Abstract
Accumulating evidence suggests that TAMs contribute to tumor progression. Recently, vasohibin-1 and vasohibin-2 were detected in endothelial cells and considered as intrinsic angiogenesis inhibitors. However, it is not known whether they are also expressed in cancer cells or tumor-associated macrophages (TAMs). Realtime RT-PCR was used to investigate the vasohibin-1 and vasohibin-2 expression in four gastric cancer cell lines, including a non-metastatic cell line AGS, and metastatic cell lines HGC-27, Hs-746T and NCI-N87, co-cultured with or without TAMs. The effect of hypoxic conditions on vasohibin expression was evaluated as well, and the correlation between vasohibin-1, vasohibin-2 and VEGF-A expression under different culture conditions was analyzed. We found that both vasohibin-1 and vasohibin-2 were expressed in the four gastric cancer cell lines and in TAMs. Under normal conditions, vasohibin-1 and vasohibin-2 expressions were significantly upregulated by TAMs in all the gastric cancer cell lines. Under hypoxia, both vasohibin-1 and vasohibin-2 expressions were significantly decreased in the distant metastasis cancer cell line Hs-746T, cultured with or without TAMs (P < 0.001). After induction by TAMs or hypoxia, the vasohibin-1 and vasohibin-2 expressions correlated with that of VEGF-A. In addition, TAMs, when co-cultured with the metastatic cancer cell lines, showed hypoxia-induced vasohibin-1 upregulation (P < 0.05). In conclusion, both vasohibin-1 and vasohibin-2 mRNA are expressed in gastric cancer cells and in TAMs, and their expressions are altered by hypoxia.
Similar content being viewed by others
References
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.
SEER Cancer Statistics Review (1975–2008) http://seer.cancer.gov/csr/1975_2008/results_merged/topic_survival.pdf.
Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial Award lecture. Cancer Res. 1986;46:467–73.
Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990;82:4–6.
Kitadai Y. Angiogenesis and lymphangiogenesis of gastric cancer. J Oncol. 2010;2010:468725.
Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature. 2000;407:242–8.
Veikkola T, Alitalo K. VEGFs, receptors and angiogenesis. Semin Cancer Biol. 1999;9:211–20.
Sugiura T, Inoue Y, Matsuki R, Ishii K, Takahashi M, Abe M, Shirasuna K. VEGF-C and VEGF-D expression is correlated with lymphatic vessel density and lymph node metastasis in oral squamous cell carcinoma: implications for use as a prognostic marker. Int J Oncol. 2000;34:673–80.
O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994;79:315–28.
O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88:277–85.
O’Reilly MS, Pirie-Shepherd S, Lane WS, Folkman J. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science. 1999;285:1926–8.
Tolsma SS, Volpert OV, Good DJ, Frazier WA, Polverini PJ, Bouck N. Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity. J Cell Biol. 1993;122:497–511.
Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, Bouck NP. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science. 1999;285:245–8.
Kerbel RS. Vasohibin as an endothelium derived negative feedback regulator of angiogenesis. J Clin Invest. 2004;114:884–6.
Nasu T, Maeshima Y, Kinomura M, Hirokoshi-Kawahara K, Tanabe K, Sugiyama H, Sonoda H, Sato Y, Makino H. Vasohibin-1, a negative feedback regulator of angiogenesis, ameliorates renal alterations in a mouse model of diabetic nephropathy. Diabetes. 2009;58:2365–75.
Shen J, Yang X, Xiao WH, Hackett SF, Sato Y, Campochiaro PA. Vasohibin is up-regulated by VEGF in the retina and suppresses VEGF receptor 2 and retinal neovascularization. FASEB J. 2006;20:723–5.
Yoshinaga K, Ito K, Moriya T, Nagase S, Takano T, Niikura H, Yaegashi N, Sato Y. Expression of vasohibin as a novel endothelium-derived angiogenesis inhibitor in endometrial cancer. Cancer Sci. 2008;99:914–9.
