Astrocytes facilitate melanoma brain metastasis via secretion of IL‐23

Abstract

Melanoma is the leading cause of skin cancer mortality. The major cause of melanoma mortality is metastasis to distant organs, frequently to the brain. The microenvironment plays a critical role in tumourigenesis and metastasis. In order to treat or prevent metastasis, the interactions of disseminated tumour cells with the microenvironment at the metastatic organ have to be elucidated. However, the role of brain stromal cells in facilitating metastatic growth is poorly understood. Astrocytes are glial cells that function in repair and scarring of the brain following injury, in part via mediating neuroinflammation, but the role of astrocytes in melanoma brain metastasis is largely unresolved. Here we show that astrocytes can be reprogrammed by human brain-metastasizing melanoma cells to express pro-inflammatory factors, including the cytokine IL-23, which was highly expressed by metastases-associated astrocytes in vivo. Moreover, we show that the interactions between astrocytes and melanoma cells are reciprocal: paracrine signalling from astrocytes up-regulates the secretion of the matrix metalloproteinase MMP2 and enhances the invasiveness of brain-metastasizing melanoma cells. IL-23 was sufficient to increase melanoma cell invasion, and neutralizing antibodies to IL-23 could block this enhanced migration, implying a functional role for astrocyte-derived IL-23 in facilitating the progression of melanoma brain metastasis. Knocking down the expression of MMP2 in melanoma cells resulted in inhibition of IL-23-induced invasiveness. Thus, our study demonstrates that bidirectional signalling between melanoma cells and astrocytes results in the formation of a pro-inflammatory milieu in the brain, and in functional enhancement of the metastatic potential of disseminated melanoma cells.

PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain MetastasesIn VitroandIn Vivo

“…Buparlisib This inflammatory cytokine in turn causes the melanoma cells to secrete the matrix metalloproteinase MMP2, thereby enhancing their invasiveness (27).…”

Emerging findings into molecular mechanism of brain metastasis

“…Moreover, astrocytes lately were confirmed its significant bidirectional relationship to melanoma cell. Brain‐metastasizing melanoma cells would stimulate astrocytes to express the pro‐inflammatory interleukin 23 (IL‐23) cytokine which in turn stimulate the secretion of matrix metalloproteinase‐2 (MMP‐2) 96. Nevertheless, STAT3 regulates the expression of MMP‐2, both human brain metastatic melanoma cells and tissue biopsies show increased STAT3 activity compared to cutaneous melanoma cells 97.…”

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“…Immortalized human brain microvascular endothelial cells (hCMEC/D3) were kindly provided by Dr. Clara Nahmias and Prof. Pierre-Olivier Couraud (Inserm, U1016, Institut Cochin, Paris, France) and were maintained as described by Weksler et al [59]. Human astrocytes were maintained as described previously [5]. Immortalized human microglia-SV40 cell line was purchased from ABM (ABM, Milton, Canada) and were maintained on 100μg/ml collagen I, rat tail (BD Biosciences, Bedford, MA, USA) in 10% fetal calf serum (FCS) supplemented Prigrow III medium (ABM).…”

“…Astrocytes, for example, interact with tumor cells in the brain whereby, these interactions may promote metastasis growth [5,6]. Furthermore, interaction of glioma initiating cells with macrophages/microglia up-regulate B7-H4 expression in the latter cells, blocking effective T-cell immune responses [7].…”

“…In a previous study we demonstrated that astrocytes have the capacity to chemo-attract melanoma cells thereby enhancing their ability to transmigrate through BEC [5]. We therefore evaluated whether ANGPTL4 affecs the transendothelial migration (TEM) of melanoma cells in a blood-brain barrier (BBB) model simulating the extravasation of melanoma cells through BEC towards www.impactjournals.com/oncotarget astrocytes.…”