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

Direct link
ELTD1 is dispensable for vascular development and tumor angiogenesis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Anna Dimberg)ORCID iD: 0000-0002-0914-6562
(English)Manuscript (preprint) (Other academic)
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. 

National Category
Basic Medicine
URN: urn:nbn:se:uu:diva-247888OAI: oai:DiVA.org:uu-247888DiVA: diva2:797720
Available from: 2015-03-24 Created: 2015-03-24 Last updated: 2015-07-07
In thesis
1. Endothelial activation and inflammation in the tumor microenvironment
Open this publication in new window or tab >>Endothelial activation and inflammation in the tumor microenvironment
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 46 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1087
tumor angiogenesis, endothelial activation, leukocyte recruitment, VEGF-A, αB-crystallin, ELTD1
National Category
Cell and Molecular Biology
urn:nbn:se:uu:diva-247889 (URN)978-91-554-9212-0 (ISBN)
Public defence
2015-05-08, C5 Fåhraeussalen, Rudbecklaboratoriet, Uppsala, 13:00 (English)
Available from: 2015-04-16 Created: 2015-03-24 Last updated: 2015-07-07

Open Access in DiVA

No full text

Search in DiVA

By author/editor
Huang, Hua
By organisation
Department of Immunology, Genetics and Pathology
Basic Medicine

Search outside of DiVA

GoogleGoogle Scholar

Total: 2779 hits
ReferencesLink to record
Permanent link

Direct link