Ryk is essential for Wnt-5a-dependent invasiveness in human glioma

Abstract

Glioblastoma is characterized by marked invasiveness, but little is known about the mechanism of invasion in glioblastoma cells. Wnts are secreted ligands that regulate cell proliferation, differentiation, motility and fate at various developmental stages. In adults, misregulation of the Wnt pathway is associated with several diseases. Recently, we reported that Wnt-5a was overexpressed and correlated with cell motility and infiltrative activity through the regulation of matrix metalloproteinase (MMP)-2 in glioma-derived cells. Although several receptors for Wnt-5a were identified, the receptors of Wnt-5a that mediate cellular responses of glioma were not clearly identified. Knockdown of receptor-like tyrosine kinase (Ryk) but not that of Ror2 suppressed the activity of MMP-2 and Wnt-5a-dependent invasive activity in glioma cells. These results suggest that Ryk is important for the Wnt-5a-dependent induction of MMP-2 and invasive activity in glioma-derived cells and that Ryk might have a novel patho-physiological function in adult cancer invasion. Furthermore, not only the expression of Wnt-5a but also that of Frizzled (Fz)-2 and Ryk was correlated with the WHO histological grade in 38 human glioma tissues. Taking these findings together, Fz-2 and Ryk could be therapeutic or pharmacological target molecules for the control of Wnt-5a-dependent invasion of human glioma in the near future.

Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells

“…Findings on Wnt5a roles and functions in these tumors are restricted to the observed increased motility in cultured cell lines (25,27). Recently, however, it has been shown that the enhanced migration caused in hGBMs by reduced Wnt inhibitor 1 activity is mediated by Wnt5a (48).…”

“…It has been shown that Wnt5a is overexpressed in high-grade gliomas, but the role for Wnt5a in regulating proliferation and migration in gliomas has only been demonstrated, in a few cell lines, in vitro (23)(24)(25)(26)(27). Here, we explore whether Wnt5a can function as a master regulator of the invasive capacity of hGBMs.…”

Glycoprotein non-metastaticmelanoma protein B promotes glioma motility and angiogenesis through the Wnt/β-catenin signaling pathway

“…30,31 Additionally, Wnt signaling is associated with the activity of MMPs, which may co-regulate the progression of glioma. 10,32 Zhang et al 33 reported that intracellular Wnt/b-Catenin could induce MMP-9 expression in endometrial stromal cells by binding interaction between b-catenin/TCF3/ LEF1 complex with MMP-9 promoter. Additionally, the Wnt/b-catenin signaling is correlated with MMP-1 and MMP-7 levels in other tumor cells.…”

microRNA regulation of Wnt signaling pathways in development and disease

“…Further, Ryk-deficient mice exhibit defects similar to Wnt/PCP mutants, such as the misorientation of stereocilia in the inner ear [91]. In glioma-derived cells, Ryk is important for the Wnt5a-dependent induction of matrix metalloproteinase (MMP-2) that degrades extracellular matrix to facilitate cancer cell motility and increase invasive activity [92]. Thus, Ryk is a pharmacological target for human glioma.…”