Skip to main content

Advertisement

SpringerLink
Log in

Monocyte chemoattractant protein 1 and CD40 ligation have a synergistic effect on vascular endothelial growth factor production through cyclooxygenase 2 upregulation in gastric cancer

  • Alimmentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 1996;56:4625–4629.

    PubMed  CAS  Google Scholar 

  2. Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res 2006;66:605–612.

    Article  PubMed  CAS  Google Scholar 

  3. Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Okumura H, Matsumoto M, et al. Tumor-associated macrophage (TAM) infiltration in gastric cancer. Anticancer Res 2003;23:4079–4083.

    PubMed  CAS  Google Scholar 

  4. Ohta M, Kitadai Y, Tanaka S, Yoshihara M, Yasui W, Mukaida N, et al. Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human gastric carcinomas. Int J Oncol 2003;22:773–778.

    PubMed  CAS  Google Scholar 

  5. Salcedo R, Ponce ML, Young HA, Wasserman K, Ward JM, Kleinman HK, et al. Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression. Blood 2000;96:34–40.

    PubMed  CAS  Google Scholar 

  6. Zhang L, Khayat A, Cheng H, Graves DT. The pattern of monocyte recruitment in tumors is modulated by MCP-1 expression and influences the rate of tumor growth. Lab Invest 1997;76: 579–590.

    PubMed  CAS  Google Scholar 

  7. Koide N, Nishio A, Sato T, Sugiyama A, Miyagawa S. Significance of macrophage chemoattractant protein-1 expression and macrophage infiltration in squamous cell carcinoma of the esophagus. Am J Gastroenterol 2004;99:1667–1674.

    Article  PubMed  CAS  Google Scholar 

  8. Mizuno H, Sakamoto C, Matsuda K, Wada K, Uchida T, Noguchi H, et al. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology 1997;112:387–397.

    Article  PubMed  CAS  Google Scholar 

  9. Tsujii M, Kawano S, DuBois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 1997;94:3336–3340.

    Article  PubMed  CAS  Google Scholar 

  10. Tatsuguchi A, Matsui K, Shinji Y, Gudis K, Tsukui T, Kishida T, et al. Cyclooxygenase-2 expression correlates with angiogenesis and apoptosis in gastric cancer tissue. Hum Pathol 2004;35: 488–495.

    Article  PubMed  CAS  Google Scholar 

  11. Miura S, Tatsuguchi A, Wada K, Takeyama H, Shinji Y, Hiratsuka T, et al. Cyclooxygenase-2-regulated vascular endothelial growth factor release in gastric fibroblast. Am J Physiol Gastrointest Liver Physiol 2004;287:G444–G451.

    Article  PubMed  CAS  Google Scholar 

  12. Zhang Y, Cao HJ, Graf B, Meekins H, Smith TJ, Phipps RP. CD40 engagement up-regulates cyclooxygenase-2 expression and prostaglandin E2 production in human lung fibroblasts. J Immunol 1998;160:1053–1057.

    PubMed  CAS  Google Scholar 

  13. Inoue Y, Otsuka T, Niiro H, Nagano S, Arinobu Y, Ogami E, et al. Novel regulatory mechanisms of CD40-induced prostanoid synthesis by IL-4 and IL-10 in human monocytes. J Immunol 2004;172:2147–2154.

    PubMed  CAS  Google Scholar 

  14. Danese S, Sans M, Fiocchi C. The CD40/CD40L costimulatory pathway in inflammatory bowel disease. Gut 2004;53:1035–1043.

    Article  PubMed  CAS  Google Scholar 

  15. Melter M, Reinders ME, Sho M, Pal S, Geehan C, Denton MD, et al. Ligation of CD40 induces the expression of vascular endothelial growth factor by endothelial cells and monocytes and promotes angiogenesis in vivo. Blood 2000;96:3801–3808.

    PubMed  CAS  Google Scholar 

  16. Sobin LH, Wittekind C (eds). TNM classification of malignant tumors, 5th ed. New York: Wiley-Liss; 1997.

    Google Scholar 

  17. Futagami S, Hiratsuka T, Tatsuguchi A, Suzuki K, Kusunoki M, Shinji Y, et al. Monocyte chemoattractant protein 1 (MCP-1) released from Helicobacter pylori stimulated gastric epithelial cells induces cyclooxygenase 2 expression and activation in T cells. Gut 2003;52:1257–1264.

    Article  PubMed  CAS  Google Scholar 

  18. Reul RM, Fang JC, Denton MD, Geehan C, Long C, Mitchell RN, et al. CD40 and CD40 ligand (CD154) are coexpressed on microvessels in vivo in human cardiac allograft rejection. Transplantation 1997;64:1765–1774.

    Article  PubMed  CAS  Google Scholar 

  19. Tang KF, Tan SY, Chan SH, Chong SM, Loh KS, Tan LK, et al. A distinct expression of CC chemokines by macrophages in nasopharyngeal carcinoma: implication for the intense tumor infiltration by T lymphocytes and macrophages. Hum Pathol 2001;32: 42–49.

