Seneca Valley Virus Exploits TEM8, a Collagen Receptor Implicated in Tumor Growth

Abstract

Recent studies reveal that Seneca Valley Virus (SVV) exploits tumor endothelial marker 8 (TEM8) for cellular entry, the same surface receptor pirated by bacterial-derived anthrax toxin. This observation is particularly significant as SVV is a known oncolytic virus which selectively infects and kills tumor cells, particularly those of neuroendocrine origin. TEM8 is a transmembrane glycoprotein that is preferentially upregulated in some tumor cell and tumor-associated stromal cell populations. Both TEM8 and SVV have been evaluated for targeting of tumors of multiple origins, but the connection between the two was previously unknown. Here, we review currently understood interactions between TEM8 and SVV, anthrax protective antigen (PA), and collagen VI, a native binding partner of TEM8, with an emphasis on potential therapeutic directions moving forward.

Keywords: Protective Antigen; Seneca Valley Virus; TEM8/ANTXR1; anthrax; neuroendocrine tumors; small cell lung cancer; type VI collagen.

Figure 1

Interactions between TEM8 and type VI collagen, Protective Antigen (PA) and (SVV). The two cell surface receptors, TEM8 and CMG2, can both bind type VI collagen and PA, but only TEM8 can bind SVV. Shown is a type VI collagen tetramer, with each chain comprising three separate α chains [α1(VI), α2(VI), and α3(VI)]. We've highlighted here the C-terminal portion of the α3(VI) chain (C1-C5). The C2-C5 chains are not found in mature fibrils and are proteolytically cleaved by an unknown protease during microfibril maturation; whether C5 binds in the context of a microfibril or in the context of a cleaved C5 domain is not known, so we present both possibilities.