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Arce, M., Pinto, M. P., Galleguillos, M., Munoz, C., Lange, S., Ramirez, C., . . . Owen, G. I. (2019). Coagulation Factor Xa Promotes Solid Tumor Growth, Experimental Metastasis and Endothelial Cell Activation. Cancers, 11(8), Article ID 1103.
Open this publication in new window or tab >>Coagulation Factor Xa Promotes Solid Tumor Growth, Experimental Metastasis and Endothelial Cell Activation
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 8, article id 1103Article in journal (Refereed) Published
Abstract [en]

Hypercoagulable state is linked to cancer progression; however, the precise role of the coagulation cascade is poorly described. Herein, we examined the contribution of a hypercoagulative state through the administration of intravenous Coagulation Factor Xa (FXa), on the growth of solid human tumors and the experimental metastasis of the B16F10 melanoma in mouse models. FXa increased solid tumor volume and lung, liver, kidney and lymph node metastasis of tail-vein injected B16F10 cells. Concentrating on the metastasis model, upon coadministration of the anticoagulant Dalteparin, lung metastasis was significantly reduced, and no metastasis was observed in other organs. FXa did not directly alter proliferation, migration or invasion of cancer cells in vitro. Alternatively, FXa upon endothelial cells promoted cytoskeleton contraction, disrupted membrane VE-Cadherin pattern, heightened endothelial-hyperpermeability, increased inflammatory adhesion molecules and enhanced B16F10 adhesion under flow conditions. Microarray analysis of endothelial cells treated with FXa demonstrated elevated expression of inflammatory transcripts. Accordingly, FXa treatment increased immune cell infiltration in mouse lungs, an effect reduced by dalteparin. Taken together, our results suggest that FXa increases B16F10 metastasis via endothelial cell activation and enhanced cancer cell-endothelium adhesion advocating that the coagulation system is not merely a bystander in the process of cancer metastasis.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
cancer, metastasis, melanoma, blood coagulation, vascular endothelium, inflammation
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-394646 (URN)10.3390/cancers11081103 (DOI)000484438000063 ()31382462 (PubMedID)
Funder
Swedish Cancer Society, CAN 2017/502
Available from: 2019-10-17 Created: 2019-10-17 Last updated: 2019-10-17Bibliographically approved
Roodakker, K. R., Alhuseinalkhudhur, A., Al-Jaff, M., Georganaki, M., Zetterling, M., Berntsson, S. G., . . . Smits, A. (2019). Region-by-region analysis of PET, MRI, and histology in en bloc-resected oligodendrogliomas reveals intra-tumoral heterogeneity. European Journal of Nuclear Medicine and Molecular Imaging, 46(3), 569-579
Open this publication in new window or tab >>Region-by-region analysis of PET, MRI, and histology in en bloc-resected oligodendrogliomas reveals intra-tumoral heterogeneity
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2019 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no 3, p. 569-579Article in journal (Refereed) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-356591 (URN)10.1007/s00259-018-4107-z (DOI)000457151600005 ()30109401 (PubMedID)
Funder
Erik, Karin och Gösta Selanders Foundation
Available from: 2018-08-14 Created: 2018-08-08 Last updated: 2019-04-06Bibliographically approved
Barbera, S., Nardi, F., Elia, I., Realini, G., Lugano, R., Santucci, A., . . . Orlandini, M. (2019). The small GTPase Rab5c is a key regulator of trafficking of the CD93/Multimerin-2/1 integrin complex in endothelial cell adhesion and migration. Cell Communication and Signaling, 17, Article ID 55.
Open this publication in new window or tab >>The small GTPase Rab5c is a key regulator of trafficking of the CD93/Multimerin-2/1 integrin complex in endothelial cell adhesion and migration
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2019 (English)In: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 17, article id 55Article in journal (Refereed) Published
Abstract [en]

Background

In the endothelium, the single-pass membrane protein CD93, through its interaction with the extracellular matrix protein Multimerin-2, activates signaling pathways that are critical for vascular development and angiogenesis. Trafficking of adhesion molecules through endosomal compartments modulates their signaling output. However, the mechanistic basis coordinating CD93 recycling and its implications for endothelial cell (EC) function remain elusive.

