CCL2 as a potential therapeutic target for clear cell renal cell carcinoma

摘要

We previously reported that the pVHL‐atypical PKC‐JunB pathway contributed to promotion of cell invasiveness and angiogenesis in clear cell renal cell carcinoma (ccRCC), and we detected chemokine (C‐C motif) ligand‐2 (CCL2) as one of downstream effectors of JunB. CCL2 plays a critical role in tumorigenesis in other types of cancer, but its role in ccRCC remains unclear. In this study, we investigated the roles and therapeutic potential of CCL2 in ccRCC. Immunohistochemical analysis of CCL2 expression for ccRCC specimens showed that upregulation of CCL2 expression correlated with clinical stage, overall survival, and macrophage infiltration. For functional analysis of CCL2 in ccRCC cells, we generated subclones of WT8 cells that overexpressed CCL2 and subclones 786‐O cells in which CCL2 expression was knocked down. Although style="fixed-case">CCL2 expression did not affect cell proliferation in vitro, style="fixed-case">CCL2 overexpression enhanced and style="fixed-case">CCL2 knockdown suppressed tumor growth, angiogenesis, and macrophage infiltration in vivo. We then depleted macrophages from tumor xenografts by administration of clodronate liposomes to confirm the role of macrophages in cc style="fixed-case">RCC. Depletion of macrophages suppressed tumor growth and angiogenesis. To examine the effect of inhibiting style="fixed-case">CCL2 activity in cc style="fixed-case">RCC, we administered style="fixed-case">CCL2 neutralizing antibody to primary style="fixed-case">RCC xenografts established from patient surgical specimens. Inhibition of style="fixed-case">CCL2 activity resulted in significant suppression of tumor growth, angiogenesis, and macrophage infiltration. These results suggest that style="fixed-case">CCL2 is involved in angiogenesis and macrophage infiltration in cc style="fixed-case">RCC, and that style="fixed-case">CCL2 could be a potential therapeutic target for cc style="fixed-case">RCC.