Skip to main content

Advertisement

Springer Nature Link
Log in

Octreotide acts as an antitumor angiogenesis compound and suppresses tumor growth in nude mice bearing human hepatocellular carcinoma xenografts

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

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.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5A-C.
Fig. 6.
Fig. 7A,B.
Fig. 8.
Fig. 9.
Fig. 10A,B.

Similar content being viewed by others

References

  • Albini A, Florio T, Giunciuglio D, Masiello L, Carlone S, Corsaro A, Thellung S, Cai T, Noonan DM, Schettini G (1999) Somatostatin controls Kaposi's sarcoma tumor growth through inhibition of angiogenesis. FASEB J 13:647–655

    CAS  PubMed  Google Scholar 

  • Boehm T, Folkman J, Browder T, O'Reilly MS (1997) Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390:404–407

    CAS  PubMed  Google Scholar 

  • Cascinu S, Del Ferro E, Ligi M, Staccioli MP, Giordani P, Catalano V, Agostinelli R, Muretto P, Catalano G (2001) Inhibition of vascular endothelial growth factor by octreotide in colorectal cancer patients. Cancer Invest 19:8–12

    Article  CAS  PubMed  Google Scholar 

  • Curtis SB, Hewitt J, Yakubovitz S, Anzarut A, Hsiang YN, Buchan AM (2000) Somatostatin receptor subtype expression and function in human vascular tissue. Am J Physiol Heart Circ Physiol 278:H1815–1822

    CAS  PubMed  Google Scholar 

  • Danesi R, Del Tacca M (1996) The effects of the somatostatin analog octreotide on angiogenesis in vitro. Metabolism 45:49–50

    CAS  Google Scholar 

  • Danesi R, Agen C, Benelli U, Paolo AD, Nardini D, Bocci G, Basolo F, Campagni A, Tacca MD (1997) Inhibition of experimental angiogenesis by the somatostatin analogue octreotide acetate (SMS 201–995). Clin Cancer Res 3:265–272

    CAS  PubMed  Google Scholar 

  • Dimitroulopoulos D, Xinopoulos D, Tsamakidis K, Zisimopoulos A, Andriotis E, Markidou S, Panagiotakos D, Chrysohoou C, Bazinis A, Paraskevas E (2002) The role of sandostatin LAR in treating patients with advanced hepatocellular cancer. Hepatogastroenterology 49:1245–1250

    CAS  PubMed  Google Scholar 

  • Evers BM, Parekh D, Townsend CM Jr, Thompson JC (1991) Somatostatin and analogues in the treatment of cancer (review). Ann Surg 213:190–198

    CAS  PubMed  Google Scholar 

  • Florio T, Schettini G (1996) Multiple intracellular effectors modulate physiological functions of the cloned somatostatin receptors (review). J Mol Endocrinol 17:89–100

    CAS  PubMed  Google Scholar 

  • Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4–6

    Google Scholar 

  • Folkman J (1996) Fighting cancer by attacking its blood supply. Sci Am. 275:150–154

    Google Scholar 

  • Gorrin-Rivas MJ, Arii S, Mori A, Takeda Y, Mizumoto M, Furutani M, Imamura M (2000) Implications of human macrophage metalloelastase and vascular endothelial growth factor gene expression in angiogenesis of hepatocellular carcinoma. Ann Surg 231:67–73

    CAS  PubMed  Google Scholar 

  • Grant DS, Tashiro K, Segui-Real B, Yamada Y, Martin GR, Kleinman HK (1989) Two different laminin domains mediate the differentiation of human endothelial cells into capillary-like structures in vitro. Cell 58:933–943

    CAS  PubMed  Google Scholar 

  • Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364

    PubMed  Google Scholar 

  • Higgins RD, Yan Y, Schrier BK (2002) Somatostatin analogs inhibit neonatal retinal neovascularization. Exp Eye Res 74:553–559

    Article  CAS  Google Scholar 

  • Jaffe EA, Nachman RL, Becker CG, Minick CR (1973) Culture of human endothelial cells derived from umbilical veins: identification by morphologic and immunologic criteria. J Clin Invest 52:2745–2756

