Targeting tumor invasion: the roles of MDA-9/Syntenin

Abstract

Introduction Melanoma differentiation-associated gene – 9 (MDA-9)/Syntenin has become an increasingly popular focus for investigation in numerous cancertypes. Originally implicated in melanoma metastasis, it has diverse cellular roles and is consistently identified as a regulator of tumor invasion and angiogenesis. As a potential target for inhibiting some of the most lethal aspects of cancer progression, further insight into the function of MDA-9/Syntenin is mandatory. Areas covered Recent literature and seminal articles were reviewed to summarize the latest collective understanding of MDA-9/Syntenin’s role in normal and cancerous settings. Insights into its participation in developmental processes are included, as is the functional significance of the N- and C-terminals and PDZ domains of MDA-9/Syntenin. Current reports highlight the clinical significance of MDA-9/Syntenin expression level in a variety of cancers, often correlating directly with reduced patient survival. Also presented are assessments of roles of MDA-9/Syntenin in cancer progression as well as its functions as an intracellular adapter molecule. Expert opinion Multiple studies demonstrate the importance of MDA-9/ Syntenin in tumor invasion and progression. Through the use of novel drug design approaches, this protein may provide a worthwhile therapeutic target. As many conventional therapies do not address, or even enhance, tumor invasion, an anti-invasive approach would be a worthwhile addition in cancer therapy.

Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin

“…mda-9/syntenin expression correlates positively with astrocytoma grade, as analyzed through tissue samples and gene expression databases (11), and is most highly expressed in GBM. In both melanoma and glioma, MDA-9/Syntenin is involved in NF-κB activation through a proto-oncogene tyrosine-protein kinase Src (c-Src)/p38 MAPK signaling pathway (13,15). Inhibiting MDA-9/Syntenin expression reduces NF-κB target gene expression such as matrix metalloproteinase-2 (MMP-2), a critical secreted metalloproteinase involved in GBM invasion.…”

“…PDZ domains are common to a number of scaffolding proteins, and are critical for facilitating protein-protein interactions throughout various regions of the cell. MDA-9/Syntenin uses these motifs to successfully facilitate the interaction of c-Src-focal adhesion kinase (FAK) kinase complexes, noted for involvement in proinvasive signaling in cancer (13,15). In these contexts, inhibiting the interaction between MDA-9/Syntenin and its targets in GBM might provide a strategy to inhibit invasive functions of this gene.…”

“…MDA-9/Syntenin amplifies Src and NF-κB signaling in melanoma and glioma (13,14,20). Src is a recognized enhancer of invasive signals in cancer settings, and has demonstrated involvement in postradiation signaling (19).…”

“…MDA-9/Syntenin serves critical roles in signal transduction, as well as in cell-cell and cell-matrix adhesion (12,13). In addition to its roles in melanoma metastasis and tumor progression, MDA-9/Syntenin is highly expressed and involved in breast, gastric, and urothelial cell cancers (10,13).…”

“…MDA-9/Syntenin serves critical roles in signal transduction, as well as in cell-cell and cell-matrix adhesion (12,13). In addition to its roles in melanoma metastasis and tumor progression, MDA-9/Syntenin is highly expressed and involved in breast, gastric, and urothelial cell cancers (10,13). MDA-9/Syntenin is an important regulator of GBM invasion, angiogenesis, and tumor progression (14), and inhibiting MDA-9/Syntenin expression decreases GBM invasion (14,15) and enhances survival.…”