Expression of gelatinase (MMP-2 and MMP-9) and cyclooxygenase-2 (COX-2) in endometrial carcinoma

Objective: Matrix metalloproteinases (MMPs) are key players in the degradation of extracellular matrix and basement membranes, and are thus important in tumor invasion. Gelatinases (MMP-2 and MMP-9) in particular are prognostic factors in many solid tumors. In this study the immunohistochemical expression of both COX-2 and matrix metalloproteinases has been shown for the first time in endometrium carcinoma.

Methods: Forty-two endometrial carcinoma tissues were immunostained for MMP2 antibody (1:100, Rabbit polyclonal), MMP9 antibody (1:100, Rabbit polyclonal) and CoX2 antibody (1:100, Epitope specific rabbit antibody).

Results: 90.5% of the cases were positive for MMP-2 and MMP-9, and 83.3% of the cases were positive for COX-2. A statistically significant association was found between COX-2 overexpression and FIGO stage (p = 0.001). A positive correlation was also found with histological grade (p = 0.006), myometrial invasion (p = 0.033), vascular invasion (p = 0.017), and lymphatic invasion (p = 0.007). A positive correlation was found between MMP-2 overexpression and vascular and lymphatic invasion (p = 0.030 and p = 0.003, respectively). MMP-9 overexpression was also found to be correlated with vascular and lymphatic invasion (p = 0.001 and p = 0.012, respectively). Furthermore, there was a statistically significant correlation between MMP-2 and MMP-9 overexpression (p = 0.0001).

Conclusion: The results showed that COX-2, MMP-2 and MMP-9 were expressed in a high percentage of primary endometrial carcinomas and their expressions may be associated closely with parameters of tumor aggressiveness.

Endometrial carcinoma; MMP-2; MMP-9; COX-2

[1] Ronnett B.M., Zaino R.J., Ellenson L.H., Kurman R.J.: "Endometrial Carcinoma". In: Kurman R.J. (ed.). Blaustein's Pathology of the Female Genital Tract, (5'h edition), New York, SpringerVerlag., 2001, 501.

[2] American Cancer Society: "Cancer Facts and Figures 2006" Atlanta, Ga: American Cancer Society, 2006, 14.

[3] Mikuta J.J.: "International Federation of Gynecology and Obstetrics Staging of Endometrial Cancer 1988". Cancer, 1993, 71, 460.

[4] Folkman J.: "Tumor angiogenesis". Adv. Cancer Res., 1985, 43, 175.

[5) Toyoki H., Fujimoto J., Sato E.: "Clinical implications of expression of cyclooxygenase-2 related to angiogenesis in uterine endometrial cancers". Eur. Soc. Med. Oneal., 2005, 16, 51.

[6] Woessner F.J.: "Matrix metalloproteinases and their inhibitors in connective tissue remodeling". FASEB J., 1991, 5, 2145.

[7] Yu A.E., Hewitt R.E., Kleiner D.E.: "Molecular regulation of eellular invasion-role of gelatinase A and TIMP-2". Biochem. Cell. Biol.. 1996, 74, 823.

[8] Liotta L., Steetler-Stevenson W.: "Metalloproteinases and cancer invasion". Semin. Cancer Biol., 1990, 1, 99.

[9] Chambers A., Matrisian L.: "Changing views of the role of matnx metalloproteinases in metastasis". J. Natl. Cancer Inst., 1997, 89, 1260.

[10] Vane J.R., Bakhle Y.S., Botting R.M.: "Cyclooxygenase 1 and 2" Ann. Rev. Pharmacol Toxicol., 1998, 38, 97.

[11] Dixon D.A.: "Regulation of CoX-2 expression in human cancers". Prog. Exp. Tumor Res., 2003, 37, 52.

[12] Ali-Fehmi R., Che M., Khalifeh I. et al.: "The effect of cyclooxygenase-2 expression on tumor vascularity in advanced stage ovarian serous carcinoma". Cancer, 2003, 98, 1423.

[13] Polette M., Birembaut P.: "Matrix metalloproteinases in breast carcinoma". Breast J.. 1996, 2, 209.

[14] Joo Y.E., Rew J.S., Seo Y.H. et al.: "Cyclooxygenase-2 overexpression correlates with vascular endothelial growth factor expression and tumor angiogenesis in gastric cancer". J. Clin. Gastroenterol., 2003, 37, 28.

[15] Myata Y., Koga S., Kanda S. et al.: "Expression of cyclooxygenase-2 in renal cell carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, expression of matrix metalloproteinase-2, and survival". Clin. Cancer Res., 2003, 9, 1741.