    CAS  Google Scholar 

  • Koizumi M, Onda M, Tanaka N, Seya T, Yamada T, Takahashi Y (2002) Antiangiogenic effect of octreotide inhibits the growth of human rectal neuroendocrine carcinoma. Digestion 65:200–206

    Article  CAS  PubMed  Google Scholar 

  • Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, Manousos ON (1998) Treatment of hepatocellular carcinoma with octreotide: a randomized controlled study. Gut 42:442–447

    CAS  PubMed  Google Scholar 

  • Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ (1996) Octreotide (review). N Engl J Med 334:246–254

    Article  CAS  PubMed  Google Scholar 

  • Lawnicka H, Stepien H, Wyczolkowska J, Kolago B, Kunert-Radek J, Komorowski J (2000) Effect of somatostatin and octreotide on proliferation and vascular endothelial growth factor secretion from murine endothelial cell line (HECa10) culture. Biochem Biophys Res Commun 268:567–571

    Article  CAS  PubMed  Google Scholar 

  • Leavesley DI, Ferguson GD, Wayner EA, Cheresh DA (1992) Requirement of the integrin ß3 subunit for carcinoma cell spreading or migration on vitronectin and fibrinogen. J Cell Biol 117:1101–1107.

    CAS  PubMed  Google Scholar 

  • Li Y, Tang ZY, Ye SL, Liu YK, Chen J, Xue Q, Chen J, Gao DM, Bao WH (2001) Establishment of cell clones with different metastatic potential from the metastatic hepatocellular carcinoma cell line MHCC97. World J Gastroenterol 7:630–636

    CAS  PubMed  Google Scholar 

  • Maeda K, Chung YS, Ogawa Y, Takatsuka S, Kang SM, Ogawa M, Sawada T, Sowa M (1996) Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer 77:858–863

    Article  CAS  PubMed  Google Scholar 

  • Mentlein R, Eichler O, Forstreuter F, Held-Feindt J (2001) Somatostatin inhibits the production of vascular endothelial growth factor in human glioma cells. Int J Cancer 92:545–550

    Article  CAS  PubMed  Google Scholar 

  • Nakashio A, Fujita N, Tsuruo T (2002) Topotecan inhibits VEGF- and bFGF-induced vascular endothelial cell migration via downregulation of the PI3K-Akt signaling pathway. Int J Cancer 98:36–41

    Article  CAS  PubMed  Google Scholar 

  • Ng IO, Poon RT, Lee JM, Fan ST, Ng M, Tso WK (2001) Microvessel density, vascular endothelial growth factor, and its receptors Flt-1 and Flk-1/KDR in hepatocellular carcinoma. Am J Clin Pathol 116:838–845

    CAS  PubMed  Google Scholar 

  • Parkin DM, Pisani P, Ferlay J (1993) Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 54:594–606.

    CAS  PubMed  Google Scholar 

  • Patel PC, Barrie R, Hill N, Landeck S, Kurozawa D, Woltering EA (1994) Postreceptor signal transduction mechanisms involved in octreotide-induced inhibition of angiogenesis. Surgery 116:1148–1152

    CAS  PubMed  Google Scholar 

  • Patt YZ, Hassan MM, Lozano RD, Ellis LM, Peterson JA, Waugh KA (2000) Durable clinical response of refractory hepatocellular carcinoma to orally administered thalidomide. Am J Clin Oncol 23:319–321

    Article  CAS  PubMed  Google Scholar 

  • Rabe C, Pilz T, Allgaier HP, Halm U, Strasser C, Wettstein M, Sauerbruch T, Caselmann WH (2002) Clinical outcome of a cohort of 63 patients with hepatocellular carcinoma treated with octreotide. Z Gastroenterol 40:395–400

    Article  CAS  PubMed  Google Scholar 

  • Salani D, Taraboletti G, Rosano L, Di Castro V, Borsotti P, Giavazzi R, Bagnato A (2000) Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Am J Pathol 157:1703–1711

