Angiopoietin-1, 2 and Tie2 expressions in endometrial adenocarcinoma-the Ang2 dominant balance up-regulates tumor angiogenesis in the presence of VEGF

We investigated Ang1, Ang2 and Tie2 expressions including balance and intratumoral vessels in the role of angiogenesis of endometrial adenocarcinoma. Immunohistochemical staining was performed on 133 patients with endometrial (endometrioid) adenocarcinoma, including 73 with G1, 34 with G2, and 26 with G3. The levels of Ang1, Ang2 and Tie2 expressions were expressed as staining score. Total vessel count (TVC), microvessel count (MVC) and mean vessel diameter (VD) in the CD34-stained tissues were measured in five hot spot areas at x 200 magnification by image cytometry. These results were compared with high and low vascular endothelial growth factor (VEGF) expressions. Ang1, Ang2, Tie2 and CD34 were expressed in the cytoplasm of tumor cells. A significant correlation was found among Ang1, Ang2 and Tie2 expressions. In high VEGF cases, Ang1 expression was correlated negatively with TVC and MVC, but positively with VD, and the Angl < Ang2 group was significantly higher in TVC and MVC and tended to be smaller in VD than the Ang1 > Ang2 group. VD was significantly larger in G3 than in G1. The Ang1 < Ang2 balance may be one of the key factors for angiogenesis of endometrial carcinoma in the presence of high VEGF expression.

Angiopoietins; Tie2; Endometrial adenocarcinoma

[1] Gale N.W., Yancopoulos G.D.: "Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development". Genes Dev., 1999, 13, 1055.

[2] Davis S., Aldrich T.H., Jones P.F., Acheson A., Compton D.L., Jain V. et al.: "Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning". Cell, 1996, 87, 1161.

[3] Sato A., Iwama A., Takakura N., Nishio H., Yancopoulos G.D., Suda T.: "Characterization of TEK receptor tyrosine kinase and its ligands, angiopoietins, in human hematopoietic progenitor cells" Int. Immunol., 1998, 10, 1217.

[4] Suri C., Jones P.F., Patan S., Bartunkova S., Maisonpierre P.C., Davis S. et al.: "Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis". Cell, 1996,87, 1171.

[5] Suri C., McClain J., Thurston G., McDonald D.M., Zhou H., Oldmixon E.H. et al.: "Increased vascularization in mice overexpressing angiopoietin-1". Science, 1998, 282, 468.

[6] Maisonpierre P.C., Suri C., Jones P.F., Bartunkova S., Wiegand SJ., Radziejewski C. et al.: "Angiopoietin-2, a natural antagonist for Tie2 that山srupts in vivo angiogenesis". Science, 1997, 277, 55.

[7] Asahara T., Chen D., Takahashi T., F ujikawa K., Kearney M., Magner M. et al.: "Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization". Circ. Res., 1998, 83, 233.

[8] Abulafia O., Triest W.E., Sherer D.M.: "Angiogenesis in malignancies of the female genital tract". Gynecol. Oneal., 1999, 72, 220.

[9] Holland C.M., Day K., Evans A., Smith S.K.: "Expression of the VEGF and angiopoietin genes in endometrial atypical hyperplasia and endometrial cancer". Br. J. Cancer, 2003, 89, 891.

[10] FIGO: "FIGO news". Int. J. Gynecol. Obstet., 2003, 28, 189.

[11] Fujisawa T., Watanabe J., Akaboshi M., Ohno E., Kuramoto H "Immunohistochemical study on V EGF expression in endometrial carcinoma - comparison with p53 expression, angiogenesis, and tumor histologic grade". J. Cancer Res. Clin. Oneal., 2001, 127, 668.

[12] Hewett P., Nijjar S., Shams M., Morgan S., Gupta J., Ahmed A.: "Down-regulation of angiopoietin-1 expression in menorrhagia". Am. J. Pathol., 2002, 160, 773.

[13] Hirchenhain J., Huse I., Hess A., Bielfeld P., Bruyne F.D., Kriissel J.S.: "Differential expression of angiopoietins 1 and 2 and their receptor Tie-2 in human endometrium". Mol. Hum. Reprod., 2003, 9, 663.

[14] Akaboshi M., Watanabe J., F ujisawa T., Hattori M., Ohno E., Kuramoto H.: "Immunohistochemical expression of cdk2 and Ki-67 in human endometrial carcinoma". J. Jpn. Soc. Clin. Cytol., 2001, 40, 121.

[15] Mandriota S.J., Pepper M.S.: "Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cyto伈nes and hypoxia". Circ. Res., 1998, 83, 852.

[16] Oh H., Takagi H., Suzuma K., Otani A., Matsumura M., Honda Y. "Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells". J. Biol. Chem., 1999, 274, 15732.

[17] Mandriota S.J., Pyke C., Di Sanza C., Quinodoz P., Pittet B., Pepper M.S.: "Hypoxia-inducible angiopoietin-2 expression is mimicked by iodonium compounds and occurs in the rat brain and skin in response to systemic hypoxia and tissue ischemia". Am. J. Pathol., 2000, 156, 2077.

[18] Abdulmalek K., Ashur F., Ezer N., Ye F., Magder S., Hussain S.N.: Differential expression of Tie-2 receptors and angiopoietins in response to in vivo hypoxia in rats". Am. J. Physiol. Lung Cell. Mo/ Physiol., 2001, 281, L582.

[19] Yamakawa M., Liu L.X., Date T., Belanger A.J., Vincent K.A，Akita G.Y. et al.: "Hypoxia-inducible factor-1 mediates activation of cultured vasculai endothelial cells by inducing multiple angiogenic factors". Circ. Res., 2003, 93, 664.

[20] Etoh T., Inoue H., Tanaka S., Barnard G.F., Kitano S., Mori M.:"Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases" Cancer Res., 2001, 61, 2145.

[21] Tanaka K., Sonoo H., Kurebayashi J., Nomura T., Ohkubo S., Yamamoto Y., Yamamoto S.: "Inhibition of infiltration and angiogenesis by thrombospondin-1 in papillary thyroid carcinoma". Clin Cancer Res., 2002, 8, 1125.

[22] Holash J., Wiegand S.J., Yancopoulos G.D.: "New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF". Oncogene, 1999, 18, 5356.

[23] Yancopoulos G.D., Davis S., Gale N.W., Rudge J.S., Wiegand S.J., Holash J.: "Vascular-specific growth factors and blood vessel formation". Nature, 2000, 407, 242.

[24] Mitsuhashi N., Shimizu H., Ohtsuka M., Wakabayashi Y., Ito H., Kimura F. et al: "Angiopoietins and Tie-2 expression in angiogenesis and proliferation of human hepatocellul釭carcinoma". Hepatology, 2003, 37, 1105.

[25] Tanaka F., Ishikawa S., Yanagihara K., Miyah打a R., Kawano Y., L1 M. et al.: "Expression of angiopoietins and its clinical significance in non-small cell lung cancer". Cancer Res., 2002, 62, 7124.