The n e w e ng l a n d j o u r na l of m e dic i n e
clinical implications of basic research
TumorStromal Interactions in Medulloblastoma
Ian F. Pollack, M.D.
Medulloblastoma is the most common malig-
nant brain tumor of childhood. Currently, these
tumors are treated with surgical resection fol-
lowed by craniospinal irradiation (in children
older than 3 to 4 years of age) and chemotherapy.
Patients younger than 3 years of age, those with
metastatic tumors, and those with bulky post-
operative disease are considered to have high-
risk disease; the balance of patients are consid-
ered to have standard-risk disease. The three
features associated with high-risk disease have
formed the foundation for recent risk-adapted
treatment approaches and have changed little
during the past 20 to 30 years apart from the in-
corporation of selected histologic characteristics
of the tumor. The goal of recent studies has been
to increase cure rates among patients with high-
risk disease and reduce treatment-related sequelae
among those with standard-risk disease. These
studies have reported cure rates of more than 70%
of affected children,1 but neither therapeutic se-
quelae nor the sizable percentage of children dy-
ing from the disease has been fully eliminated.
In contrast with earlier approaches to classifi-
cation, which viewed medulloblastoma as a sin-
gle disease, recent landmark studies2,3 have shown
that medulloblastomas can be divided according
to gene expression profiles into at least four
groups, each with distinct clinical features and
mutational patterns.4 These observations herald
the application of molecular characterization to
guide treatment stratification and the implemen-
tation of molecularly targeted therapies. Although
such treatments can be precise, experience has
shown that tumors can circumvent target-direct-
ed inhibitors by acquiring mutations that confer
resistance. A second challenge is that subdivid-
ing medulloblastomas into multiple groups creates
several less common classes of tumor, the use of
which may complicate trial designs intended to
show the clinical benefit of novel therapies.
In this context, Snuderl et al.5 recently exam-
ined the question of whether targeting tumor
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stromal interactions could block tumor growth
in multiple medulloblastoma subtypes by counter-
acting pathways that provide a milieu that pro-
motes medulloblastoma survival. On the basis
of studies that reported marked overexpression
of placental growth factor (PlGF) and one of its
receptors, neuropilin 1 (NRP1), in samples from
multiple medulloblastoma subtypes, Snuderl et al.
postulated that PlGF might represent an exploit-
able target across tumor types. They tested this
hypothesis in mouse models, using human medul-
loblastoma cell lines, and in a transgenic model.
The investigators found that antibodies against
murine and human PlGF could delay tumor
growth, prolong survival, and inhibit spinal me-
tastases. The genetic silencing of human PlGF
in xenografts had similar effects. Tumor-derived
PlGF was only one component of the process, be-
cause the tumor could induce PlGF production by
the stroma (the medulloblastomas producing
PlGF were human in origin, whereas the stromal
cells producing Plgf were murine in origin). The
contribution of stromal PlGF was established
with the use of an antibody specific to the mu-
rine protein, Plgf, which inhibited tumor growth
and dissemination, a finding that suggests that
although medulloblastomas produced PlGF, stro-
ma-derived Plgf is the more critical determinant
of tumor growth (Fig. 1).
The mechanism driving stromal Plgf produc-
tion was also examined. The expression of the
signaling molecule Sonic hedgehog (Shh) was
noted to be one potential contributor. Moreover,
the administration of an Shh inhibitor decreased
levels of Plgf in medulloblastoma-bearing mice.
For situations in which stromal Plgf production
was diminished, tumor PlGF production was in-
creased, suggesting that the tumor can compen-
sate for decreases in stromal Plgf by means of
increased intrinsic production. On the basis of
the observation that the exposure of cells to Plgf
results in the activation of mitogen-activated
protein kinase (Mapk) and the protein kinase Akt,
 Clinical Implications of Basic Research
the authors concluded that Plgf both stimulates
growth and represses apoptosis; inhibiting Mapk
diminished the viability of medulloblastomas.
