Soluble VEGF receptor-2 may be a predictive marker of anti-angiogenic therapy with clinically available safe agents

Yoshiji,Hitoshi; Noguchi,Ryuichi; Ikenaka,Yasuhide; Kaji,Kosuke; Shirai,Yusaku; Aihara,Yosuke; Yamao,Junichi; Toyohara,Masahisa; Mitoro,Akira; Sawai,Masayoshi; Yoshida,Motoyuki; Morioka,Chie; Fujimoto,Masao; Uemura,Masahito; Kawaratani,Hideto; Tsujimoto,Tatsuhiro; Fukui,Hiroshi

doi:10.3892/ol.2010.196

Soluble VEGF receptor-2 may be a predictive marker of anti-angiogenic therapy with clinically available safe agents

Authors:
- Hitoshi Yoshiji
- Ryuichi Noguchi
- Yasuhide Ikenaka
- Kosuke Kaji
- Yusaku Shirai
- Yosuke Aihara
- Junichi Yamao
- Masahisa Toyohara
- Akira Mitoro
- Masayoshi Sawai
- Motoyuki Yoshida
- Chie Morioka
- Masao Fujimoto
- Masahito Uemura
- Hideto Kawaratani
- Tatsuhiro Tsujimoto
- Hiroshi Fukui
View Affiliations

Affiliations: Third Department of Internal Medicine, Nara Medical University, Nara 634-8522, Japan
Published online on: October 5, 2010 https://doi.org/10.3892/ol.2010.196
Pages: 69-73

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The identification of biomarkers of anti-angiogenic therapy that predict clinical benefit is of vital importance. We previously reported that a combination treatment with clinically available safe agents, specifically angiotensin-converting enzyme inhibitor (ACE-I) and vitamin K (VK), inhibited the cumulative recurrence of hepatocellular carcinoma (HCC) via suppression of the vascular endothelial growth factor (VEGF). The present study aimed to identify non-invasive biological markers that predict the clinically beneficial effect of this combination regimen. A combination of ACE-I (perindopril; 4 mg/day) and VK (menatetrenone; 45 mg/day) was administered for 54 months following curative therapy for HCC. The cumulative recurrence and several indices, which are reportedly considered as biological markers of anti-angiogenic therapies, were analyzed. The combined treatment of ACE-I and VK markedly inhibited the cumulative recurrence of HCC during the 54-month follow-up. The serum VEGF and soluble VEGF receptor (sVEGFR)-2 were significantly suppressed with this combination regimen, whereas sVEGFR-1 was not. In HCC patients without recurrence, a significant suppression of VEGF and sVEGFR-2 was achieved within 6 and 3 months after treatment, respectively. In conclusion, the combination treatment of ACE-I and VK is a potentially novel anti-angiogenic strategy for secondary chemoprevention against HCC since the two agents are widely used in clinical practice without serious side effects. Furthermore, sVEGFR-2 may become a useful clinical predictive marker of this combination treatment.