[16] Gallo O., Masini E., Bianchi B. et al.: "Prognostic significance of cyclooxygenase-2 pathway and angiogenesis in head and neck squamous cell carcinoma". Human Pathol., 2002, 33, 708.

[17] Tsujii M., Kawano S., Tsuji S. et al.: "Cyclooxygenase regulates angiogenesis induced by colon cancer cells". Cell, 1998, 29, 705.

[18] Lurlaro M., Loverro G., Vacca A., Cormio G.: "Angiogenesis extent and expression of matrix metalloproteinase-2 and-9 correlate with upgrading and myometrial invasion in endometrial carcinoma". Eur. J. Clin. Invest.. 1999, 29, 793.

[19] Moser L.P., Hefler L., Tempfer C., Neunteufel W.: "Immunohistochemical detection of matrix metalloproteinases 1 and 2, and tissue inhibitor of metalloproteinase 2 in Stage I and II endometrial cancer". Anticancer Res.. 1999, 19, 2365.

[20] Pilka R., Norata G.D., Domanski H., Andersson C.: "Matrix metalloproteinase-26 expression is high in endometrial hyperplasia and decreases with loss of histological differentiation in endometrial cancer". Gynecol. Oneal.. 2004, 94, 661.

[21] M1zumato H.. Saito T., Ashihara K., Nishumura M.: "Acceleration of invasive activity via matrix metalloproteinases by transfection of the estrogen receptor-a gene in endometrial carcinoma cells". Int. J. Cancer, 2002, 100, 401.

[22] Park D., Ryu H., Choi D., Park Y.: "Localization of matrix metalloproteinases on endometrial cancer cell invasion in vitro". Gynecol. Oneal., 2001, 82, 442.

[23] Aglund K., Rauvala M., Puistola U., Angstrom T.: "Gelatinases A and B in endometrial cancer MMP-9 correlates to the grade and the stage". Gynecol. Oneal., 2004, 94, 699.

[24] Nezza D., Misajon A., Zhang J., Jobling T.: "Presence of active gelatinases in endometrial carcinoma and correlation of matrix metalloproteinase expression with increasing tumor grade and invasion". American Cancer Society, 2002, 1466.

[25] Lopata A., Agresta F., Quinn MA., Smith C.: "Detection of endometrial cancer by determination of matrix metalloproteinases in the uterine cavity". Gynecol. Oneal., 2003, 90, 318.

[26] Lambropoulou M., Alexiadis G., Limberis V., Nikolettos N "Clinicopathologic and prognostic significance of cyclooxygenase-2 expression in endometrial carcinoma". Histopathology, 2005, 753.

[27] Fujiwaki R., Lida K., Kanasaki H.: "Cyclooxygenase-2 express10n in endometrial cancer: Correlation with microvessel count and expression of vascular endothelial growth factor and thymidine phosphorylase". Hum. Pathol., 2002, 33.

[28] Ohno Y., Ohno S., Suzuki N., Kamei T.: "Role of cyclooxygenase-2 in immunomodulation and prognosis of endometrial carcinoma". Int. J. Cancer, 2005, 114, 696.

[29] Toyoki H., Fujimoto H., Sato E.: "Clinical implications of expression of cyclooxygenase-2 related to angiogenesis in uterine endometrial cancers". Ann. Oneal., 2005, 16, 51.

[30] Ferrandina G., Legge F., Ranelletti F., Zannoni G.: "Cyclooxygenase-2 expression in endometrial carcinoma". American Cancer Society, 2002.

[31] Uotila P., Erkkola R., Klerni P.: "The expression of cyclooxygenase-1 and -2 in proliferative endornetriurn and endornetrial adenocarcinorna". Ann Med., 2002, 428.

[32] Ferrandina G., Ranelletti F., Gallotta V.,Martinelli E.: "Express10n of cyclooxygenase-2, receptors for estrogen and progesterone, p53, ki67, and neu protein in endornetrial cancer". Gynecol Oneal., 2005, 98, 383.

[33] Orejuela F.,Rarnondetta L., Smith J., Brown J.: "Estrogen an progesterone receptor and cyclooxygenase-2 expression in endornetrial cancer, endometrial hyperplasia, and normal endornetrium". Gynecol. Oneal., 2005, 97, 483.

[34] Fowler J., Ramirez N., MD, Cohn D.: "Corrrelation of cyclooxygenase- 2 and aromatase expression in human endornetrial cancer: Tissue rnicroarray analysis". Am. J. Obstet Gynecol., 2005, 192, 1262.