Abstract
Metastasizing tumor cells undergo a transformation that resembles a process in normal development when non-migratory epithelial cells modulate the expression of cytoskeletal and adhesion proteins to promote cell motility. Here we find a mesenchymal cadherin, Cadherin-11 (CDH11), is increased in cells exiting the ventricular zone (VZ) neuroepithelium during normal cerebral cortical development. When overexpressed in cortical progenitors in vivo, CDH11 causes premature exit from the neuroepithelium and increased cell migration. CDH11 expression is elevated in human brain tumors, correlating with higher tumor grade and decreased patient survival. In glioblastoma, CDH11-expressing tumor cells can be found localized near tumor vasculature. Endothelial cells stimulate TGFβ signaling and CDH11 expression in glioblastoma cells. TGFβ promotes glioblastoma cell motility, and knockdown of CDH11 expression in primary human glioblastoma cells inhibits TGFβ-stimulated migration. Together, these findings show that Cadherin-11 can promote cell migration in neural precursors and glioblastoma cells and suggest that endothelial cells increase tumor aggressiveness by co-opting mechanisms that regulate normal neural development.
Highlights
Mechanisms that regulate normal development can be co-opted in tumor development
Ethics Statement Glioma stem cells (GSCs) were isolated from GBM primary surgical specimens in keeping with protocols approved by the Northwestern University Institutional Review Board, NU 07C2: ‘‘Lineage determination of brain tumor stem-like cells (BTSCs) harvested from human astrocytic and oligodendroglial tumors.’’ Written informed consent was obtained from the donors or of kin for the use of tissue samples for this research
Cell Culture Glioma stem cells (GSCs) were isolated from GBM primary surgical specimens in keeping with protocols approved by the Northwestern University Institutional Review Board, NU 07C2: ‘‘Lineage determination of brain tumor stem-like cells (BTSCs) harvested from human astrocytic and oligodendroglial tumors.’’ Written informed consent was obtained from the donors or of kin for the use of tissue samples for this research
Summary
Mechanisms that regulate normal development can be co-opted in tumor development. Phenotypic and molecular alterations in cancer cells resembling the epithelial to mesenchymal transitions (EMT) that occur during normal organ development have been suggested as a critical step in the metastatic cascade [1,2,3]. As varying degrees of EMT correlate with invasiveness and poor prognosis of multiple human cancers, a greater understanding of the factors regulating EMT may lead to potential therapeutic approaches in cancer [4]. Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM cells are highly migratory and extensive infiltration of GBM cells into brain parenchyma renders curative surgical resection virtually impossible [5]. We examine whether the EMT-like processes occurring in normal neural development may regulate GBM cell migration
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