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The Role of Cyclooxygenase-2 in Mediating the Effects of Histamine on Cell Proliferation and Vascular Endothelial Growth Factor Production in Colorectal Cancer

Authors' Affiliations: Departments of ¹ General Surgery; ² Experimental Pathology and Oncology; ³ Anatomy, Histology, and Forensic Medicine; ⁴ Human Pathology and Oncology; and ⁵ Preclinical and Clinical Pharmacology, Medical School, University of Florence, Italy

Requests for reprints: Fabio Cianchi, Dipartimento di Area Critica Medico-Chirurgica, Medical School, University of Florence Viale Morgagni 85, 50134 Firenze, Italy. Phone: 3955-427-7566; Fax: 3955-422-0133; E-mail: cianchif{at}mail.unifi.it.

Purpose: Activity of histidine decarboxylase, the key enzyme in the synthesis of histamine, has been shown to be increased in several types of human tumors. We attempted to establish whether the possible involvement of histidine decarboxylase and histamine in colorectal carcinogenesis might be mediated by the activation of the cyclooxygenase-2 (COX-2) pathway.

Experimental Design: Expression/activity of histidine decarboxylase, histamine content, and prostaglandin E₂ (PGE₂) production were analyzed in 33 colorectal cancer samples and in the HT29, Caco-2, and HCT116 colon cancer cell lines. The effects of histamine, celecoxib, and H₁, H₂, and H₄ receptor antagonists on COX-2 expression/activity, cell proliferation, and vascular endothelial growth factor (VEGF) production were assessed in the three colon cancer lines that showed different constitutive COX-2 expression.

Results: We showed the up-regulation of histidine decarboxylase protein expression and activity in the tumor specimens when compared with normal colonic mucosa. Histidine decarboxylase activity and histamine content were also significantly higher in metastatic tumors than in nonmetastatic ones. These variables significantly correlated with tumor PGE₂ production. The administration of histamine increased COX-2 expression/activity, cell proliferation, and VEGF production in the COX-2-positive HT29 and Caco-2 cells. Treatment with either H₂/H₄ receptor antagonists or celecoxib prevented these effects. Histamine had no effect on both the COX-2 pathway and VEGF production in the COX-2-negative HCT116 cells.

Conclusions: Our data showed that histamine exerts both a proproliferative and a proangiogenic effect via H₂/H₄ receptor activation. These effects are likely to be mediated by increasing COX-2-related PGE₂ production in COX-2-expressing colon cancer cells.

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