Increased expression and activation of gelatinolytic matrix metalloproteinases is associated with the progression and recurrence of human cervical cancer.
Cancer-derived matrix metalloproteinases (MMPs) are proposed to be essential for tumor stromal invasion and subsequent metastasis. To explore the role of MMPs in cancer progression, we examined the expression of various MMPs and tissue inhibitors of MMPs in precancerous and cancerous lesions of the uterine cervix. Immunohistochemical studies demonstrated that MMP-2 and MMP-9 were expressed in >90% of squamous cell carcinomas (SCC) and 83-100% of high-grade squamous intraepithelial lesions (HSIL), but were less frequently expressed in low-grade squamous intraepithelial lesions and normal squamous epithelium (13%). MMP-1, MMP-14, and MMP-15 were detected in 55-81% of SCC cases, and MMP-1 was detected in 39% of HSIL. The tissue inhibitors of MMPs were weakly expressed in SCC (10-61%). By direct analysis of enzyme activities in microdissected specimens, we found that the gelatinolytic activity of MMP-9 was significantly higher in HSIL and SCC than in normal cervix (P < 0.01). The levels of active-form MMP-2 increased progressively from HSIL to SCC of stage I and more advanced stages (P < 0.01). The gelatinolytic activity of MMP-9 and active-form MMP-2 in SCC were strongly correlated with lymphovascular permeation and subsequent lymph node metastasis (P < 0.02). Moreover, the gelatinolytic activity and immunoreactive percentage of both MMP-2 and MMP-9 were significantly higher in SCC cases who had a recurrence than in those who remained free of disease (P < 0.001). Thus, our data demonstrate progressively up-regulated expression of MMP-2 and MMP-9 with SCC progression, and significant associations among their gelatinolytic activity and stage, nodal metastasis, and recurrence.
Sheu
Bor-Ching
BC
Department of Obstetrics and Gynecology, National Taiwan University College of Medicine, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei 100, Taiwan. bcsheu@ha.mc.ntu.edu.tw
Lien
Huang-Chun
HC
Ho
Hong-Nerng
HN
Lin
Ho-Hsiung
HH
Chow
Song-Nan
SN
Huang
Su-Cheng
SC
Hsu
Su-Ming
SM
D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000473:pathology; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000201:enzymology / Q000473:pathology
D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases