International Journal of Clinical Oncology

, Volume 16, Issue 2, pp 145–152 | Cite as

Expression of thrombospondin-1 and Ski are prognostic factors in advanced gastric cancer

  • Toshihiro Nakao
  • Nobuhiro Kurita
  • Masato Komatsu
  • Kozo Yoshikawa
  • Takashi Iwata
  • Toru Utsunomiya
  • Mitsuo ShimadaEmail author
Original Article



It has been suggested that thrombospondin-1 (TSP-1) plays a role in angiogenesis in many cancers. In addition, TSP-1 has been shown to suppress tumor growth by activating transforming growth factor-β (TGF-β). Recent studies have shown that Ski protein suppresses TGF-β signaling. The aim of this study was to investigate the role of TSP-1 and Ski expression in advanced gastric cancer.


Sixty-five recurrent patients who underwent resection of advanced gastric cancer (n = 62) or who had unresectable tumors (n = 3) between March 2003 and October 2007 participated in this study. All patients were treated with chemotherapy after collection of the tumor tissue. Twenty-three of them were also treated with chemotherapy before collection of the tumor specimen. The TSP-1, Ski, vascular endothelial growth factor (VEGF) and TGF-β protein expression were examined by immunohistochemical staining, and microvessels in the tumor were counted.


There were 17 (26.2%) gastric cancers with positive staining for TSP-1. There was no relationship between TSP-1 expression and clinicopathological factors.

TSP-1 expression had positive association with VEGF expression, microvessel density (MVD) and TGF-β expression. However, there was no relationship between TSP-1 and Ski expression. TSP-1 correlated with good survival in advanced gastric cancer, and Ski correlated with poor survival in the patients with TGF-β-positive advanced gastric cancer.


This study shows that TSP-1 enhances angiogenesis due to its positive correlation with VEGF and MVD, and is a good prognostic factor for survival in advanced gastric cancer. This study also shows that Ski inhibits the prolonged effects of TGF-β for survival in advanced gastric cancer.


Thrombospondin-1 Gastric cancer Ski TGF-β Prognosis VEGF 



Grant support was provided by the Research Support Foundation of The University of Tokushima and TAIHO Pharmaceutical Co., Ltd.

Conflict of interest

There is no conflict of interest to declare.


