Human astrocytes secrete IL-6 to promote glioma migration and invasion through upregulation of cytomembrane MMP14

Abstract

The brain microenvironment has emerged as an important component in malignant progression of human glioma. However, astrocytes, the most abundant glial cells in the glioma microenvironment, have as yet a poorly defined role in the development of this disease, particularly with regard to invasion. Here, we co-cultured human astrocytes with human glioma cell lines, U251 and A172, in an in vitro transwell system in order to ascertain their influence on migration and invasion of gliomas. mRNA and protein expression assays were subsequently used to identify candidate proteins mediating this activity. Astrocytes significantly increased migration and invasion of both U251 and A172 cells in migration and invasion (plus matrigel) assays. Membrane type 1 matrix metalloproteinase (MMP14) originating from glioma cells was identified in qRT-PCR as the most highly up-regulated member of the MMP family of genes (~ 3 fold, p < 0.05) in this system. A cytokine array and ELISA were used to identify interleukin-6 (IL-6) as a highly increased factor in media collected from astrocytes, especially under co-culture conditions. IL-6 was also the key cytokine inducing cytomembrane MMP14 expression, the active form of MMP14, in glioma cells. Knockdown of MMP14 with siRNA led to decreased migration and invasion. Taken together, our results indicated that cytomembrane MMP14 was induced by IL-6 secreted from astrocytes, thereby enhancing the migration and invasion of glioma cells through activation of MMP2. Therefore, this IL-6 and MMP14 axis between astrocytes and glioma cells may become a potential target for treatment of glioma patients.

Astrocytes, the rising stars of the glioblastoma microenvironment

“…The report then suggests that TAAs in the perivascular niche promote the uPAR‐plasmin cascade to increase MMPs activation in GBM cells, consequently favoring invasion (Figure ). In a similar way, reactive astrocytes have been observed to secrete IL‐6, a protein able to enhance primary GBM cell invasion in vitro (Chen et al, ; Li et al, ). Indeed, GBM development, aggressiveness, and poor prognosis have been linked to the high expression of IL‐6 (Jiang, Han, Cheng, Wang, & Wu, ; Tchirkov et al, ).…”

“…GAP junctions allow the transfer of cGAMP from glioblastoma cells to surrounding tumor associated astrocytes (inspired by Chen et al, , Chen, Xia, et al, —Servier medical art). Gap junctions established through Cx43 and PCDH7 allow the transfer of cGAMP from GBM cells to TAAs.…”

Astrocytes enhance glioblastoma growth

“…Only few experimental studies have analyzed functional roles of astrocytes in GBM biology. These studies have predominantly focused on roles of astrocytes in GBM invasion (Chen et al, ; Le et al, ; Shabtay‐Orbach, Amit, Binenbaum, Na'ara, & Gil, ; Sin et al, ). Other studies have demonstrated interactions between astrocytes and GBM cells affecting drug‐sensitivity of GBM cells, or their response to hypoxia (Chen et al, ; Jin et al, ; Lin, Liu, Ling, & Xu, ; Yang et al, ).…”

Basolateral localization of MMP14 drives apicobasal polarity change during EMT independently of its catalytic activity

“…Indeed, MMP14 is a direct activator of MMP2 (Sato et al, 1994) which can cleave collagen IV, a key component of the basal membranes of epithelial tissues (Halfter et al, 2015). Numerous studies have demonstrated the ability of MMP14 to promote invasion via its catalytic activity (Cathcart et al, 2016;Chen et al, 2016;Macpherson et al, 2014). However, its known functions are not restricted to proteolysis of matrix components in the context of cell migration.…”