Experimental Study Of The Effect Of Octreotide On Angiogenesis Induced By Hepatocellular Carcinoma And Recurrence And Metastasis Of Hepatocellular Carcinoma After Curative Resection

Hepatocellular carcinoma (HCC) is generally considered to be a hypervascular tumor. Tumor cells can produce several angiogenic factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), which are supposed to induce neovascularization. Anti-angiogenic therapy can inhibit the growth, recurrence and metastasis of HCC. It has been recently reported that octreotide administration significantly improves survival and is a valuable alternative in the treatment of inoperable HCC. We had previously demonstrated that octreotide inhibited the growth of experimental liver tumor after partial hepatectomy. However, the exact mechanism of the antitumor effect of octreotide on HCC has not been elucidated. Octreotide has been recently suggested to inhibit experiment angiogenesis and suppress tumor growth through inhibition of angiogenesis. In this study, Using MTT assay, invasion assay, migration assay, and Matrigel assay, the effect of octreotide on endothelial cells stimulated by vascular endothelial growth factor (VEGF) was evaluated in vitro. LCI-D20 corneal micropocket model in nude mice was used to evaluate the effect of octreotide on angiogenesis induced by human HCC in vivo. Male nude mice were subcutaneously implanted with LCI-D20 tumor tissues for the tumor xenograft studies. Microvessel density was analyzed in CD34-stained tumor sections by immunohistochemical SP method. The metastatic model of human HCC in nude mice LCI-D20 was used to evaluate whether octreotide could suppress recurrence and metastasis of HCC after curative resection in nude mice through inhibition of angiogenesis. In vitro, octreotide inhibited the proliferation, invasion, anddifferentiation of HUVECs elicited by VEGF, while the effect of octreotide on the proliferation of HCC cells MHCC97-H and MHCC97-L was not obvious. In vivo, octreotide was sufficiently potent to suppress nude mice corneal neovascularization induced by tumor tissues from LCI-D20. Systemic administrations of octreotide produced a significant suppression of the growth of LCI-D20. Immunohistochemical studies of tumor tissues revealed decreased microvessel density in octreotide-treated animals as compared with controls. Octreotide dose-dependently inhibited recurrence and metastasis of HCC after curative resection in nude mice through inhibition of angiogenesis. The present study demonstrates that octreotide is able to inhibit angiogenesis induced by HCC and recurrence and metastasis of HCC after curative resection. It is reasonable to consider that the somatostatin analogue octreotide used as an adjuvant anti-angiogenic treatment administrated after or during conventional therapy (surgical, radiological and chemical), may provide a new approach to the treatment of HCC.