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Langenkamp, E., Zhang, L., Lugano, R., Huang, H., Elhassan, T. E., Georganaki, M., . . . Dimberg, A. (2015). Elevated Expression of the C-Type Lectin CD93 in the Glioblastoma Vasculature Regulates Cytoskeletal Rearrangements That Enhance Vessel Function and Reduce Host Survival. Cancer Research, 75(21), 4504-4516
Öppna denna publikation i ny flik eller fönster >>Elevated Expression of the C-Type Lectin CD93 in the Glioblastoma Vasculature Regulates Cytoskeletal Rearrangements That Enhance Vessel Function and Reduce Host Survival
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2015 (Engelska)Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, nr 21, s. 4504-4516Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Glioblastoma is an aggressive brain tumor characterized by an abnormal blood vasculature that is hyperpermeable. Here, we report a novel role for CD93 in regulating angiogenesis in this setting by modulating cell-cell and cell-matrix adhesion of endothelial cells. Tissue microarray analysis demonstrated that vascular expression of CD93 was correlated with poor survival in a clinical cohort of patients with high-grade astrocytic glioma. Similarly, intracranial growth in the GL261 mouse model of glioma was delayed significantly in CD93(-/-) hosts, resulting in improved survival compared with wild-type mice. This effect was associated with increased vascular permeability and decreased vascular perfusion of tumors, indicating reduced vessel functionality in the absence of CD93. RNAi-mediated attenuation of CD93 in endothelial cells diminished VEGF-induced tube formation in a three-dimensional collagen gel. CD93 was required for efficient endothelial cell migration and proper cell polarization in vitro. Further, in endothelial cells where CD93 was attenuated, decreased cell spreading led to a severe reduction in cell adhesion, a lack of proper cell contacts, a loss of VE-cadherin, and aberrant actin stress fiber formation. Our results identify CD93 as a key regulator of glioma angiogenesis and vascular function, acting via cytoskeletal rearrangements required for cell-cell and cell-matrix adhesion.

Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-269008 (URN)10.1158/0008-5472.CAN-14-3636 (DOI)000365602200009 ()26363010 (PubMedID)
Forskningsfinansiär
Cancerfonden, CAN 2011/862Barncancerfonden, PR2013-0107, PROJ11/083Vetenskapsrådet, 2013-3797, 2008-2853
Tillgänglig från: 2015-12-11 Skapad: 2015-12-11 Senast uppdaterad: 2017-12-01Bibliografiskt granskad
Huang, H. (2015). Endothelial activation and inflammation in the tumor microenvironment. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Öppna denna publikation i ny flik eller fönster >>Endothelial activation and inflammation in the tumor microenvironment
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Tumors are composed not only of malignant cells, but also of various types of normal cells, including vascular cells and infiltrating immune cells, which drive tumor development and progression. The tumor vasculature is abnormal and dysfunctional due to sustained tumor angiogenesis driven by high levels of pro-angiogenic factors. Proteins differentially expressed in tumor vessels affect vascular function and the tumor microenvironment and may serve as targets for therapy. The tumor is also a site of sustained chronic inflammation. The recruitment and activation of inflammatory cells significantly influence tumor progression and regression. Targeting molecules regulating tumor angiogenesis and inflammation in the tumor microenvironment is therefore a promising strategy for the treatment of cancer. This thesis is aiming to understand and investigate the molecular regulation of these two processes in tumors.

αB-crystallin is a heat shock protein previously proposed as a target for cancer therapy due to its role in increasing survival of tumor cells and enhancing tumor angiogenesis. In this thesis, we demonstrate a novel role of αB-crystallin in limiting expansion of CD11b+Gr1+ immature myeloid cells in pathological conditions, including tumor development. In addition, we show that αB-crystallin regulates leukocyte recruitment by promoting expression of adhesion molecules ICAM-1, VCAM-1 and E-selectin during TNF-α-induced endothelial activation. Therefore, targeting of αB-crystallin may influence tumor inflammation by regulating immature myeloid cell expansion and leukocyte recruitment.

Abnormal, dysfunctional vessels are characteristic of glioblastomas, which are aggressive malignant brain tumors. We have identified the orphan G-protein coupled receptor ELTD1 as highly expressed in glioblastoma vessel and investigated its role in tumor angiogenesis. Interestingly, deficiency of ELTD1 was associated with increased growth of orthotopic GL261 glioma and T241 fibrosarcoma, but did not affect vessel density in any model. Further investigation is warranted to evaluate whether ELTD1 serves a suitable vascular target for glioblastoma treatment.