Finally, to evaluate the receptor pathways un-
derlying the effects of PlGF, the authors exam-
ined the contributions of the vascular endothelial
growth factor receptor 1 (VEGFR1) and NRP1.
Whereas the knockdown of NRP1 inhibited tu-
mor growth and spinal metastases, no such ef-
fects were observed with the downregulation of
VEGFR1. Antibodies against NRP1 inhibited tu-
mor growth and improved survival; conversely,
the overexpression of NRP1 in clinical samples
was associated with inferior overall survival.
The findings reported by Snuderl et al.5 raise
several questions. First, how can these observa-
tions be exploited therapeutically? The authors
suggest using antibodies against NRP1 or PlGF,
which are in clinical trials for the treatment of
other solid tumors. However, the delivery of
antibodies to brain tumors is complicated by
the bloodbrain and bloodcerebrospinal fluid
(CSF) barriers, although the bloodbrain barrier
may be compromised in patients with medullo-
blastomas and the bloodCSF barrier may be cir-
cumvented by means of intrathecal delivery. Small-
molecule inhibitors, if developed, would provide
an alternative approach. Second, what degree of
clinical effect can be anticipated? The authors
preclinical studies showed that blocking PlGF
resulted in a delay in tumor growth and fewer
metastases, but not tumor elimination, which
raises concerns about the extent of clinical ac-
tivity that may be observed with stromal-targeted
therapies. As with many treatment strategies, it is
expected that multiagent approaches will be re-
quired to effectively treat medulloblastoma, and
the prioritization of PlGF inhibition as a compo-
nent of any investigational treatment regimen will
probably be influenced by the genetic character-
istics of the medulloblastoma, which may favor
alternative genomically defined approaches to
treatment. Finally, given the predisposition of
solid tumors to acquire resistance to the inhibi-
tion of tumor-driven growth and survival path-
ways, can the targeting of stroma, rather than
tumor cells, avoid this process? Further studies
will be required to address this issue and the
relative efficacy of tumor-targeted therapies as
compared with stromal-targeted therapies.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
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The New England Journal of Medicine
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Copyright 2013 Massachusetts Medical Society. All rights reserved.
Figure 1. The Influence of Tumor and Stromal Placental Growth Factor
in NRP1-Mediated Signaling.
This schematic representation of the model based on observations by
Snuderl et al.5 highlights the potential contributions of human tumor-
produced and stroma-produced placental growth factor (PlGF) to tumor-
mediated neuropilin 1 (NRP1) signaling, also showing the resultant growth
in medulloblastomas and the promotion of the survival of malignant cells.
Medulloblastoma cells produce PlGF to stimulate NRP1 in an autocrine
fashion (at left) and can also stimulate this pathway to an even greater ex-
tent by influencing paracrine PlGF production (at right). The model proposed
by Snuderl et al.5 suggests that this paracrine pathway is mediated through
the effects on patched homologue 1 (PTCH1), driven by the secretion of Sonic
hedgehog (SHH) by the medulloblastoma. The SHHPTCH1 interaction
activates a signaling cascade within the surrounding stromal cells, the com-
ponents of which are only partially defined (pink area in the cerebral granule
cell). The signaling cascade promotes the release of stromal PlGF and the
resultant stimulation of paracrine NRP1. Adapted from Snuderl et al.5
From the Department of Neurosurgery, Childrens Hospital of
Pittsburgh of UPMC, University of Pittsburgh School of Medi-
cine, Pittsburgh.
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5. Snuderl M, Batista A, Kirkpatrick DN, et al. Targeting pla-
cental growth factor/neuropilin 1 pathway inhibits growth and
spread of medulloblastoma. Cell 2013;152:1065-76.
DOI: 10.1056/NEJMcibr1302851
Copyright 2013 Massachusetts Medical Society.
1943