Monocyte chemoattractant protein 1 and CD40 ligation have a synergistic effect on vascular endothelial growth factor production through cyclooxygenase 2 upregulation in gastric cancer.
BACKGROUND
Recent studies have reported that expression of monocyte chemoattractant protein 1 (MCP-1) and its receptor (CCR2) and CD40 ligation on mesenchymal cells play important roles in tumor development. Cyclooxygenase 2 (COX-2) has also been shown to contribute to tumor angiogenesis. We examined the interaction between MCP-1 and CD40 ligation in mesenchymal cells in gastric cancer to determine the effect of these factors on vascular endothelial growth factor (VEGF) production via upregulation of COX-2 expression.


METHODS
COX-2, prostaglandin E2 (PGE2), and VEGF production were evaluated in CD40 ligand (CD40L)-stimulated macrophages. CD40L and MCP-1 mRNA levels in gastric cancer tissues were evaluated by real-time polymerase chain reaction (PCR). Localizations of MCP-1, CD40L, CD34, CD40, and CCR2 in 34 gastric cancer tissue specimens were evaluated by single-or double-label immunohistochemistry.


RESULTS
COX-2 expression levels were significantly higher in CD40L-stimulated macrophages and correlated with increased PGE2 and VEGF production. Addition of MCP-1 to CD40L-stimulated macrophages had a synergistic effect on COX-2 expression and subsequent PGE2 and VEGF production. CD40L and MCP-1 mRNA levels were significantly higher in poorly differentiated gastric cancers than in H. pylori-infected gastritis patients. High microvessel density was significantly associated with MCP-1 and CCR2 scores and lymph node metastasis.


CONCLUSIONS
MCP-1 and CD40L had a synergistic effect on COX-2 expression and subsequent VEGF production in gastric cancer.
Futagami
Seiji
S
Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Tokyo, 113-8603, Japan.
Tatsuguchi
Atsushi
A
Hiratsuka
Tetsuro
T
Shindo
Tomotaka
T
Horie
Akane
A
Hamamoto
Tatsuhiko
T
Ueki
Nobue
N
Kusunoki
Masafumi
M
Miyake
Kazumasa
K
Gudis
Katya
K
Tsukui
Taku
T
Sakamoto
Choitsu
C
D000230:Adenocarcinoma / Q000473:pathology; D000328:Adult; D000368:Aged; D023201:CD40 Ligand / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005756:Gastritis / Q000382:microbiology / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000473:pathology; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism; D013274:Stomach Neoplasms / Q000473:pathology*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C515334:CCR2 protein, human; D018932:Chemokine CCL2; D012333:RNA, Messenger; D054390:Receptors, CCR2; D042461:Vascular Endothelial Growth Factor A; D023201:CD40 Ligand; D051546:Cyclooxygenase 2