Octreotide acts as an antitumor angiogenesis compound and suppresses tumor growth in nude mice bearing human hepatocellular carcinoma xenografts.
OBJECTIVE
To investigate the effect of octreotide on angiogenesis induced by human hepatocellular carcinoma (HCC) and to evaluate whether octreotide can suppress tumor growth in nude mice bearing human HCC xenografts through inhibition of angiogenesis.


METHODS
Using MTT assay, invasion assay, migration assay, and Matrigel assay, the effects of octreotide on endothelial cells stimulated by vascular endothelial growth factor (VEGF) were evaluated in vitro. MTT assay was also used to investigate the effects of octreotide on human HCC cells with high (MHCC97-H) and low (MHCC97-L) metastatic potential that were established from the animal model of human HCC LCI-D20 in nude mice. The expression of somatostatin receptor (SSTR) subtypes in human umbilical vein endothelial cells (HUVECs), MHCC97-H, and MHCC97-L cells was detected by RT-PCR analysis. An 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 the immunohistochemical SP method.


RESULTS
In vitro, octreotide inhibited the proliferation, invasion, and differentiation of HUVECs elicited by VEGF. RT-PCR analysis demonstrated that HUVECs expressed the somatostatin receptor subtype SSTR3. 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. In cell culture, MHCC97-H and MHCC97-L cells were insensitive to octreotide at concentrations that significantly inhibited endothelial cells proliferation. The HCC cells used did not express any known SSTRs. Immunohistochemical studies of tumor tissues revealed decreased microvessel density in octreotide-treated animals as compared with controls.


CONCLUSIONS
The present study demonstrates that the somatostatin analogue octreotide is a potent antitumor angiogenesis compound and the antiproliferative effect of octreotide on tumor growth in nude mice bearing HCC xenografts may be mediated, at least in part, by its suppressive effect on blood vessel supply. The somatostatin analogue octreotide might provide a useful and relatively nontoxic adjuvant therapy in the treatment of HCC.
Jia
Wei-Dong
WD
Department of General Surgery, Anhui Provincial Hospital, 4 Lu Jiang Road, 230001 Hefei, P.R. China. jwd@whir.net
Xu
Ge-Liang
GL
Xu
Rong-Nan
RN
Sun
Hui-Chuan
HC
Wang
Lu
L
Yu
Ji-Hai
JH
Wang
Jian
J
Li
Jian-Sheng
JS
Zhai
Zhi-Ming
ZM
Xue
Qiong
Q
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000188:drug therapy*; D016228:Endothelial Growth Factors / Q000494:pharmacology; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008113:Liver Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008833:Microcirculation; D009389:Neovascularization, Pathologic; D015282:Octreotide / Q000494:pharmacology*; D012039:Regional Blood Flow; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D018931:Antineoplastic Agents, Hormonal; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D015282:Octreotide