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Oncogene. 2018 Jul;37(30):4110-4121. doi: 10.1038/s41388-018-0255-7. Epub 2018 Apr 30.

The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth.

Author information

1
Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands.
2
Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands.
3
Ablynx N.V., Technologiepark 21, Zwijnaarde, 9052, Belgium.
4
Department of Medicine Solna, Experimental Cardiovascular Research Unit and Department of Medicine and Neurology, Center for Molecular Medicine, Karolinska Institute, Stockholm, 171 77, Sweden.
5
Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands. mj.smit@vu.nl.

Abstract

Glioblastoma (GBM) is the most aggressive and an incurable type of brain cancer. Human cytomegalovirus (HCMV) DNA and encoded proteins, including the chemokine receptor US28, have been detected in GBM tumors. US28 displays constitutive activity and is able to bind several human chemokines, leading to the activation of various proliferative and inflammatory signaling pathways. Here we show that HCMV, through the expression of US28, significantly enhanced the growth of 3D spheroids of U251- and neurospheres of primary glioblastoma cells. Moreover, US28 expression accelerated the growth of glioblastoma cells in an orthotopic intracranial GBM-model in mice. We developed highly potent and selective US28-targeting nanobodies, which bind to the extracellular domain of US28 and detect US28 in GBM tissue. The nanobodies inhibited chemokine binding and reduced the constitutive US28-mediated signaling with nanomolar potencies and significantly impaired HCMV/US28-mediated tumor growth in vitro and in vivo. This study emphasizes the oncomodulatory role of HCMV-encoded US28 and provides a potential therapeutic approach for HCMV-positive tumors using the nanobody technology.

PMID:
29706656
PMCID:
PMC6062493
DOI:
10.1038/s41388-018-0255-7
[Indexed for MEDLINE]
Free PMC Article

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