Lessons from the bone marrow: how malignant glioma cells attract adult haematopoietic progenitor cells.
Stem and progenitor cells (PCs) of various lineages have become attractive vehicles to improve therapeutic gene delivery to cancers, notably glioblastoma. Here we report that adult human and murine haematopoietic PCs display a tropism for intracerebral gliomas but not for normal brain tissue in mice. Organotypic hippocampal slice culture and spheroid confrontation assays confirm a directed PC migration towards glioma cells ex vivo and in vitro. RNA interference-mediated disruption of transforming growth factor beta (TGF-beta) synthesis by the glioma cells strongly inhibits PC migration. We delineate a CXC chemokine ligand (CXCL) 12-dependent pathway of TGF-beta-induced PC migration that is facilitated by MMP-9-mediated stem cell factor cleavage in vitro. Moreover, neutralizing antibodies to CXCL12 strongly reduce PC homing to experimental gliomas in vivo. Thus, we define here the molecular mechanism underlying the glioma tropism of the probably most easily accessible PC population suitable for cancer therapy, that is, adult haematopoietic PC.
Tabatabai
Ghazaleh
G
Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Bähr
Oliver
O
Möhle
Robert
R
Eyüpoglu
Ilker Y
IY
Boehmler
Andreas M
AM
Wischhusen
Jörg
J
Rieger
Johannes
J
Blümcke
Ingmar
I
Weller
Michael
M
Wick
Wolfgang
W
D000328:Adult; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology; D002633:Chemotaxis; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019089:Stem Cell Factor / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D014407:Tumor Cells, Cultured
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019089:Stem Cell Factor; D016212:Transforming Growth Factor beta; D020780:Matrix Metalloproteinase 9