Anti-angiogenic drugs targeting VEGF signaling is widely used in the clinic for various types of cancer. However, the influences of anti-angiogenic treatment on tumor inflammation have not been thoroughly investigated. We demonstrate that VEGF inhibits TNF-α-induced endothelial activation by repressing NF-κB activation and expression of chemokines involved in T-cell recruitment. Sunitinib, a small molecule kinase inhibitor targeting VEGF/VEGFR2 signaling increased expression of chemokines CXCL10, CXCL11, and enhanced T-lymphocyte infiltration into tumors. Our study suggests that anti-angiogenic therapy may improve immunotherapy by enhancing endothelial activation and facilitating immune cell infiltration into tumors.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2015. s. 46
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1087
Nyckelord
tumor angiogenesis, endothelial activation, leukocyte recruitment, VEGF-A, αB-crystallin, ELTD1
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-247889 (URN)978-91-554-9212-0 (ISBN)
Disputation
2015-05-08, C5 Fåhraeussalen, Rudbecklaboratoriet, Uppsala, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2015-04-16 Skapad: 2015-03-24 Senast uppdaterad: 2018-06-26
Cedervall, J., Zhang, Y., Huang, H., Zhang, L., Femel, J., Dimberg, A. & Olsson, A.-K. (2015). Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals. Cancer Research, 75(13), 2653-2662
Öppna denna publikation i ny flik eller fönster >>Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals
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2015 (Engelska)Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, nr 13, s. 2653-2662Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1 beta, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites.

Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-259098 (URN)10.1158/0008-5472.CAN-14-3299 (DOI)000357334700008 ()26071254 (PubMedID)
Forskningsfinansiär
Cancerfonden, 11 0653Vetenskapsrådet, 2010-6903-75363-44, 2012-77PK-22157-01-2
Tillgänglig från: 2015-07-28 Skapad: 2015-07-27 Senast uppdaterad: 2017-12-04Bibliografiskt granskad
Huang, H., Langenkamp, E., Georganaki, M., Loskog, A., Fuchs, P. F., Dieterich, L. C., . . . Dimberg, A. (2015). VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation. The FASEB Journal, 29(1), 227-238
Öppna denna publikation i ny flik eller fönster >>VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation
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2015 (Engelska)Ingår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, nr 1, s. 227-238Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) signaling pathway is in clinical use, but its effect on vascular function and the tumor microenvironment is poorly understood. Here, we investigate cross-talk between VEGF and proinflammatory TNF-α signaling in endothelial cells and its impact on leukocyte recruitment. We found that cotreatment with VEGF decreased TNF-α-induced Jurkat cell adhesion to human microvascular endothelial cells by 40%. This was associated with inhibition of TNF-α-mediated regulation of 86 genes, including 2 T-lymphocyte-attracting chemokines, CXCL10 and CXCL11 [TNF-α concentration 1 ng/ml; 50% inhibition/inhibitory concentration (IC50) VEGF, 3 ng/ml]. Notably, VEGF directly suppressed TNF-α-induced gene expression through negative cross-talk with the NF-κB-signaling pathway, leading to an early decrease in IFN regulatory factor 1 (IRF-1) expression and reduced phosphorylation of signal transducer and activator of transcription 1 (p-Stat1) at later times. Inhibition of VEGF signaling in B16 melanoma tumor-bearing mice by sunitinib treatment resulted in up-regulation of CXCL10 and CXCL11 in tumor vessels, accompanied by up to 18-fold increased infiltration of CD3(+) T-lymphocytes in B16 tumors. Our results demonstrate a novel role of VEGF in negative regulation of NF-κB signaling and endothelial activation in the tumor microenvironment and provide evidence that pharmacological inhibition of VEGF signaling enhances T-lymphocyte recruitment through up-regulation of chemokines CXCL10 and CXCL11.-Huang, H., Langenkamp, E., Georganaki, M., Loskog, A., Fuchs, P. F., Dieterich, L. C., Kreuger, J., Dimberg, A. VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation.

Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper
Identifikatorer
urn:nbn:se:uu:diva-239496 (URN)10.1096/fj.14-250985 (DOI)000347378600022 ()25361735 (PubMedID)
Anmärkning

Författare två och tre delar andraförfattarskapet.