    CAS  PubMed  Google Scholar 

  • Sun FX, Tang ZY, Lui KD, Ye SL, Xue Q, Gao DM, Ma ZC (1996) Establishment of a metastatic model of human hepatocellular carcinoma in nude mice via orthotopic implantation of histologically intact tissues. Int J Cancer 66:239–243

    Article  CAS  PubMed  Google Scholar 

  • Sun HC, Li XM, Xue Q, Chen J, Gao DM, Tang ZY (1999) Study of angiogenesis induced by metastatic and non-metastatic liver cancer by corneal micropocket model in nude mice. World J Gastroenterol 5:116–118

    PubMed  Google Scholar 

  • Tanaka S, Sugimachi K, Yamashita Yi Y, Ohga T, Shirabe K, Shimada M, Wands JR, Sugimachi K (2002) Tie2 vascular endothelial receptor expression and function in hepatocellular carcinoma. Hepatology 35:861–867

    Article  CAS  PubMed  Google Scholar 

  • Tian J, Tang ZY, Ye SL, Liu YK, Lin ZY, Chen J, Xue Q (1999) New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis. Br J Cancer 81:814–821

    CAS  PubMed  Google Scholar 

  • Troyanovsky B, Levchenko T, Mansson G, Matvijenko O, Holmgren L (2001) Angiomotin: an angiostatin binding protein that regulates endothelial cell an migration and tube formation. J Cell Biol 152:1247–1254

    Article  CAS  PubMed  Google Scholar 

  • Voest EE, Kenyon BM, O'Reilly MS, Truitt G, D'Amato RJ, Folkman J (1995) Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst 87:581–586

    CAS  PubMed  Google Scholar 

  • Wang L, Tang ZY, Qin LX, Wu XF, Sun HC, Xue Q, Ye SL (2000) High-dose and long-term therapy with interferon-alfa inhibits tumor growth and recurrence in nude mice bearing human hepatocellular carcinoma xenografts with high metastatic potential. Hepatology 32:43–48

    CAS  PubMed  Google Scholar 

  • Woltering EA, Barrie R, O'Dorisio TM, Arce D, Ure T, Cramer A, Holmes D, Robertson J, Fassler J (1991) Somatostatin analogues inhibit angiogenesis in the chick chorioallantoic membrane. J Surg Res 50:245–251

    CAS  PubMed  Google Scholar 

  • Xu GL, Yi SH, Xu RN (2001) Effects of octreotide on implanted liver tumor after partial hepatectomy in rats. Chin J Surg 39:948–950

    Google Scholar 

  • Yamaguchi R, Yano H, Iemura A, Ogasawara S, Haramaki M, Kojiro M (1998) Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 28:68–77

    Google Scholar 

  • Ziche M, Morbidelli L, Masini E, Amerini S, Granger HJ, Maggi CA, Geppetti P, Ledda F (1994) Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest 94:2036–2044

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of General Surgery, Anhui Provincial Hospital, 4 Lu Jiang Road, 230001, Hefei, P.R. China

    Wei-Dong Jia, Ge-Liang Xu, Rong-Nan Xu, Ji-Hai Yu & Jian-Sheng Li

  2. Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, P.R. China

    Hui-Chuan Sun, Lu Wang & Qiong Xue

  3. Department of Central Laboratory, Anhui Provincial Hospital, Hefei, China

    Jian Wang & Zhi-Ming Zhai

Authors
  1. Wei-Dong Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ge-Liang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rong-Nan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hui-Chuan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ji-Hai Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jian-Sheng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhi-Ming Zhai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qiong Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei-Dong Jia.

Additional information

The work was supported by the grant from the Natural Science Foundation of Anhui and Anke Pharmaceutical Co. limited (NO.01043708)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jia, WD., Xu, GL., Xu, RN. et al. Octreotide acts as an antitumor angiogenesis compound and suppresses tumor growth in nude mice bearing human hepatocellular carcinoma xenografts. J Cancer Res Clin Oncol 129, 327–334 (2003). https://doi.org/10.1007/s00432-003-0447-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-003-0447-5

Keywords

Search

Navigation