Expression of matrix metalloproteinase-2 in preinvasive and invasive carcinoma of the uterine cervix

Purpose: To study the immunohistochemical expression of matrix metalloproteinase-2 (MMP-2) in preinvasive and invasive carcinoma of the uterine cervix so as to demonstrate whether the expression of MMP-2 is an early or late event in the process of dedifferentiation and cancer progression.

Methods: A total number of 50 samples of cervical tissue were studied for MMP-2 immunoreactivity. The cases were selected to include ten normal cases used as a control group, 20 CIN cases and 20 cervical carcinoma cases. The CIN group was subdivided into CIN1 (n = 7), CIN2 (n = 6) and CIN3 (n = 7), while the carcinoma group was represented by squamous cell carcinoma (n = 16) and adenocarcinoma (n = 4).

Results: MMP-2 expression was totally absent in control cervices and low-grade squamous intraepithelial lesions, while high-grade squamous intraepithelial neoplasia and invasive carcinoma showed up-regulation of MMP-2 expression with no significant difference concerning the type of carcinoma. This overexpression of MMP-2 points to the possibility that it is an early marker of tumor progression in cervical carcinoma.

Conclusions: MMP-2 has a key role in extracellular matrix degradation and invasion in carcinoma of the uterine cervix. Its expression in high-grade squamous intraepithelial lesions may denote a potential risk for invasion and metastasis.

Metastasis; MMP-2; CIN; Cervical carcinoma

[1] Aznavoorian S., Loitta L.A., Murphy A.N., Stetler-Stevenson W.G.: "Molecular aspects of tumor cell invasion and metastasis". Cancer, 1993, 71, 1368.

[2] Brummer O., Bohmer G., Flemming P., Hollwitz B., Kuhnel H., Petry U.: "MMP-1 and MMP-2 in cervix uteri in different steps of malignant transformation". Gynecol. Oneal., 2002, 84, 222.

[3] Liotta L.A., Steier-Stevenson W.G.: "Metalloproteinases and cancer invasion". Sem. Cancer Biol., 1990, 1, 99.

[4] Alexander C.M., Werb Z.: "Extracellular matrix degradation". In. Hay E.D. (ed.). "Cell biology of the extracellular matrix". 2"'ed., New York, Plenum Press, 1991, 255.

[5] Davidson B., Ben-Baruch G., Goldberg I., Gotlieb W., Kopolovic J., Lerner-Geval, Reich R.: "MMP-2 and TIMP-2 expression correlates with poor prognosis in cervical carcinoma. A clinicopathologic study using immunohistochemistry and mRNA in situhybridization". Gynecol. Oneal., 1999, 73, 372.

[6] Kumaki F., Matsui K., Kawai Y., Y n Z.X., Ferrans V., Travis W.: "Expression of matrix metalloproteinases in invasive pulmonary adenocercinoma with bronchoalveolar component and atypical adenomatous hyperplasia". Am. J. Pathol., 2001, 159, 2125.

[7] Salmela M.T., Karjalainen-Lindsberg M.L., Puolakkainen P., Saarialho- Kere V.: "Up-regulation and differential expression of matrilysin (MMP-7) and metalloelastase (MMP-12) and their inhibitors TIMP-1 and TIMP-3 in Barrett's oesophageal adenocarcinoma". Br. J. Cancer, 2001, 85, 383.

[8] Asha-Nair S., Karuagaran D., Nair M.B., Sudhakaran P.R "Changes in matrix metalloprotei nases and their endogenous inhibitors during tumor progression in the uterine cervix". J. Cancer Res. Clin. Oneal., 2003, 129. 123.

[9] Jones J.L., Walker R.A.: "Control of matrix metallo-proteinase activity in cancer". J. Pathol., 1997, 183, 377.

[10] Grazetti G., Civattini A., Lucarini G., Goteri G., De-Nictolis M.,Biagini G.: "Microinvasive cervical carcinoma and cervical implications of 72-kDa metalloproteinase immunostaining". Gynecol. Oneal., 1996, 61, 197.

[11] Zhou C.Y., Yoo J.F., Chem X.D.: "Expression of matrix metalloproteinase-2, 9 and their inhibitor-TIMPI, 2 in human squamous cell carcinoma of uterine cervix". Ai-Zheng, 2002, 21, 735.

[12] Talvensaari A., Apaja-Sarkkinen M., Hoyhat M., Westerlund A., Puistola U., Turepeenniemi T.: "Matrix metalloproteinase-2 immunoreactive protein appears early in cervical epithelial dedifferentiation". Gynecol. Oneal., 1999, 72, 306.

[13] Mitra A., Chakrbarti J., Chattopadhyay N., Chatterjee A.: "Membrane- associated MMP-2 in human cervical cancer". J. Environ. Pathol. Toxicol. Oncol., 2003, 22, 93.

[14] Yoshida H., Hattori K., Honda K., Hyun Y., lshiko 0., Monmura M. e: al.: "Expression of survivin and matrix metallodroteinases in adenocarcinoma and squamous cell carcinoma of the uterine cervix". Oncol. Rep., 2002, 9, 565.