Astrocytes influence medulloblastoma phenotypes and CD133 surface expression.

Emily Gronseth,Chris Koceja,Kevin Rarick,Ankan Gupta,Suresh Kumar,Raman G Kutty,Ling Wang,Ramani Ramchandran,Gianpaolo Papaccio

doi:10.1371/journal.pone.0235852

Abstract

The medulloblastoma (MB) microenvironment is diverse, and cell-cell interactions within this milieu is of prime importance. Astrocytes, a major component of the microenvironment, have been shown to impact primary tumor cell phenotypes and metastasis. Based on proximity of MB cells and astrocytes in the brain microenvironment, we investigated whether astrocytes may influence MB cell phenotypes directly. Astrocyte conditioned media (ACM) increased Daoy MB cell invasion, adhesion, and in vivo cellular protrusion formation. ACM conditioning of MB cells also increased CD133 surface expression, a key cancer stem cell marker of MB. Additional neural stem cell markers, Nestin and Oct-4A, were also increased by ACM conditioning, as well as neurosphere formation. By knocking down CD133 using short interfering RNA (siRNA), we showed that ACM upregulated CD133 expression in MB plays an important role in invasion, adhesion and neurosphere formation. Collectively, our data suggests that astrocytes influence MB cell phenotypes by regulating CD133 expression, a key protein with defined roles in MB tumorgenicity and survival.

Highlights

Medulloblastoma (MB) is a pediatric brain tumor that can occur in the cerebellum or in the brainstem
We validated three microarray targets (NFASC, L1CAM, NCAM2) related to adhesion network, which were up in Astrocyte conditioned media (ACM)-treated MB cells at both mRNA (S1C Fig) and proteins levels (S1D Fig). These results demonstrated the breadth of effects of astrocyte-secreted factors on MB cells, and pointed to adhesion-related phenotypes
The MB microenvironment is comprised of various cell types, and depending on where the tumor is located, cells such as astrocytes, microglia, and others [35] can interact with MB cells

Summary

Introduction

Medulloblastoma (MB) is a pediatric brain tumor that can occur in the cerebellum or in the brainstem. Large genomic studies have stratified the tumors into at least four molecular subtypes [1, 2] which has been critical to advance research and clinical understanding of MB. Analyzing the genomic landscape of the tumor cells themselves is important, it is well appreciated that the tumor microenvironment has an important role in contributing to tumor cell fate. It’s been shown that various factors in a tumor microenvironment have significant effects on response to therapy [3, 4]. To improve current treatments for MB, understanding how factors and cells within the MB tumor microenvironment may be influencing tumor cells is necessary.

Methods

Results

Conclusion