Methods

Human umbilical vein ECs (HUVECs) and human dermal blood ECs (HDBEC) were used in this study. Fluorescence confocal microscopy was employed to follow CD93 retrieval, recycling, and protein colocalization in spreading cells. To better define CD93 trafficking, drug treatments and transfected chimeric wild type and mutant CD93 proteins were used. The scratch assay was used to evaluate cell migration. Gene silencing strategies, flow citometry, and quantification of migratory capability were used to determine the role of Rab5c during CD93 recycling to the cell surface.

Results

Here, we identify the recycling pathway of CD93 following EC adhesion and migration. We show that the cytoplasmic domain of CD93, by its interaction with Moesin and F-actin, is instrumental for CD93 retrieval in adhering and migrating cells and that aberrant endosomal trafficking of CD93 prevents its localization at the leading edge of migration. Moreover, the small GTPase Rab5c turns out to be a key component of the molecular machinery that is able to drive CD93 recycling to the EC surface. Finally, in the Rab5c endosomal compartment CD93 forms a complex with Multimerin-2 and active 1 integrin, which is recycled back to the basolaterally-polarized cell surface by clathrin-independent endocytosis.

Conclusions

Our findings, focusing on the pro-angiogenic receptor CD93, unveil the mechanisms of its polarized trafficking during EC adhesion and migration, opening novel therapeutic opportunities for angiogenic diseases.

Keywords
Cell polarity, Cell spreading, Moesin, C1qRp
National Category
Cell and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:uu:diva-387584 (URN)10.1186/s12964-019-0375-x (DOI)000469353900001 ()31138217 (PubMedID)
Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-06-26Bibliographically approved
Lugano, R., Vemuri, K., Yu, D., Bergqvist, M., Smits, A., Essand, M., . . . Dimberg, A. (2018). CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.. Journal of Clinical Investigation, 128(8), 3280-3297
Open this publication in new window or tab >>CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.
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2018 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 8, p. 3280-3297Article in journal (Refereed) Published
Abstract [en]

Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel-associated extracellular matrix. CD93 is a transmembrane receptor that is up-regulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates integrin-β1-signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation. The CD93 localization to endothelial filopodia was stabilized by interaction with multimerin-2 (MMRN2), which inhibited its proteolytical cleavage. The CD93-MMRN2 complex was required for activation of integrin-β1, phosphorylation of focal adhesion kinase (FAK) and fibronectin fibrillogenesis in endothelial cells. Consequently, tumor vessels in gliomas implanted orthotopically in CD93-deficient mice showed diminished activation of integrin-β1 and lacked organization of fibronectin into fibrillar structures. These findings demonstrate a key role of CD93 in vascular maturation and organization of the extracellular matrix in tumors, identifying it as a potential target for therapy.

Keywords
Brain cancer, Fibronectin, Oncology, Vascular Biology, endothelial cells
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-350902 (URN)10.1172/JCI97459 (DOI)000440461500015 ()29763414 (PubMedID)
Funder
Swedish Cancer Society, CAN 2014/832Swedish Cancer Society, CAN 2017/502Swedish Cancer Society, CAN 2015/1216Swedish Childhood Cancer Foundation, PR2015-0133Swedish Childhood Cancer Foundation, NCP2015-0075Swedish Research Council, 2016-02495
Available from: 2018-05-17 Created: 2018-05-17 Last updated: 2018-11-08Bibliographically approved
Nowak-Sliwinska, P., Alitalo, K., Allen, E., Anisimov, A., Aplin, A. C., Auerbach, R., . . . Griffioen, A. W. (2018). Consensus guidelines for the use and interpretation of angiogenesis assays. Angiogenesis, 21(3), 425-532
Open this publication in new window or tab >>Consensus guidelines for the use and interpretation of angiogenesis assays
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2018 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 21, no 3, p. 425-532Article, review/survey (Refereed) Published
Abstract [en]

