Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain.

Kyeong Jin Kang,Hye Jin Song,Ju Youn Jin,Jung Hyun Her,Do-Hyun Nam,Se Jeong Lee,Sang Mi Kang,Yeup Yoon,Won Young Kang,Yu Kyeong Hwang,Kyeung Min Joo

doi:10.1186/s12885-015-2034-y

Abstract

BackgroundGlioblastoma multiforme (GBM) is characterized by extensive local invasion, which is in contrast with extremely rare systemic metastasis of GBM. Molecular mechanisms inhibiting systemic metastasis of GBM would be a novel therapeutic candidate for GBM in the brain.MethodsPatient-derived GBM cells were primarily cultured from surgical samples of GBM patients and were inoculated into the brains of immune deficient BALB/c-nude or NOD-SCID IL2Rgammanull (NSG) mice. Human NK cells were isolated from peripheral blood mononucleated cells and expanded in vitro.ResultsPatient-derived GBM cells in the brains of NSG mice unexpectedly induced spontaneous lung metastasis although no metastasis was detected in BALB/c-nude mice. Based on the difference of the innate immunity between two mouse strains, NK cell activities of orthotopic GBM xenograft models based on BALB/c-nude mice were inhibited. NK cell inactivation induced spontaneous lung metastasis of GBM cells, which indicated that NK cells inhibit the systemic metastasis. In vitro cytotoxic activities of human NK cells against GBM cells indicated that cytotoxic activity of NK cells against GBM cells prevents systemic metastasis of GBM and that NK cells could be effective cell therapeutics against GBM. Accordingly, NK cells transplanted into orthotopic GBM xenograft models intravenously or intratumorally induced apoptosis of GBM cells in the brain and showed significant therapeutic effects.ConclusionsOur results suggest that innate NK immunity is responsible for rare systemic metastasis of GBM and that sufficient supplementation of NK cells could be a promising immunotherapeutic strategy for GBM in the brain.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-2034-y) contains supplementary material, which is available to authorized users.

Highlights

Glioblastoma multiforme (GBM) is characterized by extensive local invasion, which is in contrast with extremely rare systemic metastasis of GBM
For orthotopic GBM xenograft models, anesthetized 6week-old BALB/c-nude or NOD-SCID IL2Rgammanull (NSG) mice were secured in a rodent stereotactic frame
Spontaneous lung metastasis of patient-derived GBM cells in orthotopic xenograft animal models using NSG mice One of issues that could increase the translational value of the orthotopic xenograft model using patient-derived GBM cells, is an experimental protocol that would improve the in vivo tumor-take rate and shorten the latent period for the formation of detectable xenograft tumors

Summary

Introduction

Glioblastoma multiforme (GBM) is characterized by extensive local invasion, which is in contrast with extremely rare systemic metastasis of GBM. Unmet medical need new therapeutic modalities with novel treatment mechanisms targeting GBM cells that evade and/or withstand currently available therapies. GBMs are known as highly invasive tumors in the brain, extra-cranial metastasis does rarely occur [6,7,8,9]. This clinical characteristic of GBMs could be due to several reasons; short survival length of GBM patients, unique structure of micro-vessels in the CNS, lack of lymphatic systems in the CNS, and immune-privileged microenvironments [10,11,12]. The underlying mechanisms of the limited systemic metastatic potential of GBM cells are interesting from a scientific perspective, but could provide clues leading to novel therapeutic modalities and unique treatment mechanisms

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