Changes in matrix metalloproteinases and their endogenous inhibitors during tumor progression in the uterine cervix.
OBJECTIVE
To study the role of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in cervical tumorigenesis, we analyzed 70 cervical tissue specimens that included 15 low-grade squamous intraepithelial lesions (SILs), 20 high-grade SILs, 25 squamous cell carcinomas (SCCs) and 10 specimens of normal cervical tissue.


METHODS
The gelatinolytic activity of MMP-9 and MMP-2 was determined by zymographic analysis. The expression of MMP-9 and MMP-2 and TIMP-1 and TIMP-2 was determined by immunohistochemistry.


RESULTS
All the samples had 72/66 kDa gelatinase activity; 92 kDa gelatinase activity was detected only in high-grade SILs and SCCs. Immunohistochemical analysis showed weak positivity for MMP-2 in normal cervical epithelium and low-grade SILs. However, high-grade SILs and SCCs showed intense cellular and stromal reactivity for MMP-2 and MMP-9. For TIMP-1 and TIMP-2, normal cervical epithelium and low-grade SILs showed intense immunostaining, >50% of high-grade SILs showed positivity, and 95% of SCCs showed intense stromal and cellular reactivity.


CONCLUSIONS
Increase in the relative activity of these gelatinases and enhanced immunostaining for MMPs and TIMPs with tumor progression suggest that they may play a crucial role in cervical cancer progression. A significant association between stage of the lesion and expression of MMPs and TIMPs ( P<0.01) was found. Immunohistochemical studies indicate that these MMPs may be of basal cell origin in cervical tissue, although the mechanism of their upregulation is not clearly understood.
Asha Nair
S
S
Division of Cancer Biology, Rajiv Gandhi Centre for Biotechnology, 695014, Thiruvananthapuram, Kerala, India.
Karunagaran
D
D
Nair
M B
MB
Sudhakaran
P R
PR
D000328:Adult; D000368:Aged; D015153:Blotting, Western; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D020782:Matrix Metalloproteinases / Q000032:analysis*; D008875:Middle Aged; D009367:Neoplasm Staging; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D019714:Tissue Inhibitor of Metalloproteinases / Q000032:analysis*; D002583:Uterine Cervical Neoplasms / Q000737:chemistry* / Q000201:enzymology / Q000473:pathology
D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases