Blockade of a chemokine, CCL2, reduces chronic colitis-associated carcinogenesis in mice.
Accumulating evidence indicates the crucial contribution of chronic inflammation to various types of carcinogenesis, including colon carcinoma associated with ulcerative colitis and asbestosis-induced malignant mesothelioma. Ulcerative colitis-associated colon carcinogenesis can be recapitulated in mice by azoxymethane administration followed by repetitive dextran sulfate sodium ingestion. In the course of this carcinogenesis process, the expression of a macrophage-tropic chemokine, CCL2, was enhanced together with intracolonic massive infiltration of macrophages, which were a major source of cyclooxygenase (COX)-2, a crucial mediator of colon carcinogenesis. Mice deficient in CCL2-specific receptor, CCR2, exhibited less macrophage infiltration and lower tumor numbers with attenuated COX-2 expression. Moreover, CCL2 antagonists decreased intracolonic macrophage infiltration and COX-2 expression, attenuated neovascularization, and eventually reduced the numbers and size of colon tumors, even when given after multiple colon tumors have developed. These observations identify CCL2 as a crucial mediator of the initiation and progression of chronic colitis-associated colon carcinogenesis and suggest that targeting CCL2 may be useful in treating colon cancers, particularly those associated with chronic inflammation.
Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Boryana Konstantinova
BK
Popivanova
Feodora Ivanova
FI
Kostadinova
Kengo
K
Furuichi
Mohamed M
MM
Shamekh
Toshikazu
T
Kondo
Takashi
T
Wada
Kensuke
K
Egashira
Naofumi
N
Mukaida
D000818:Animals; D001397:Azoxymethane; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D016264:Dextran Sulfate; D005260:Female; D005857:Germanium; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009942:Organometallic Compounds / Q000494:pharmacology; D011422:Propionates; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D009942:Organometallic Compounds; D011422:Propionates; D012333:RNA, Messenger; D054390:Receptors, CCR2; D005857:Germanium; C066750:propagermanium; D016264:Dextran Sulfate; D051546:Cyclooxygenase 2; D001397:Azoxymethane