Essential contribution of a chemokine, CCL3, and its receptor, CCR1, to hepatocellular carcinoma progression.
We previously observed that a chemokine, macrophage inflammatory protein-1 alpha/CCL3, and its receptor, CCR1, were aberrantly expressed in human hepatocellular carcinoma (HCC) tissues. Here, we show that CCL3 and CCR1 are also expressed in 2 different models of this cancer; N-nitrosodiethylamine (DEN)-induced HCC and HCC induced by hepatitis B virus surface (HBs) antigen-primed splenocyte transfer to myelo-ablated syngeneic HBs antigen transgenic mice. At 10 months after DEN treatment, foci number and sizes were remarkably reduced in CCR1- and CCL3-deficient mice, compared with those of wild-type (WT) mice, although tumor incidence were marginally, but significantly, higher in CCR1- and CCL3-deficient mice than in WT mice. Of note is that tumor angiogenesis was also markedly diminished in CCL3- and CCR1-deficient mice, with a concomitant reduction in the number of intratumoral Kupffer cells, a rich source of growth factors and matrix metalloproteinases (MMPs). Among growth factors and MMPs that we examined, only MMP9 and MMP13 gene expression was augmented progressively in liver of WT mice after DEN treatment. Moreover, MMP9, but not MMP13, gene expression was attenuated in CCR1- and CCL3-deficient mice, compared with that of WT mice. Furthermore, MMP9 was expressed mainly by mononuclear cells but not hepatoma cells, and MMP9-expressing cell numbers were decreased in CCR1- or CCL3-deficient mice, compared with WT mice. These observations suggest the contribution of the CCR1-CCL3 axis to HCC progression.
Yang
Xiaoqin
X
Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Lu
Peirong
P
Fujii
Chifumi
C
Nakamoto
Yasunari
Y
Gao
Ji-Liang
JL
Kaneko
Shuichi
S
Murphy
Philip M
PM
Mukaida
Naofumi
N
D000477:Alkylating Agents / Q000008:administration & dosage; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D004052:Diethylnitrosamine / Q000008:administration & dosage; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D006515:Hepatitis B virus; D008113:Liver Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000235:genetics; D013154:Spleen / Q000166:cytology
D000477:Alkylating Agents; C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D004052:Diethylnitrosamine; D020782:Matrix Metalloproteinases