View Figures

View References

1	Schafer DF and Sorrell MF: Hepatocellular carcinoma. Lancet. 353:1253–1257. 1999. View Article : Google Scholar : PubMed/NCBI
2	Kerbel RS: Tumor angiogenesis: past, present and the near future. Carcinogenesis. 21:505–515. 2000. View Article : Google Scholar : PubMed/NCBI
3	Guo RP, Zhong C, Shi M, et al: Clinical value of apoptosis and angiogenesis factors in estimating the prognosis of hepatocellular carcinoma. J Cancer Res Clin Oncol. 132:547–555. 2006. View Article : Google Scholar : PubMed/NCBI
4	Iavarone M, Lampertico P, Iannuzzi F, et al: Increased expression of vascular endothelial growth factor in small hepatocellular carcinoma. J Viral Hepat. 14:133–139. 2007. View Article : Google Scholar : PubMed/NCBI
5	Li CY, Shan S, Huang Q, et al: Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models. J Natl Cancer Inst. 92:143–147. 2000. View Article : Google Scholar
6	Bergers G and Benjamin LE: Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 3:401–410. 2003. View Article : Google Scholar
7	Bergers G, Javaherian K, Lo KM, Folkman J and Hanahan D: Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science. 284:808–812. 1999. View Article : Google Scholar : PubMed/NCBI
8	Brandvold KA, Neiman P and Ruddell A: Angiogenesis is an early event in the generation of myc-induced lymphomas. Oncogene. 19:2780–2785. 2000. View Article : Google Scholar : PubMed/NCBI
9	Yoshiji H, Kuriyama S, Yoshii J, et al: Halting the interaction between vascular endothelial growth factor and its receptors attenuates liver carcinogenesis in mice. Hepatology. 39:1517–1524. 2004. View Article : Google Scholar : PubMed/NCBI
10	Frachon S, Gouysse G, Dumorti J, et al: Endothelial cell marker expression in dysplastic lesions of the liver: an immunohistochemical study. J Hepatol. 34:850–857. 2001. View Article : Google Scholar : PubMed/NCBI
11	Kerbel RS: Tumor angiogenesis. N Engl J Med. 358:2039–2049. 2008. View Article : Google Scholar : PubMed/NCBI
12	Wilhelm SM, Carter C, Tang L, et al: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64:7099–7109. 2004. View Article : Google Scholar : PubMed/NCBI
13	Llovet JM, Ricci S, Mazzaferro V, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 359:378–390. 2008. View Article : Google Scholar : PubMed/NCBI
14	Eskens FA and Verweij J: The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors: a review. Eur J Cancer. 42:3127–3139. 2006. View Article : Google Scholar
15	Verheul HM and Pinedo HM: Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer. 7:475–485. 2007. View Article : Google Scholar : PubMed/NCBI
16	Berenson A: A cancer drug shows promise, at a price that many can’t pay. The New York Times. A1:C22006.PubMed/NCBI
17	Yoshiji H, Kuriyama S, Noguchi R, et al: Combination of vitamin K(2) and the angiotensin-converting enzyme inhibitor, perindopril, attenuates the liver enzyme-altered preneoplastic lesions in rats via angiogenesis suppression. J Hepatol. 42:687–693. 2005. View Article : Google Scholar
18	Yoshiji H, Noguchi R, Yamazaki M, et al: Combined treatment of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates hepatic dysplastic nodule in a patient with liver cirrhosis. World J Gastroenterol. 13:3259–3261. 2007.
19	Yoshiji H, Noguchi R, Toyohara M, et al: Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma. J Hepatol. 51:315–321. 2009. View Article : Google Scholar
20	Murukesh N, Dive C and Jayson GC: Biomarkers of angiogenesis and their role in the development of VEGF inhibitors. Br J Cancer. 102:8–18. 2010. View Article : Google Scholar : PubMed/NCBI
21	Kokudo N and Makuuchi M: Evidence-based clinical practice guidelines for hepatocellular carcinoma in Japan: the J-HCC guidelines. J Gastroenterol. 44:119–121. 2009. View Article : Google Scholar : PubMed/NCBI
22	Makuuchi M, Kokudo N, Arii S, et al: Development of evidence-based clinical guidelines for the diagnosis and treatment of hepatocellular carcinoma in Japan. Hepatol Res. 38:37–51. 2008. View Article : Google Scholar : PubMed/NCBI
23	Okita K: Management of hepatocellular carcinoma in Japan. J Gastroenterol. 41:100–106. 2006. View Article : Google Scholar
24	Ferrara N: VEGF as a therapeutic target in cancer. Oncology. 69(Suppl 3): 11–16. 2005. View Article : Google Scholar
25	Dowlati A, Gray R, Sandler AB, Schiller JH and Johnson DH: Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab – an Eastern Cooperative Oncology Group Study. Clin Cancer Res. 14:1407–1412. 2008.
26	Nagaoka S, Yoshida T, Akiyoshi J, et al: The ratio of serum placenta growth factor to soluble vascular endothelial growth factor receptor-1 predicts the prognosis of hepatocellular carcinoma. Oncol Rep. 23:1647–1654. 2010.
27	Yoshiji H, Kuriyama S, Yoshii J, et al: Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma. Hepatology. 35:834–842. 2002. View Article : Google Scholar : PubMed/NCBI
28	Wierzbowska A, Robak T, Wrzesien-Kus A, Krawczynska A, Lech-Maranda E and Urbanska-Rys H: Circulating VEGF and its soluble receptors sVEGFR-1 and sVEGFR-2 in patients with acute leukemia. Eur Cytokine Netw. 14:149–153. 2003.PubMed/NCBI
29	Corradini SG, Morini S, Liguori F, et al: Differential vascular endothelial growth factor A protein expression between small hepatocellular carcinoma and cirrhosis correlates with serum vascular endothelial growth factor A and alpha-fetoprotein. Liver Int. 29:103–112. 2009. View Article : Google Scholar
30	Deprimo SE, Bello CL, Smeraglia J, et al: Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med. 5:322007. View Article : Google Scholar : PubMed/NCBI