Tillgänglig från: 2014-12-29 Skapad: 2014-12-29 Senast uppdaterad: 2018-01-17Bibliografiskt granskad
Dieterich, L. C., Schiller, P., Huang, H., Wawrousek, E. F., Loskog, A., Wanders, A., . . . Dimberg, A. (2013). alpha B-Crystallin regulates expansion of CD11b(+)Gr-1(+) immature myeloid cells during tumor progression. The FASEB Journal, 27(1), 151-162
Öppna denna publikation i ny flik eller fönster >>alpha B-Crystallin regulates expansion of CD11b(+)Gr-1(+) immature myeloid cells during tumor progression
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2013 (Engelska)Ingår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, nr 1, s. 151-162Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The molecular chaperone αB-crystallin has emerged as a target for cancer therapy due to its expression in human tumors and its role in regulating tumor angiogenesis. αB-crystallin also reduces neuroinflammation, but its role in other inflammatory conditions has not been investigated. Here, we examined whether αB-crystallin regulates inflammation associated with tumors and ischemia. We found that CD45+ leukocyte infiltration is 3-fold increased in tumors and ischemic myocardium in αB-crystallin-deficient mice. Notably, αB-crystallin is prominently expressed in CD11b+ Gr-1+ immature myeloid cells (IMCs), known as regulators of angiogenesis and immune responses, while lymphocytes and mature granulocytes show low αB-crystallin expression. αB-Crystallin deficiency results in a 3-fold higher accumulation of CD11b+ Gr-1+ IMCs in tumors and a significant rise in CD11b+ Gr-1+ IMCs in spleen and bone marrow. Similarly, we noted a 2-fold increase in CD11b+ Gr-1+ IMCs in chronically inflamed livers in αB-crystallin-deficient mice. The effect of αB-crystallin on IMC accumulation is limited to pathological conditions, as CD11b+ Gr-1+ IMCs are not elevated in naive mice. Through ex vivo differentiation of CD11b+ Gr-1+ cells, we provide evidence that αB-crystallin regulates systemic expansion of IMCs through a cell-intrinsic mechanism. Our study suggests a key role of αB-crystallin in limiting expansion of CD11b+ Gr-1+ IMCs in diverse pathological conditions.—Dieterich, L. C., Schiller, P., Huang, H., Wawrousek, E. F., Loskog, A., Wanders, A., Moons, L., Dimberg, A. αB-Crystallin regulates expansion of CD11b+Gr-1+ immature myeloid cells during tumor progression.

Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-187588 (URN)10.1096/fj.12-213017 (DOI)000313103200015 ()23033322 (PubMedID)
Tillgänglig från: 2012-12-07 Skapad: 2012-12-07 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
Dieterich, L. C., Huang, H., Massena, S., Golenhofen, N., Phillipson, M. & Dimberg, A. (2013). alpha B-crystallin/HspB5 regulates endothelial-leukocyte interactions by enhancing NF-kappa B-induced up-regulation of adhesion molecules ICAM-1, VCAM-1 and E-selectin. Angiogenesis, 16(4), 975-983
Öppna denna publikation i ny flik eller fönster >>alpha B-crystallin/HspB5 regulates endothelial-leukocyte interactions by enhancing NF-kappa B-induced up-regulation of adhesion molecules ICAM-1, VCAM-1 and E-selectin
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2013 (Engelska)Ingår i: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 16, nr 4, s. 975-983Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

alpha B-crystallin is a small heat shock protein, which has pro-angiogenic properties by increasing survival of endothelial cells and secretion of vascular endothelial growth factor A. Here we demonstrate an additional role of alpha B-crystallin in regulating vascular function, through enhancing tumor necrosis factor alpha (TNF-alpha) induced expression of endothelial adhesion molecules involved in leukocyte recruitment. Ectopic expression of alpha B-crystallin in endothelial cells increases the level of E-selectin expression in response to TNF-alpha, and enhances leukocyte-endothelial interaction in vitro. Conversely, TNF-alpha-induced expression of intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and E-selectin is markedly inhibited in endothelial cells isolated from alpha B-crystallin-deficient mice. This is associated with elevated levels of I kappa B in alpha B-crystallin deficient cells and incomplete degradation upon TNF-alpha stimulation. Consistent with this, endothelial adhesion molecule expression is reduced in inflamed vessels of alpha B-crystallin deficient mice, and leukocyte rolling velocity is increased. Our data identify alpha B-crystallin as a new regulator of leukocyte recruitment, by enhancing pro-inflammatory nuclear factor kappa B-signaling and endothelial adhesion molecule expression during endothelial activation.

