In a new study entitled “CXCR3 signaling in BRAFWT melanoma increases IL-8 expression and tumorigenicity,” researchers revealed that CXCR3 signaling promotes wild-type BRAF melanoma progression by inducing invasive and metastatic characteristics. The study was published in the open-access journal PLOS One.
Melanoma progression is most commonly associated (approximately 50% of the cases) with the oncogenic mutation BRAFV600E. However, melanoma can also progress in the absence of this mutation, making the exploration of the mechanisms that allow melanoma invasion and metastasis in the absence of BRAFV600E critical medical interest.
CXCR3, a chemokine receptor (chemokines are a class of secreted molecules that induce migration of target cells), is expressed at higher levels in several cancer cell lines and, in the case of melanoma (particularly at the invasive vertical growth phase, VGP) its high levels correlate with more aggressive tumors and poor patient outcomes.
In this study, researchers at the Norris Cotton Cancer Center showed that two radial growth phase (RGP) melanoma (an early and less aggressive stage of melanoma) cell lines, BOWES and WM35, increase CXCR3 expression in vitro when inserted in a stressed environment and submitted to nutrient deprivation. Notably, while BOWES cells have wild-type (thus non-mutated) BRAF, WM35 contains the BRAFV600E mutation. In BOWES cells, the authors found CXCR3 induced the expression of IL-8, which has been previously shown to significantly increase RGP melanoma tumorigenicity and metastatic potential.
The team also performed in vivo studies, observing that mice injected with BOWES CXCR3 exhibited increased tumor frequency and lymph node metastasis with IL-8 expression.
The authors highlight that these results add to the evidence that in melanomas carrying wild-type BRAF, CXCR3 triggers a significant increase in IL-8 expression, resulting in more aggressive tumors that are able to invade and metastasize.
David W. Mullins, study lead author commented in a press release, “We hypothesized that a melanoma may be able to sense that its environments is becoming inhospitable, and then respond by activating ‘escape mechanisms’ to leave the environment in search of greener pastures. We demonstrate that melanomas up-regulate the chemokine receptor CXCR3 in response to stress, including nutrient or oxygen deprivation, then use CXCR3 to launch migratory processes. Understanding this mechanism may lead to therapies to interfere with cancer metastasis and could help improve the efficacy of conventional or immune-based therapies.”