Abstract
A NPC-derived pleiotrophin promotes glioma invasion into the subventricular zone.
Major finding: A NPC-derived pleiotrophin promotes glioma invasion into the subventricular zone.
Mechanism: The pleiotrophin chemoattractant complex activates the RhoA/ROCK signaling pathway in glioma.
Impact: The pleiotrophin chemoattractant complex may be a potential therapeutic target to inhibit HGG invasion.
High-grade gliomas (HGG) are diffusely infiltrating, aggressive brain tumors that frequently spread to the lateral ventricle subventricular zone (SVZ), which is comprised of neural precursor cells (NPC) and is a neural stem cell niche that is thought to serve as a reservoir for glioma cells that contribute to relapse. Although it remains unclear whether adult HGGs spread to or arise in the SVZ, diffuse intrinsic pontine glioma (DIPG), which is the most common pediatric HGG, arises in the pons and spreads to the SVZ. To elucidate the mechanisms underlying DIPG spread to the SVZ, Qin and colleagues evaluated labeled cells isolated from a DIPG metastasis in the SVZ and showed that SVZ-derived DIPG cells xenografted to the pons invade toward the SVZ and that glioma cells preferentially migrated in vitro towards SVZ-derived NPCs compared to NPCs isolated from other ventricular zones. Analysis of conditioned medium identified 4 NPC-derived growth factors—pleiotrophin (PTN), SPARC, SPARCL1, and HSP0B—which were shown to form a chemoattractant complex that was required for glioma cell invasion toward NPC-conditioned medium, and depletion of individual growth factors showed that all 4 were necessary for glioma invasion in vitro. PTN expression was enriched in the stem-cell niche of the SVZ in adult and late postnatal murine brain and in adult and pediatric human brain, whereas SPARC, SPARCL1, and HSP90B are more broadly expressed, suggesting that PTN mediates the chemoattraction of DIPG and other glioma cells to SVZ NPCs, and the PTN chemoattractant complex was shown to mediate DIPG invasion via the RhoA/ROCK signaling pathway. Ptn ablation or in vivo knockdown of Hsp90b1 reduced DIPG invasion into the SVZ in vivo, and treatment with ROCK inhibitors reduced DIPG cell invasion toward SVZ NPCs in vitro. These findings describe the role of NPCs in HGG invasion into the SVZ, and suggest a potential strategy to target HGG invasion.
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