Nyckelord
alpha B-crystallin, Chaperone, ICAM-1, VCAM-1, E-selectin, NF-kappa B
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-209155 (URN)10.1007/s10456-013-9367-4 (DOI)000324326900019 ()
Tillgänglig från: 2013-10-15 Skapad: 2013-10-15 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
Dieterich, L. C., Mellberg, S., Langenkamp, E., Zhang, L., Zieba, A., Salomäki, H., . . . Dimberg, A. (2012). Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization. Journal of Pathology, 228(3), 378-390
Öppna denna publikation i ny flik eller fönster >>Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization
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2012 (Engelska)Ingår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 228, nr 3, s. 378-390Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Glioblastoma are aggressive astrocytic brain tumours characterized by microvascular proliferation and an abnormal vasculature, giving rise to brain oedema and increased patient morbidity. Here, we have characterized the transcriptome of tumour-associated blood vessels and describe a gene signature clearly associated with pleomorphic, pathologically altered vessels in human glioblastoma (grade IV glioma). We identified 95 genes differentially expressed in glioblastoma vessels, while no significant differences in gene expression were detected between vessels in non-malignant brain and grade II glioma. Differential vascular expression of ANGPT2, CD93, ESM1, ELTD1, FILIP1L and TENC1 in human glioblastoma was validated by immunohistochemistry, using a tissue microarray. Through qPCR analysis of gene induction in primary endothelial cells, we provide evidence that increased VEGF-A and TGFβ2 signalling in the tumour microenvironment is sufficient to invoke many of the changes in gene expression noted in glioblastoma vessels. Notably, we found an enrichment of Smad target genes within the distinct gene signature of glioblastoma vessels and a significant increase of Smad signalling complexes in the vasculature of human glioblastoma in situ. This indicates a key role of TGFβ signalling in regulating vascular phenotype and suggests that, in addition to VEGF-A, TGFβ2 may represent a new target for vascular normalization therapy.

Nyckelord
angiogenesis, brain tumour, growth factor, laser microdissection, microarray, tumour endothelial marker, vasculature
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-184941 (URN)10.1002/path.4072 (DOI)000309916000012 ()
Anmärkning

De två första författarna delar förstaförfattarskapet.

Tillgänglig från: 2012-11-19 Skapad: 2012-11-15 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Huang, H.ELTD1 is dispensable for vascular development and tumor angiogenesis.
Öppna denna publikation i ny flik eller fönster >>ELTD1 is dispensable for vascular development and tumor angiogenesis
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

ELTD1 is an orphan member of the adhesion-G-protein-coupled receptor family that is widely expressed in the microvasculature, frequently up-regulated in tumor vessels and has recently been suggested as a target for anti-angiogenic therapy. Here, we have evaluated the role of ELTD1 in developmental and tumor angiogenesis. ELTD1-/- mice were viable, fertile and born at normal mendelian ratios. Retinal angiogenesis and blood vessel formation in liver, kidney and lung was similar in wild-type and ELTD1-/- mice. Consistent with this, siRNA-mediated knockdown ELTD1 did not affect sprouting angiogenesis in vitro. Tumor growth of orthotopic GL261 tumors and subcutaneous T241 fibrosarcomas was increased in ELTD1-/- mice, while B16 melanoma and MB49 carcinomas implanted subcutaneously grew equally well in ELTD1-/- and wild-type mice. Importantly, vascular density was not affected by ELTD1-deficiency in any tumor model. Vascular leakage and T-cell infiltration were reduced in ELTD1-/- T241 tumors while no differences were detected in GL261 tumors. Taken together, our results show that ELTD1 is dispensable for vascular development and tumor angiogenesis and that targeting ELTD1 pharmacologically may results in enhanced tumor growth. 

Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper
Identifikatorer
urn:nbn:se:uu:diva-247888 (URN)
Tillgänglig från: 2015-03-24 Skapad: 2015-03-24 Senast uppdaterad: 2018-06-26
Organisationer
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0002-0914-6562

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