MMP-1 and MMP-2 in the cervix uteri in different steps of malignant transformation--an immunohistochemical study.
OBJECTIVE
Enzymatic degradation of the extracellular matrix (ECM) represents a key element in the multistage process of tumor invasion and metastasis. This process requires extensive degradation of ECM components such as basement membrane collagen (type IV) and interstitial collagen (type I, II, III). Matrix metalloproteinase-2 (MMP-2) specifically cleaves collagen type IV, the major collagen of the basement membrane. MMP-1 digests interstitial collagen type I and III, the main collagen types of the stromal extracellular matrix. We investigated protein levels of MMP-1 and MMP-2 in different stages of malignant transformation.


METHODS
Using the APAAP method we analyzed 10 normal cervical tissues, 11 cervical intraepithelial neoplasia 1 (CIN 1), 8 CIN 2 and 10 CIN 3 lesions, and 15 invasive squamous cell carcinomas. These data were compared with the HPV DNA status tested by hybrid capture II.


RESULTS
Only a few isolated epithelial cells stained positively for MMP-1 and MMP-2 in normal cervical tissue and CIN 1 lesions. The CIN 2 and CIN 3 group displayed a heterogeneous distribution of MMP expression. 3 CIN 2 and 8 CIN 3 lesions showed strong MMP-2 and weak MMP-1 expression in the dysplastic epithelial cells. 5 CIN 2 and 2 CIN 3 lesions stained negatively. Invasive carcinomas showed a coexpression for MMP-1 and MMP-2 in malignant epithelial cells and peritumoral stroma cells. All MMP-2-positive cases tested positive for the HPV high-risk group.


CONCLUSIONS
The expression of MMP-2 protein in preinvasive lesions of the cervix uteri and a consecutive coexpression of MMP-1 and MMP-2 in invasive cancer suggest a gradually increasing invasive potential. MMP-2 expression, when focally observed in high-grade squamous intraepithelial lesions of the cervix, may indicate tumor areas with an increased risk for invasive growth.
Brummer
Oliver
O
Department of Gynecologic Oncology, Medizinische Hochschule Hannover, Germany. oliver.brummer@gmx.de
Böhmer
Gerd
G
Hollwitz
Bettina
B
Flemming
Peer
P
Petry
K-Ulrich
KU
Kühnle
Henning
H
D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D009367:Neoplasm Staging; D027383:Papillomaviridae / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000201:enzymology* / Q000473:pathology / Q000821:virology
D004279:DNA, Viral; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1