ERK-dependent downregulation of the atypical chemokine receptor D6 drives tumor aggressiveness in Kaposi sarcoma.
D6 is an atypical chemokine receptor acting as a decoy and scavenger for inflammatory CC chemokines expressed in lymphatic endothelial cells. Here, we report that D6 is expressed in Kaposi sarcoma (KS), a tumor ontogenetically related to the 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 the growth of tumors, while adoptive transfer of wild-type, but not CCR2(-/-) macrophages, increased the growth rate of D6-competent neoplasms. In the KS model with the B-Raf V600E-activating mutation, inhibition of B-Raf or the downstream ERK pathway induced D6 expression; in progressing human KS tumors, the activation of ERK correlates 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 patients with KS.
Authors' Affiliations: Humanitas Clinical and Research Center; Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Rozzano;
Benedetta
B
Savino
Authors' Affiliations: Humanitas Clinical and Research Center; Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Rozzano;
Nicoletta
N
Caronni
Authors' Affiliations: Humanitas Clinical and Research Center;
Achille
A
Anselmo
Authors' Affiliations: Humanitas Clinical and Research Center;
Fabio
F
Pasqualini
Authors' Affiliations: Humanitas Clinical and Research Center; Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Rozzano;
Elena Monica
EM
Borroni
Authors' Affiliations: Humanitas Clinical and Research Center;
Gianluca
G
Basso
Authors' Affiliations: Humanitas Clinical and Research Center;
Giuseppe
G
Celesti
Authors' Affiliations: Humanitas Clinical and Research Center;
Luigi
L
Laghi
UO Dermatologia, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
Athanasia
A
Tourlaki
UO Dermatologia, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
Vinicio
V
Boneschi
UO Dermatologia, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
Lucia
L
Brambilla
Department of Clinical Sciences "Luigi Sacco," Università degli Studi di Milano; and.
Manuela
M
Nebuloni
Department of Clinical Sciences "Luigi Sacco," Università degli Studi di Milano; and.
Gianluca
G
Vago
Authors' Affiliations: Humanitas Clinical and Research Center; Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Rozzano;
Alberto
A
Mantovani
Authors' Affiliations: Humanitas Clinical and Research Center; Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Rozzano;
Massimo
M
Locati
Authors' Affiliations: Humanitas Clinical and Research Center; Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Rozzano; raffaella.bonecchi@humanitasresearch.it.
Raffaella
R
Bonecchi
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation / Q000276:immunology*; D064593:Heterografts; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000276:immunology; D054447:Receptors, CCR10 / Q000096:biosynthesis* / Q000276:immunology; D012514:Sarcoma, Kaposi / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D000097628:Chemokine Receptor D6
D016207:Cytokines; D018836:Inflammation Mediators; D054447:Receptors, CCR10; D042461:Vascular Endothelial Growth Factor A; D000097628:Chemokine Receptor D6