Characterization of TEM1/endosialin in human and murine brain tumors.
BACKGROUND
TEM1/endosialin is an emerging microvascular marker of tumor angiogenesis. We characterized the expression pattern of TEM1/endosialin in astrocytic and metastatic brain tumors and investigated its role as a therapeutic target in human endothelial cells and mouse xenograft models.


METHODS
In situ hybridization (ISH), immunohistochemistry (IH) and immunofluorescence (IF) were used to localize TEM1/endosialin expression in grade II-IV astrocytomas and metastatic brain tumors on tissue microarrays. Changes in TEM1/endosialin expression in response to pro-angiogenic conditions were assessed in human endothelial cells grown in vitro. Intracranial U87MG glioblastoma (GBM) xenografts were analyzed in nude TEM1/endosialin knockout (KO) and wildtype (WT) mice.


RESULTS
TEM1/endosialin was upregulated in primary and metastatic human brain tumors, where it localized primarily to the tumor vasculature and a subset of tumor stromal cells. Analysis of 275 arrayed grade II-IV astrocytomas demonstrated TEM1/endosialin expression in 79% of tumors. Robust TEM1/endosialin expression occurred in 31% of glioblastomas (grade IV astroctyomas). TEM1/endosialin expression was inversely correlated with patient age. TEM1/endosialin showed limited co-localization with CD31, alphaSMA and fibronectin in clinical specimens. In vitro, TEM1/endosialin was upregulated in human endothelial cells cultured in matrigel. Vascular Tem1/endosialin was induced in intracranial U87MG GBM xenografts grown in mice. Tem1/endosialin KO vs WT mice demonstrated equivalent survival and tumor growth when implanted with intracranial GBM xenografts, although Tem1/endosialin KO tumors were significantly more vascular than the WT counterparts.


CONCLUSIONS
TEM1/endosialin was induced in the vasculature of high-grade brain tumors where its expression was inversely correlated with patient age. Although lack of TEM1/endosialin did not suppress growth of intracranial GBM xenografts, it did increase tumor vascularity. The cellular localization of TEM1/endosialin and its expression profile in primary and metastatic brain tumors support efforts to therapeutically target this protein, potentially via antibody mediated drug delivery strategies.
Carson-Walter
Eleanor B
EB
Department of Neurosurgery, The University of Rochester, Rochester, NY, USA. eleanor_carson-walter@urmc.rochester.edu
Winans
Bethany N
BN
Whiteman
Melissa C
MC
Liu
Yang
Y
Jarvela
Sally
S
Haapasalo
Hannu
H
Tyler
Betty M
BM
Huso
David L
DL
Johnson
Mahlon D
MD
Walter
Kevin A
KA
D000367:Age Factors; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics*; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
D015703:Antigens, CD; D000951:Antigens, Neoplasm; C078203:CD248 protein, human