Open AccessCCL 2 as a potential therapeutic target for clear cell renal cell carcinoma
Author(s) -
Arakaki Ryuichiro,
Yamasaki Toshinari,
Kanno Toru,
Shibasaki Noboru,
Sakamoto Hiromasa,
Utsunomiya Noriaki,
Sumiyoshi Takayuki,
Shibuya Shinsuke,
Tsuruyama Tatsuaki,
Nakamura Eijiro,
Ogawa Osamu,
Kamba Tomomi
Publication year - 2016
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.886
Subject(s) - angiogenesis , cancer research , cell growth , chemistry , carcinogenesis , oncogene , cell , downregulation and upregulation , in vivo , chemokine , pathology , biology , cancer , medicine , cell cycle , receptor , biochemistry , microbiology and biotechnology , gene
We previously reported that the pVHL ‐atypical PKC ‐JunB pathway contributed to promotion of cell invasiveness and angiogenesis in clear cell renal cell carcinoma (cc RCC ), and we detected chemokine (C‐C motif) ligand‐2 ( CCL 2) as one of downstream effectors of JunB. CCL 2 plays a critical role in tumorigenesis in other types of cancer, but its role in cc RCC remains unclear. In this study, we investigated the roles and therapeutic potential of CCL 2 in cc RCC . Immunohistochemical analysis of CCL 2 expression for cc RCC specimens showed that upregulation of CCL 2 expression correlated with clinical stage, overall survival, and macrophage infiltration. For functional analysis of CCL 2 in cc RCC cells, we generated subclones of WT 8 cells that overexpressed CCL 2 and subclones 786‐O cells in which CCL 2 expression was knocked down. Although CCL 2 expression did not affect cell proliferation in vitro, CCL 2 overexpression enhanced and CCL 2 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 RCC . Depletion of macrophages suppressed tumor growth and angiogenesis. To examine the effect of inhibiting CCL 2 activity in cc RCC , we administered CCL 2 neutralizing antibody to primary RCC xenografts established from patient surgical specimens. Inhibition of CCL 2 activity resulted in significant suppression of tumor growth, angiogenesis, and macrophage infiltration. These results suggest that CCL 2 is involved in angiogenesis and macrophage infiltration in cc RCC , and that CCL 2 could be a potential therapeutic target for cc RCC .