in gliomas. VEGF but not PIGF overexpressed by glioma cells restored the tumor growth rate in Flt-1 TK-/- bone marrow chimera. VEGF and PlGF overexpression by tumor cells induced an accumulation of bone marrow-derived myeloid cells into tumor tissue. This infiltration was decreased in tumors grown in Fit-I TK-/- bone marrow chimeras. When investigating chemokines and growth factors involved in myeloid cell recruitment, we determined elevated SDF-1/CXCL12 levels in VEGF- and PIGF-overexpressing tumors. Collectively, these results suggest that Flt-1 signaling in myeloid cells is essential to amplify the angiogenic response and to promote glioma growth
    Type of Publication: Journal article published
    PubMed ID: 18794121
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  • 6
    Keywords: DISEASE, fibrosis, VEGF
    Abstract: The role of vascular endothelial growth factor (VEGF) in renal fibrosis, tubular cyst formation, and glomerular diseases is incompletely understood. We studied a new conditional transgenic mouse system [Pax8-rtTA/(tetO)(7)VEGF], which allows increased tubular VEGF production in adult mice. The following pathology was observed. The interstitial changes consisted of a ubiquitous proliferation of peritubular capillaries and fibroblasts, followed by deposition of matrix leading to a unique kind of fibrosis, ie, healthy tubules amid a capillary-rich dense fibrotic tissue. In tubular segments with high expression of VEGF, cysts developed that were surrounded by a dense network of peritubular capillaries. The glomerular effects consisted of a proliferative enlargement of glomerular capillaries, followed by mesangial proliferation. This resulted in enlarged glomeruli with loss of the characteristic lobular structure. Capillaries became randomly embedded into mesangial nodules, losing their filtration surface. Serum VEGF levels were increased, whereas endogenous VEGF production by podocytes was down-regulated. Taken together, this study shows that systemic VEGF interferes with the intraglomerular cross-talk between podocytes and the endocapillary compartment. It suppresses VEGF secretion by podocytes but cannot compensate for the deficit. VEGF from podocytes induces a directional effect, attracting the capillaries to the lobular surface, a relevant mechanism to optimize filtration surface. Systemic VEGF lacks this effect, leading to severe deterioration in glomerular architecture, similar to that seen in diabetic nephropathy.
    Type of Publication: Journal article published
    PubMed ID: 19834063
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  • 7
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; carcinoma ; CELL ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; human ; IN-VIVO ; MODEL ; MODELS ; VIVO ; ACTIVATION ; murine ; BINDING ; PHOSPHORYLATION ; BREAST ; breast cancer ; BREAST-CANCER ; MOUSE ; NEOPLASIA ; CARCINOMA CELLS ; CARCINOMA-CELLS ; MORPHOLOGY ; OVEREXPRESSION ; VEGF ; REGRESSION ; endothelial cells ; BLOOD-VESSELS ; angiopoietin ; TIE2 ; tumour growth ; CELL-CELL ; PROMOTES TUMOR ANGIOGENESIS ; vessel morphology
    Abstract: Sustained growth of solid tumours can rely on both the formation of new and the co-option of existing blood vessels. Current models suggest that binding of angiopoietin-2 (Ang-2) to its endothelial Tie2 receptor prevents receptor phosphorylation, destabilizes blood vessels, and promotes vascular permeability. In contrast, binding of angiopoietin-1 (Ang-1) induces Tie2 receptor activation and supports the formation of mature blood vessels covered by pericytes. Despite the intense research to decipher the role of angiopoietins during physiological neovascularization and tumour angiogenesis, a mechanistic understanding of angiopoietin function on vascular integrity and remodelling is still incomplete. We therefore assessed the vascular morphology of two mouse mammary carcinoma xenotransplants (M6378 and M6363) which differ in their natural angiopoietin expression. M6378 displayed Ang-1 in tumour cells but no Ang-2 in tumour endothelial cells in vivo. In contrast, M6363 tumours expressed Ang-2 in the tumour vasculature, whereas no Ang-1 expression was present in tumour cells. We stably transfected M6378 mouse mammary carcinoma cells with human Ang-1 or Ang-2 and investigated the consequences on the host vasculature, including ultrastructural morphology. Interestingly, M6378/Ang-2 and M6363 tumours displayed a similar vascular morphology, with intratumoural haemorrhage and non-functional and abnormal blood vessels. Pericyte loss was prominent in these tumours and was accompanied by increased endothelial cell apoptosis. Thus, overexpression of Ang-2 converted the vascular phenotype of M6378 tumours into a phenotype similar to M6363 tumours. Our results support the hypothesis that Ang-1/Tie2 signalling is essential for vessel stabilization and endothelial cell/pericyte interaction, and suggest that Ang-2 is able to induce a switch of vascular phenotypes within tumours. Copyright (C) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
    Type of Publication: Journal article published
    PubMed ID: 19116989
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  • 8
    Keywords: CANCER ; INHIBITION ; DIFFERENTIATION ; MICE ; inflammation ; REGULATORY T-CELLS ; INDOLEAMINE 2,3-DIOXYGENASE ; kynurenine ; AH RECEPTOR ; TRYPTOPHAN 2,3-DIOXYGENASE
    Abstract: Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.
    Type of Publication: Journal article published
    PubMed ID: 21976023
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  • 9
    Keywords: CANCER ; CELLS ; PROTEINS ; REGULATOR ; PHASE-III ; MAMMALIAN TARGET ; ADJUVANT TEMOZOLOMIDE ; RECURRENT GLIOBLASTOMA ; RAPAMYCIN ; COMPLEX 2
    Abstract: An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.
    Type of Publication: Journal article published
    PubMed ID: 22562250
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  • 10
    Keywords: CANCER ; HEPATOCELLULAR-CARCINOMA ; GENE ; NERVOUS-SYSTEM ; POOR-PROGNOSIS ; RANDOMIZED-TRIAL ; OLIGODENDROGLIAL TUMORS ; IDH1 mutation ; VINCRISTINE CHEMOTHERAPY ; BRAIN-TUMOR GROUP
    Abstract: There is a lack of relevant prognostic and predictive factors in neurooncology besides mutation of isocitrate dehydrogenase 1, codeletion of 1p/19q and promoter hypermethylation of O (6) -methylguanine-DNA-methyltransferase. More importantly, there is limited translation of these factors into clinical practice. The cancer genome atlas data and also clinical correlative analyses suggest a pivotal role for the epidermal growth factor receptor /protein kinase B/mammalian target of rapamycin (mTOR) pathway in both biology and the clinical course of gliomas. However, attempts to stratify gliomas by activating alterations in this pathway have failed thus far. The tumors of 40 patients with WHO grade II gliomas without immediate postoperative genotoxic treatment and known progression and survival status at a median follow-up of 12.2 years were analyzed for expression of the mTOR complex 2 downstream target N-myc downstream regulated gene (NDRG)1 using immunohistochemistry. Baseline characteristics for NDRG1 absent/low versus moderate/high patients were similar. Time to reintervention was significantly longer in the NDRG1 group (P = 0.026). NDRG1 may become a novel biomarker to guide the decision which WHOA degrees II glioma patients may be followed without postsurgical intervention and which patients should receive genotoxic treatment early on. Validation of this hypothesis will be possible with the observational arm of the RTOG 9802 and the pretreatment step of the EORTC 22033/26032 trials.
    Type of Publication: Journal article published
    PubMed ID: 24395351
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