cofactor in hematologic malignancies containing mixed-lineage leukemia (MLL) gene
fusions (10). In both disorders, menin acts
by regulating MLL-mediated histone methylation (11, 12), which may explain why
inhibitors of menin counteract the oncogenic effects of K27M mutations. Although
the role of menin in DIPG is unclear, these
studies suggest it may be an important
Hashizume et al. took a different approach to identify therapies for K27M-
mutant DIPG. They hypothesized that the
global loss of histone methylation induced
by the K27M mutation (and the resulting
sequestration of PRC2) is critical for tumor
maintenance. The authors used patient-derived DIPG cell lines (established from
biopsies and passaged in vivo) to evaluate
the effects of a K27 demethylase inhibitor
on tumor cells. Treatment of H3.3K27M-
mutant DIPG cells with this inhibitor increased H3K27 methylation and decreased
cell growth. By contrast, treatment of cells
harboring wild-type H3.3 or a different histone mutation (H3.3G34R/V) had little effect. This suggests that global loss of H3K27
methylation may be the primary mechanism of K27M-driven gliomagenesis and
raises the possibility that demethylase inhibitors may be valuable therapeutic agents
for the disease.
The discovery of K27M mutations was an
important step forward in understanding
DIPG and promises to yield new approaches
to treating the disease. The studies of Funato
et al. and Hashizume et al. take us closer to
that goal, creating models that can be used
to study DIPG biology and demonstrating
that these models can be useful for identifying therapies. It will be interesting to see
whether these therapies synergize with one
another, or with focal radiation, the standard of care for children with DIPG. Given
the dismal prognosis associated with this
disease, there will be strong incentive to
move them forward into clinical trials. ■
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Nanovesicles known as exo- somes are secreted from a variety of cell types and cir- culate in biological fluids uch as urine and plasma. These exosomes “hijack”
membrane components and cytoplasmic contents of these cells
and play an important role in intercellular communication, often
inducing physiological changes
in recipient cells by transferring
bioactive lipids, nucleic acids, and
proteins (1). These tiny vesicles
also have been implicated in a
number of human diseases, including cancer, and are becoming an appreciated fundamental
aspect of tumor progression and
metastasis (2). Recently, Melo
et al. (3) showed that exosomes
from breast cancer cells transfer
microRNAs (miRNAs) to normal
cells and stimulate them to become cancerous. This potentially
expands the mechanisms by
which cancer spreads and may
provide opportunities to develop
exosome-based diagnostics and
Many physiological processes
involve exosomes, such as cell growth, neuronal communication, immune response activation, and cell migration, and in the case
of cancer, may transfer angiogenic proteins
or oncogenes from one cell to another (4–7).
Thus, analyzing the macromolecules harbored by exosomes could have important
diagnostic and therapeutic implications. Experimental evidence shows that exosomes
mediate interactions between cancer and
normal cells. For example, exosomes secreted
by breast cancer cells inhibit exosome release
from the normal counterparts. These cancer
exosomes may trigger extracellular acidity
in which cancer cells (but not healthy cells)
can survive and which activates hypoxia-dependent angiogenesis during tumor development (1). Exosomes can also induce drug
resistance of cancer cells by sequestering
chemotherapeutic agents (8); and can stimulate metastasis (2).
Interestingly, exosomes contain messenger RNA (mRNA) and miRNA that can be
transferred to other cells and regulate gene
expression of the target cell (9). Likewise,
miRNAs are present in apoptotic bodies
(small membrane vesicles that are produced by cells undergoing programmed cell
death) (10), or they are in the plasma, associated with Argonaute2 (AG02), the key
effector protein of a miRNA-mediated gene
silencing mechanism (11). However, miRNAs detected in human serum and saliva
are mostly concentrated inside exosomes
(12). Virally encoded miRNAs are also
found in exosomes, indicating how oncogenic viruses could manipulate the tumor
Translationally repressed mRNA
MiRNA biogenesis. MiRNAs combine with AGO2 and other proteins
in an RNA-induced silencing complex (RISC) to repress the translation
of target mRNAs.
By Eleni Anastasiadou and
Frank J. Slack
Nanovesicles derived from cells of cancer patients carry
microRNAs that initiate tumor growth in normal cells
Department of Pathology, Beth Israel Deaconess Medical
Center, Harvard Medical School, 330 Brookline Avenue,
Boston, MA 02215, USA. E-mail: firstname.lastname@example.org