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Vascular
apoptosis and involution in gliomas precede neovascularization: a
novel concept for glioma growth and angiogenesis
Zagzag D, Amirnovin R, Greco MA, Yee H, Holash J, Wiegand SJ,
Zabski S, Yancopoulos GD, Grumet M
Department of Pathology, Kaplan Cancer Center, New York University
Medical Center, New York 10016, USA. zagzag@is3.nyu.edu
Vascular changes in gliomas were analyzed by implanting
fluorescent-labeled glioma 261 cells in the brains of 28
mice.
Seven animals were killed each week for 4 weeks.
We investigated the expression of angiopoietin-2 (Ang-2) by in
situ hybridization and compared it with the distribution of
apoptotic cells identified by DNA strand breaks (using the
terminal deoxynucleotidyl transferase-mediated biotinylated
deoxyuridine triphosphate nick end labeling [TUNEL] method) and
transmission electron microscopy (TEM).
As early as 1 week after implantation, tumor cells accumulated
around vessels, which expressed Ang-2 and were TUNEL
negative.
TEM showed tumor cells adjacent to the vascular cells
"lifting up" the normal astrocytic feet processes away
from the endothelial cells and disrupting normal pericytic
cuffing.
After 2 weeks the number of perivascular glioma cells had
increased.
No increase in the number of blood vessels was detected at this
time.
Vascular cells remained positive for Ang-2 and rare ones were
TUNEL positive.
TEM showed closely packed proliferating perivascular tumor
cells.
After 3 weeks, there was vascular involution with scant zones of
tumor necrosis.
Ang-2 was still detected in vascular cells, but now numerous
vascular cells were TUNEL positive.
In addition, TEM showed apoptotic vascular cells.
After 4 weeks, there were extensive areas of tumor necrosis with
pseudopalisading and adjacent angiogenesis.
Ang-2 was detected in vascular cells at the edge of the tumors in
the invaded brain and in vessels surrounded by tumor cells.
At both 3 and 4 weeks, most of the TUNEL-positive tumor cells
lacked morphological features characteristic of apoptosis and
displayed features consistent with necrotic cell death as
determined by TEM.
Only rare tumor cells appeared truly apoptotic.
In contrast, the TUNEL-positive endothelial cells and pericytes
were round and shrunken, with condensed nuclear chromatin by TEM,
suggesting that vascular cells were undergoing an apoptotic cell
death.
These results suggest that vascular cell apoptosis and involution
preceded tumor necrosis and that angiogenesis is a later event in
tumor progression in experimental gliomas.
Moreover, Ang-2 is detected prior to the onset of apoptosis in
vascular cells and could be linked to vascular involution.
PMID: 10879735 [PubMed - indexed for MEDLINE]
Source:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10879735
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