|
|
Glial Progenitors in Adult White
Matter Are Driven to Form Malignant Gliomas by Platelet-Derived Growth
Factor-Expressing Retroviruses
Marcela Assanah,1
Richard Lochhead,2
Alfred Ogden,2 Jeffrey
Bruce,2 James
Goldman,1,3 and Peter
Canoll1
Departments of 1Pathology
and 2Neurological Surgery, and 3Center for
Neurobiology and Behavior, Columbia University, New York, New York
10032 -- Correspondence should be addressed to Dr. Peter Canoll,
Department of Pathology, Columbia University, 630 West 168th Street,
New York, NY 10032. Email: pc561@columbia.edu -- Received
Feb. 3, 2006; revised May 8, 2006; accepted May 13, 2006.
|
|
|
To test the gliomagenic potential of adult
glial progenitors, we infected adult rat white matter with
a retrovirus that expresses high levels of PDGF and green
fluorescent protein (GFP).
Tumors that closely resembled human glioblastomas formed in
100% of the animals by 14 d postinfection.
Surprisingly, the tumors were composed of a heterogeneous
population of cells, <20% of which expressed the
retroviral reporter gene (GFP).
The vast majority of both GFP+ and GFP– tumor cells
expressed markers of glial progenitors.
Thus, the tumors arose from the massive expansion of both
infected and uninfected glial progenitors, suggesting that
PDGF was driving tumor formation via autocrine and
paracrine stimulation of glial progenitor cells.
To explore this possibility further, we coinjected a
retrovirus expressing PDGF-IRES-DsRed with a control
retrovirus expressing only GFP.
The resulting tumors contained a mixture of red cells (PDGF-expressing/tumor-initiating
cells) and green cells (recruited progenitors).
Both populations were highly proliferative and
infiltrative.
In contrast, when the control GFP retrovirus was injected
alone, the animals never formed tumors and the majority of
infected cells differentiated along the oligodendrocyte
lineage.
Together, these results reveal that adult white matter
progenitors not only have the capacity to give rise to
gliomas, but resident progenitors are recruited to
proliferate within the mitogenic environment of the tumor and
in this way contribute significantly to the heterogeneous mass
of cells that compose a malignant glioma.
Key words: platelet-derived
growth factor; tumor environment; oligodendrocyte; glioblastoma
multiforme; animal model; tumor clonality
|