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Angiogenesis, Aortic ring, Endothelial cell migration, Proliferation, Microfluidic, Zebrafish, Chorioallantoic membrane (CAM), Vascular network, Intussusceptive angiogenesis, Retinal vasculature, Corneal angiogenesis, Hindlimb ischemia, Myocardial angiogenesis, Recombinant proteins, Tip cells, Plug assay, Vessel co-option
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-366665 (URN)10.1007/s10456-018-9613-x (DOI)000438644400001 ()29766399 (PubMedID)
Funder
EU, European Research Council, EU-ERC680209
Available from: 2018-11-27 Created: 2018-11-27 Last updated: 2018-11-27Bibliographically approved
Zhang, L., He, L., Lugano, R., Roodakker, K. R., Bergqvist, M., Smits, A. & Dimberg, A. (2018). IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas. Neuro-Oncology, 20(11), 1505-1516
Open this publication in new window or tab >>IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas
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2018 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 11, p. 1505-1516Article in journal (Refereed) Published
Abstract [en]

Background: Vascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades II–III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH) mutation status affects vascular phenotype.

Methods: Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the database of The Cancer Genome Atlas. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grades II–IV gliomas and nonmalignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro.

Results: Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of laminin subunit alpha 4 (LAMA4) and angiopoietin 2 (ANGPT2) in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including upregulation of ANGPT2 and serpin family H (SERPINH1), connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased transforming growth factor beta (TGFβ) and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was upregulated by stimulation of endothelial cells with TGFβ2, vascular endothelial growth factor, or cobalt chloride in vitro.

Conclusion: IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGFβ and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.

Keywords
angiogenesis, ANGPT2, glioma, IDH, tumor vessel
National Category
Basic Medicine Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-352016 (URN)10.1093/neuonc/noy088 (DOI)000448665500010 ()29846705 (PubMedID)
Funder
Swedish Cancer Society, CAN 2015/1216; CAN 2014/832; CAN 2017/502Swedish Childhood Cancer Foundation, PR2015-0133; NCP2015-0075Swedish Research Council, 2016-02495
Available from: 2018-05-31 Created: 2018-05-31 Last updated: 2019-01-08Bibliographically approved
Dimberg, A. (2018). Osteoglycin - A switch from angiogenesis to T-cell recruitment?. EBioMedicine, 35, 22-23
Open this publication in new window or tab >>Osteoglycin - A switch from angiogenesis to T-cell recruitment?
2018 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 35, p. 22-23Article in journal, Editorial material (Other academic) Published
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-369226 (URN)10.1016/j.ebiom.2018.08.020 (DOI)000445436400012 ()30126821 (PubMedID)
Funder
Swedish Cancer Society, CAN 2015/1216
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-11Bibliographically approved
Georganaki, M., van Hooren, L. & Dimberg, A. (2018). Vascular Targeting to Increase the Efficiency of Immune Checkpoint Blockade in Cancer. Frontiers in Immunology, 9, Article ID 3081.
Open this publication in new window or tab >>Vascular Targeting to Increase the Efficiency of Immune Checkpoint Blockade in Cancer
2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 3081Article, review/survey (Refereed) Published
Abstract [en]

Boosting natural immunity against malignant cells has had a major breakthrough in clinical cancer therapy. This is mainly due to the successful development of immune checkpoint blocking antibodies, which release a break on cytolytic anti-tumor-directed T-lymphocytes. However, immune checkpoint blockade is only effective for a proportion of cancer patients, and a major challenge in the field is to understand and overcome treatment resistance. Immune checkpoint blockade relies on successful trafficking of tumor-targeted T-lymphocytes from the secondary lymphoid organs, through the blood stream and into the tumor tissue. Resistance to therapy is often associated with a low density of T-lymphocytes residing within the tumor tissue prior to treatment. The recruitment of leukocytes to the tumor tissue relies on up-regulation of adhesion molecules and chemokines by the tumor vasculature, which is denoted as endothelial activation. Tumor vessels are often poorly activated due to constitutive pro-angiogenic signaling in the tumor microenvironment, and therefore constitute barriers to efficient leukocyte recruitment. An emerging possibility to enhance the efficiency of cancer immunotherapy is to combine pro-inflammatory drugs with anti-angiogenic therapy, which can enable tumor-targeted T-lymphocytes to access the tumor tissue by relieving endothelial anergy and increasing adhesion molecule expression. This would pave the way for efficient immune checkpoint blockade. Here, we review the current understanding of the biological basis of endothelial anergy within the tumor microenvironment, and discuss the challenges and opportunities of combining vascular targeting with immunotherapeutic drugs as suggested by data from key pre-clinical and clinical studies.

