A signaling mute hCMV chemokine receptor prevents melanoma growth Free

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Chemokine secretion by tumor cells enhances tumor growth and leads to progression. Previously, we have shown that tumor survival and growth is dependent on a chemokine gradient. In an effort to preserve chemokines from the tumor microenvironment, thus potentially abrogating tumor growth, we embarked on US28, a constitutively active human cytomegalovirus-encoded chemokine receptor homologue. US28 promotes different functions in vitro, like scavenging multiple chemokines from the cell microenvironment, enhancing migration of endothelial cells or inducing apoptosis.

A primary low-tumorigenic (SBcl2) and a high-tumorigenic melanoma cell line (451Lu) were transduced with a lentiviral vector, encoding either green fluorescent protein (GFP), wild-type US28 (wt) or a previously described signaling mute version of US28 (R129A), which lacks the constitutive signaling activity of the wild type receptor while maintaining its endocytic properties.

In vitro, CCL2 levels, as expected, were reduced in wt- and R129A-SBcl2 melanoma cells. When compared to GFP- and wt SBcl2 cells, the proliferation of R129A-SBcl2 cells was hampered and cell migration was reduced, as exemplified in a wound healing assay. In vivo, growth of 2x10⁶ melanoma cells injected subcutaneously into the back of SCID mice was measured. We observed that wild type US28 exerts anti-proliferative properties in the low-tumorigenic melanoma cell line SBcl2, whereas the signaling mute R129A impressively prevents melanoma growth in both cell lines.

The tumor-inhibitory properties of US28R129A are the first report, that a tailored mutation in this viral receptor prevents tumorgenesis and may represent a novel approach to interfere with tumor promoting effects of chemokines in solid tumors.