D6 is an atypical chemokine receptor acting as a decoy and scavenger for inflammatory CC chemokines expressed in lymphatic endothelial cells. Here it is reported that D6 is expressed by Kaposi's sarcoma (KS), a tumor ontogenetically related to lymphatic endothelium. Both in human tumors and in an experimental model, D6 expression levels were inversely correlated with tumor aggressiveness and increased infiltration of proangiogenic macrophages. Inhibition of monocyte recruitment reduced growth of tumors, while adoptive transfer of WT but not CCR2-/- macrophages increased the growth rate of D6-competent neoplasms. In the KS model, which presents the B-Raf V600E activating mutation, inhibition of B-Raf or downstream ERK pathway induced D6 expression, and in progressing human KS tumors activation of ERK correlate with reduced levels of D6 expression. These results indicate that activation of the K-Ras/B-Raf/ERK pathway during KS progression downregulates D6 expression, which unleashes chemokine-mediated macrophage recruitment and their acquisition of an M2-like phenotype supporting angiogenesis and tumor growth. Combined targeting of CCR2 and the ERK pathway should be considered as a therapeutic option for KS patients.
- Received November 13, 2013.
- Revision received February 17, 2014.
- Accepted March 2, 2014.
- Copyright © 2014, American Association for Cancer Research.