Histamine modulates the expression of Bcl-2 family proteins, neovascularization and growth of pancreatic carcinoma xenografts in nude mice

CRICCO G; MOHAMAD N; CROCI M; SAMBUCO L; CRESCENTI E; BERGOC R; RIVERA E; MARTÍN G

Budapest, Hungary

Congreso; European Association for Cancer Reasearch. 19th Meeting.; 2006

European Association for Cancer Reasearch.

Panc-1 cell line derives from a human pancreatic carcinoma of ductal origin. We have previously reported that these cells overexpress histamine (HA) H1 and H2 receptors and that HA distinctively modulates cell growth via these receptors. Nanomolar HA doses stimulate cell proliferation while micromolar concentrations inhibit clonogenic growth, without inducing apoptosis in a significant way. Moreover it has been reported that HA acts as an angiogenic factor on endothelial cells and also induces vascular endothelial growth factor (VEGF) synthesis in granulation tissue through H2 receptors. The aim of this work was to evaluate the action of HA on the growth of pancreatic carcinoma xenografts in nude mice (NIH: un strain). Animals were sc inoculated with 3x106 PANC-1 cells. The developed tumours were histologically described as undifferentiated adenocarcinomas (G4). When tumour volume reached 65 mm3, animals received the following treatments during 25 days: HA (1mg/kg day, sc), ranitidine (H2 antagonist, 50 mg/kg day, po) or loratadine (H1 antagonist, 2.5 mg/ kg day, po). We evaluated the macroscopic tumour growth, neovascularizaton and apoptosis induced by the treatments above mentioned. Tumour growth was significantly increased in HA and loratadine (Lor) treated animals. The tumour expression of Bcl-2 family members determined by immunohistochemistry showed that Bcl-2/Bax ratio is enhanced by HA and Lor while this ratio remains unchanged in ranitidine (Ran) treated mice. Tumour vascularization assessment by Masson trichromic stain revealed that peri and intratumoural vessel density was augmented by HA. In addition, the immunohistochemical evaluation indicated that the intratumoural levels of HA and VEGF, both angiogenic and growth factors, were higher in faster growing tumours (HA and Lor treated animals) In summary, HA stimulates orthotopic pancreatic tumour cell proliferation in vivo exerting a direct antiapoptotic action. This effect on tumour growth is associated to an increased tumour synthesis of HA and VEGF which may regulate tumour-stroma interactions. POSTER