uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Lugano, Roberta
Publications (6 of 6) Show all publications
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
Show others...
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
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
Show others...
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., Ramachandran, M. & Dimberg, A. (2019). Tumor angiogenesis: causes, consequences, challenges and opportunities. Cellular and Molecular Life Sciences (CMLS)
Open this publication in new window or tab >>Tumor angiogenesis: causes, consequences, challenges and opportunities
2019 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071Article in journal (Refereed) Epub ahead of print
Abstract [en]

Tumor vascularization occurs through several distinct biological processes, which not only vary between tumor type and anatomic location, but also occur simultaneously within the same cancer tissue. These processes are orchestrated by a range of secreted factors and signaling pathways and can involve participation of non-endothelial cells, such as progenitors or cancer stem cells. Anti-angiogenic therapies using either antibodies or tyrosine kinase inhibitors have been approved to treat several types of cancer. However, the benefit of treatment has so far been modest, some patients not responding at all and others acquiring resistance. It is becoming increasingly clear that blocking tumors from accessing the circulation is not an easy task to accomplish. Tumor vessel functionality and gene expression often differ vastly when comparing different cancer subtypes, and vessel phenotype can be markedly heterogeneous within a single tumor. Here, we summarize the current understanding of cellular and molecular mechanisms involved in tumor angiogenesis and discuss challenges and opportunities associated with vascular targeting.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
Angiogenesis, Cancer, Endothelial, Vascular targeting, VEGF, Anti-angiogenic therapy
National Category
Cell Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-397923 (URN)10.1007/s00018-019-03351-7 (DOI)000494382600001 ()31690961 (PubMedID)
Funder
Swedish Cancer Society, CAN 2017/502Swedish Research Council, 2016-02495Swedish Cancer SocietySwedish Childhood Cancer Foundation, PR2018-0148
Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2019-12-06Bibliographically 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.
Show others...
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
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
Show others...
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
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
Open this publication in new window or tab >>Elevated Expression of the C-Type Lectin CD93 in the Glioblastoma Vasculature Regulates Cytoskeletal Rearrangements That Enhance Vessel Function and Reduce Host Survival
Show others...
2015 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 21, p. 4504-4516Article in journal (Refereed) 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.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-269008 (URN)10.1158/0008-5472.CAN-14-3636 (DOI)000365602200009 ()26363010 (PubMedID)
Funder
Swedish Cancer Society, CAN 2011/862Swedish Childhood Cancer Foundation, PR2013-0107, PROJ11/083Swedish Research Council, 2013-3797, 2008-2853
Available from: 2015-12-11 Created: 2015-12-11 Last updated: 2017-12-01Bibliographically approved
Organisations

Search in DiVA

Show all publications