    Article  PubMed  CAS  Google Scholar 

  20. Grunstein J, Roberts WG, Mathieu-Costello O, Hanahan D, Johnson RS. Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. Cancer Res 1999;59:1592–1598.

    PubMed  CAS  Google Scholar 

  21. Garlichs CD, Geis T, Goppelt-Struebe M, Eskafi S, Schmidt A, Schulze-Koops H, et al. Induction of cyclooxygenase-2 and enhanced release of prostaglandin E2 and I2 in human endothelial cells by engagement of CD40. Atherosclerosis 2002;163:9–16.

    Article  PubMed  CAS  Google Scholar 

  22. Tanaka S, Tatsuguchi A, Futagami S, Gudis K, Wada K, Seo T, et al. Monocyte chemoattractant protein-1 and macrophage cyclooxygenase-2 expression in colonic adenoma. Gut 2006;55: 54–61.

    Article  PubMed  CAS  Google Scholar 

  23. Nakashima E, Mukaida N, Kubota Y, Kuno K, Yasumoto K, Ichimura F, et al. Human MCAF gene transfer enhances the metastatic capacity of a mouse cachectic adenocarcinoma cell line in vivo. Pharm Res 1995;12:1598–1604.

    Article  PubMed  CAS  Google Scholar 

  24. Valkovic T, Lucin K, Krstulja M, Dobi-Babic R, Jonjic N. Expression of monocyte chemotactic protein-1 in human invasive ductal breast cancer. Pathol Res Pract 1998;194:335–340.

    PubMed  CAS  Google Scholar 

  25. Ohta M, Kitadai Y, Tanaka S, Yoshihara M, Yasui W, Mukaida N, et al. Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human esophageal squamous cell carcinomas. Int J Cancer 2002;102: 220–224.

    Article  PubMed  CAS  Google Scholar 

  26. Kuroda T, Kitadai Y, Tanaka S, Yang X, Mukaida N, Yoshihara M, et al. Monocyte chemoattractant protein-1 transfection induces angiogenesis and tumorigenesis of gastric carcinoma in nude mice via macrophage recruitment. Clin Cancer Res 2005;11:7629–7636.

    Article  PubMed  CAS  Google Scholar 

  27. Zhao H, Qin R, Chen X, Sheng X, Wu J, Wang D, et al. Microvessel density is a prognostic marker of human gastric cancer. World J Gastroenterol 2006;12:7598–7603.

    PubMed  Google Scholar 

  28. Valkovic T, Dobrila F, Melato M, Sasso F, Rizzardi C, Jonjic N. Correlation between vascular endothelial growth factor, angiogenesis, and tumor-associated macrophages in invasive ductal breast carcinoma. Virchows Arch 2002;440:583–588.

    Article  PubMed  CAS  Google Scholar 

  29. Danese S, Katz JA, Saibeni S, Papa A, Gasbarrini A, Vecchi M, et al. Activated platelets are the source of elevated levels of soluble CD40 ligand in the circulation of inflammatory bowel disease patients. Gut 2003;52:1435–1441.

    Article  PubMed  CAS  Google Scholar 

  30. Buning C, Kruger K, Sieber T, Schoeler D, Schriever F. Increased expression of CD40 ligand on activated T cells of patients with colon cancer. Clin Cancer Res 2002;8:1147–1151.

    PubMed  CAS  Google Scholar 

  31. Ochoa O, Sun D, Reyes-Reyna SM, Waite LL, Michalek JE, McManus LM, et al. Delayed angiogenesis and VEGF production in CCR2-/-mice during impaired skeletal muscle regeneration. Am J Physiol Regul Integr Comp Physiol 2007;293:R651–R61.

    PubMed  CAS  Google Scholar 

  32. Nakao S, Kuwano T, Tsutsumi-Miyahara C, Ueda S, Kimura YN, Hamano S, et al. Infiltration of COX-2-expressing macrophages is a prerequisite for IL-1 beta-induced neovascularization and tumor growth. J Clin Invest 2005;115:2979–2991.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan

    Seiji Futagami, Atsushi Tatsuguchi, Tetsuro Hiratsuka, Tomotaka Shindo, Akane Horie, Tatsuhiko Hamamoto, Nobue Ueki, Masafumi Kusunoki, Kazumasa Miyake, Katya Gudis, Taku Tsukui & Choitsu Sakamoto

Authors
  1. Seiji Futagami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Atsushi Tatsuguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tetsuro Hiratsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomotaka Shindo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akane Horie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tatsuhiko Hamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nobue Ueki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masafumi Kusunoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kazumasa Miyake
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Katya Gudis
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Taku Tsukui
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Choitsu Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Futagami, S., Tatsuguchi, A., Hiratsuka, T. et al. Monocyte chemoattractant protein 1 and CD40 ligation have a synergistic effect on vascular endothelial growth factor production through cyclooxygenase 2 upregulation in gastric cancer. J Gastroenterol 43, 216–224 (2008). https://doi.org/10.1007/s00535-007-2151-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-007-2151-8

Key words

Search

Navigation