  1. 1.
  2. 2.
    Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108PubMedCrossRefGoogle Scholar
  3. 3.
    Ganguly P (1971) Isolation and properties of a thrombin-sensitive protein from human blood platelets. J Biol Chem 246(13):4286–4290PubMedGoogle Scholar
  4. 4.
    Maeda K, Nishiguchi Y, Kang SM et al (2001) Expression of thrombospondin-1 inversely correlated with tumor vascularity and hematogenous metastasis in colon cancer. Oncol Rep 8(4):763–766PubMedGoogle Scholar
  5. 5.
    Yamaguchi M, Sugio K, Ondo K et al (2002) Reduced expression of thrombospondin-1 correlates with a poor prognosis in patients with non-small cell lung cancer. Lung Cancer 36(2):143–150PubMedCrossRefGoogle Scholar
  6. 6.
    Grossfeld GD, Ginsberg DA, Stein JP et al (1997) Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression. J Natl Cancer Inst 89(3):219–227PubMedCrossRefGoogle Scholar
  7. 7.
    Morelli D, Lazzerini D, Cazzaniga S et al (1998) Evaluation of the balance between angiogenic and antiangiogenic circulating factors in patients with breast and gastrointestinal cancers. Clin Cancer Res 4(5):1221–1225PubMedGoogle Scholar
  8. 8.
    Kasper HU, Ebert M, Malfertheiner P et al (2001) Expression of thrombospondin-1 in pancreatic carcinoma: correlation with microvessel density. Virchows Arch 438:116–120PubMedCrossRefGoogle Scholar
  9. 9.
    Yamashita Y, Kurohiji T, Tuszynski GP et al (1998) Plasma thrombospondin levels in patients with colorectal carcinoma. Cancer 82:632–638PubMedCrossRefGoogle Scholar
  10. 10.
    Heldin CH, Miyazono K, ten Dijke P (1997) TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390:465–471PubMedCrossRefGoogle Scholar
  11. 11.
    Maeda K, Nishiguchi Y, Yashiro M et al (2000) Expression of vascular endothelial growth factor and thrombospondin-1 in colorectal carcinoma. Int J Mol Med 5:373–378PubMedGoogle Scholar
  12. 12.
    Poon RT, Chung KK, Cheung ST et al (2004) Clinical significance of thrombospondin 1 expression in hepatocellular carcinoma. Clin Cancer Res 10:4150–4157PubMedCrossRefGoogle Scholar
  13. 13.
    Pratt DA, Miller WR, Dawes J (1989) Thrombospondin in malignant and non-malignant breast tissue. Eur J Cancer Clin Oncol 25:343–350PubMedCrossRefGoogle Scholar
  14. 14.
    Luo Ski K, Sno N (2004) Negative regulators of TGF-beta signaling. Curr Opin Genet Dev 14:65–70CrossRefGoogle Scholar
  15. 15.
    Zhang J, Ito R, Oue N et al (2003) Expression of thrombospondin-1 is correlated with microvessel density in gastric carcinoma. Virchows Arch 442:563–568PubMedGoogle Scholar
  16. 16.
    Takahata M, Inoue Y, Tsuda H et al (2009) SKI and MEL1 cooperate to inhibit transforming growth factor-beta signal in gastric cancer cells. J Biol Chem 284:3334–3344PubMedCrossRefGoogle Scholar
  17. 17.
    Saito H, Tsujitani S, Ikeguchi M et al (1998) Relationship between the expression of vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue. Br J Cancer 78:1573–1577PubMedCrossRefGoogle Scholar
  18. 18.
    Saito H, Tsujitani S, Oka S et al (1999) The expression of transforming growth factor-beta1 is significantly correlated with the expression of vascular endothelial growth factor and poor prognosis of patients with advanced gastric carcinoma. Cancer 86:1455–1462PubMedCrossRefGoogle Scholar
  19. 19.
    Vermeulen PB, Gasparini G, Fox SB et al (1996) Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation. Eur J Cancer 32A:2474–2484PubMedCrossRefGoogle Scholar
  20. 20.
    Fondevila C, Metges JP, Fuster J et al (2004) p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer. Br J Cancer 90:206–215PubMedCrossRefGoogle Scholar
  21. 21.
    Greenaway J, Lawler J, Moorehead R et al (2007) Thrombospondin-1 inhibits VEGF levels in the ovary directly by binding and internalization via the low density lipoprotein receptor-related protein-1 (LRP-1). J Cell Physiol 210:807–818PubMedCrossRefGoogle Scholar
  22. 22.
    Poon RT, Chung KK, Cheung ST et al (2004) Clinical significance of thrombospondin 1 expression in hepatocellular carcinoma. Clin Cancer Res 10:4150–4157PubMedCrossRefGoogle Scholar
  23. 23.
    Hironaka S, Hasebe T, Kamijo T et al (2002) Biopsy specimen microvessel density is a useful prognostic marker in patients with T(2–4)M(0) esophageal cancer treated with chemoradiotherapy. Clin Cancer Res 8:124–130PubMedGoogle Scholar
  24. 24.
    Kiyono K, Suzuki HI, Morishita Y et al (2009) c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-beta signaling in diffuse-type gastric carcinoma. Cancer Sci 100:1809–1816PubMedCrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2010

Authors and Affiliations

  • Toshihiro Nakao
    • 1
  • Nobuhiro Kurita
    • 1
  • Masato Komatsu
    • 1
  • Kozo Yoshikawa
    • 1
  • Takashi Iwata
    • 1
  • Toru Utsunomiya
    • 1
  • Mitsuo Shimada
    • 1
    Email author
  1. 1.Department of Surgery, Institute of Health BioscienceThe University of TokushimaTokushimaJapan

Personalised recommendations