Keywords
angiogenesis, cancer, checkpoint blockade, PD-1, PD-L1, CTLA-4, VEGF, endothelial activation
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-373915 (URN)10.3389/fimmu.2018.03081 (DOI)000454094100002 ()
Funder
Swedish Research Council, Dnr 2016-02495Swedish Cancer Society, CAN 2015/1216Swedish Cancer Society, CAN 2017/502Swedish Childhood Cancer Foundation, PR2015-0133Swedish Childhood Cancer Foundation, NCP2015-0075
Available from: 2019-01-17 Created: 2019-01-17 Last updated: 2019-01-17Bibliographically approved
Eriksson, E., Milenova, I., Wenthe, J., Moreno, R., Ullenhag, G., Dimberg, A., . . . Loskog, A. S. (2017). Activating CD40 While Inhibiting IL6R Induces Cytokine Production without PDL1 Upregulation in DCs. Paper presented at 20th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), MAY 10-13, 2017, Washington, DC. Molecular Therapy, 25(5 S1), 54-54
Open this publication in new window or tab >>Activating CD40 While Inhibiting IL6R Induces Cytokine Production without PDL1 Upregulation in DCs
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2017 (English)In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 25, no 5 S1, p. 54-54Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-331371 (URN)000401083600113 ()
Conference
20th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), MAY 10-13, 2017, Washington, DC
Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2017-10-18Bibliographically approved
Eriksson, E., Moreno, R., Milenova, I. Y., Liljenfeldt, L., Dieterich, L. C., Christiansson, L., . . . Loskog, A. (2017). Activation of myeloid and endothelial cells by CD40L gene therapy supports T-cell expansion and migration into the tumor microenvironment. Gene Therapy, 24(2), 92-103
Open this publication in new window or tab >>Activation of myeloid and endothelial cells by CD40L gene therapy supports T-cell expansion and migration into the tumor microenvironment
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2017 (English)In: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 24, no 2, p. 92-103Article in journal (Refereed) Published
Abstract [en]

CD40 is an interesting target in cancer immunotherapy due to its ability to stimulate T-helper 1 immunity via maturation of dendritic cells and to drive M2 to M1 macrophage differentiation. Pancreatic cancer has a high M2 content that has shown responsive to anti-CD40 agonist therapy and CD40 may thus be a suitable target for immune activation in these patients. In this study, a novel oncolytic adenovirus armed with a trimerized membrane-bound extracellular CD40L (TMZ-CD40L) was evaluated as a treatment of pancreatic cancer. Further, the CD40L mechanisms of action were elucidated in cancer models. The results demonstrated that the virus transferring TMZ-CD40L had oncolytic capacity in pancreatic cancer cells and could control tumor progression. TMZ-CD40L was a potent stimulator of human myeloid cells and T-cell responses. Further, CD40L-mediated stimulation increased tumor-infiltrating T cells in vivo, which may be due to a direct activation of endothelial cells to upregulate receptors for lymphocyte attachment and transmigration. In conclusion, CD40L-mediated gene therapy is an interesting concept for the treatment of tumors with high levels of M2 macrophages, such as pancreatic cancer, and an oncolytic virus as carrier of CD40L may further boost tumor killing and immune activation.

National Category
Other Medical Biotechnology
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-318170 (URN)10.1038/gt.2016.80 (DOI)000394682800006 ()27906162 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2017-10-10Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-4422-9125

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