Tamaki K, Sasano H, Maruo Y, Takahashi Y, Miyashita M, Moriya T, Sato Y, Hirakawa H, Tamaki N, Watanabe M, Ishida T, Ohuchi N. Vasohibin-1 as a potential predictor of aggressive behavior of ductal carcinoma in situ of the breast. Cancer Sci. 2010;101:1051–8.
Hosaka T, Kimura H, Heishi T, Suzuki Y, Miyashita H, Ohta H, Sonoda H, Moriya T, Suzuki S, Kondo T, Sato Y. Vasohibin-1 expression in endothelium of tumor blood vessels regulates angiogenesis. Am J Pathol. 2009;175:430–9.
Shibuya T, Watanabe K, Yamashita H, Shimizu K, Miyashita H, Abe M, Moriya T, Ohta H, Sonoda H, Shimosegawa T, Tabayashi K, Sato Y. Isolation of vasohibin-2 as a sole homologue of VEGF inducible endothelium-derived angiogenesis inhibitor vasohibin: a comparative study on their expressions. Arterioscler Thromb Vasc Biol. 2006;26:1051–7.
Kimura H, Miyashita H, Suzuki Y, Kobayashi M, Watanabe K, Sonoda H, Ohta H, Fujiwara T, Shimosegawa T, Sato Y. Distinctive localization and opposed roles of vasohibin-1 and vasohibin-2 in the regulation of angiogenesis. Blood. 2009;113:4810–8.
Mantovani A, Allavena P, Sica A. Balkwill inflammation. Nature. 2008;454:436–44.
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.
Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.
Lewis CE, Hughes R. Inflammation and breast cancer. Micro environmental factors regulating macrophage function in breast tumors: hypoxia and angiopoietin-2. Breast Cancer Res. 2007;9:209.
Gottfried E, Faust S, Fritsche J, Kunz-Schughart LA, Andreesen R, Miyake K, Kreutz M. Identification of genes expressed in tumor-associated macrophages. Immunobiology. 2003;207:351–9.
Hosaka T, Kimura H, Heishi T, Suzuki Y, Miyashita H, Ohta H, Sonoda H, Moriya T, Suzuki S, Kondo T, Sato Y. Vasohibin-1 expression in endothelium of tumor blood vessels regulates angiogenesis. Am J Pathol. 2009;175:430–9.
Kimura H, Miyashita H, Suzuki Y, Kobayashi M, Watanabe K, Sonoda H, Ohta H, Fujiwara T, Shimosegawa T, Sato Y. Distinctive localization and opposed roles of vasohibin-1 and vasohibin-2 in the regulation of angiogenesis. Blood. 2009;13:4810–8.
Chen J, De S, Brainard J, Byzova TV. Metastatic properties of prostate cancer cells are controlled by VEGF. Cell Commun Adhes. 2004;11:1–11.
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–57.
Watanabe K, Hasegawa Y, Yamashita H, Shimizu K, Ding Y, Abe M, Ohta H, Imagawa K, Hojo K, Maki H, Sonoda H, Sato Y. Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis. J Clin Invest. 2004;114:898–907.
Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer. 2002;2:727–39.
Folkman J. Endogenous angiogenesis inhibitors. APMIS. 2004;112:496–507.
Kerr DJ. Targeting angiogenesis in cancer: clinical development of bevacizumab. Nat Clin Pract Oncol. 2004;1:39–43.
AVAGAST Trial. Bevacizumab Disappoints in Gastric Cancers, but May Have Benefit. http://www.medconnect.com.sg/tabid/92/ct1/c37173/AVAGAST-Trial-Bevacizumab-Disappoints-in-Gastric-Cancers-but-May-Have-Benefit/Default.aspx.
Conflict of interest
There are no conflicts of interest.
Author information
Authors and Affiliations
Corresponding authors
Additional information
H. Mustonen and P. Puolakkainen have the equal last authorship.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Shen, Z., Kauttu, T., Seppänen, H. et al. Vasohibin-1 and vasohibin-2 expression in gastric cancer cells and TAMs. Med Oncol 29, 2718–2726 (2012). https://doi.org/10.1007/s12032-012-0212-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12032-012-0212-1