Matrix metalloproteinase-2 (MMP-2) and its tissue inhibitor (TIMP-2) are prognostic factors in cervical cancer, related to invasive disease but not to high-risk human papillomavirus (HPV) or virus persistence after treatment of CIN.

Abstract

OBJECTIVE:

Matrix metalloproteinase-2 (MMP-2) and its tissue inhibitor (TIMP-2) are important regulators of cancer invasion and metastasis. Their associations to high-risk (HR) human papillomavirus (HPV) in cervical intra-epithelial neoplasia (CIN) and cervical cancer (CC) are unexplored and their prognostic significance in CC remains controversial.

MATERIALS AND METHODS:

As part of our HPV-PathogenISS study, a series of 150 CCs and 152 CIN lesions were examined using immunohistochemical (IHC) staining for MMP-2 and TIMP-2 and tested for HPV using PCR with 3 primer sets (MY09/11, GP5+/GP6+, SPF). Follow-up data were available from all squamous cell carcinoma patients and 67 CIN lesions had been monitored with serial PCR for HPV after cone treatment.

RESULTS:

MMP-2 increased with the grade of CIN, with major up-regulation upon transition to invasive cancer (OR 20.78) (95%CI 7.16-60.23) (p=0.0001). TIMP-2 retained its normal expression until CIN3, with dramatic down-regulation in invasive disease (p=0.0001 for trend). Thus, the MMP2:TIMP-2 ratio increased with progressive CIN, exceeding the value 1.0 only in invasive disease. Both MMP-2 and TIMP-2 are highly specific (TIMP-2; 100%) discriminators of CIN with 100% positive predictive value (TIMP-2), but suffer from low sensitivity and negative predictive value. Neither MMP-2 nor TIMP-2 showed any significant association with HR HPV or virus persistence/clearance. TIMP-2 (but not MMP-2) was a significant predictor of survival in univariate (Kaplan-Meier) analysis (p=0.007), but lost its significance in multivariate (Cox) analysis.

CONCLUSION:

The activities of MMP-2 and TIMP-2 in cervical carcinogenesis seem to be unrelated to HR-HPV The inverse MMP-2:TIMP-2 ratio is a sign of poor prognosis. A combination of a TIMP-2 assay with another test showing high SE and high NPV (e.g., HCII for HPV) should provide a potential screening tool capable of accurate detection of CIN.

• Authors: M Branca, M Ciotti, C Giorgi, D Santini, L Di Bonito, S Costa, A Benedetto, D Bonifacio, P Di Bonito, P Paba, L Accardi, S Syrjänen, C Favalli, K Syrjänen, HPV-PathogenISS Study Group
• Journal: Anticancer research (Anticancer Res) 2006 Mar-Apr Vol. 26 Issue 2B Pg. 1543-56 ISSN: 0250-7005 [Print] Greece
• PMID: 16619570 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tissue Inhibitor of Metalloproteinase-2
• Matrix Metalloproteinase 2

Topics

• Adult
• Aged
• Aged, 80 and over
• Carcinoma, Squamous Cell (enzymology, pathology, virology)
• Female
• Humans
• Immunohistochemistry
• Matrix Metalloproteinase 2 (biosynthesis)
• Middle Aged
• Neoplasm Invasiveness
• Papillomaviridae
• Papillomavirus Infections (enzymology, pathology)
• Prognosis
• Prospective Studies
• Tissue Inhibitor of Metalloproteinase-2 (biosynthesis)
• Uterine Cervical Neoplasms (enzymology, pathology, virology)
• Uterine Cervical Dysplasia (enzymology, pathology, virology)