Expression of Metalloproteinases and Their Inhibitors in Adenocarcinoma of the Uterine Cervix

SUMMARYMetalloproteinases (MMPs), a family of enzymes that participate in extracellular matrix degradation and remodeling, may play a role in tumor invasion and metastasis and have been correlated with tumor behavior and survival. The action of MMPs is regulated by tissue inhibitors of MMPs (TIMPs). Adenocarcinomas of the uterine cervix are neoplasms that primarily affect young women and are associated with human papillomavirus (HPV). Eighteen cervical adenocarcinomas and 5 controls were immunohistochemically analyzed for the expression of MMP-2, MMP-3, MMP-9, and their inhibitors, TIMP-1 and TIMP-2, in tumor cells and peritumoral stromal cells. These cells were also studied for the presence of MMP-2, MMP-9, and TIMP-2 mRNA by in situ hybridization (ISH). HPV status was studied using ISH for HPV 16 and 18. MMP-2 and −9 were expressed immunohistochemically in tumor cells in 17 of 18 tumors, MMP-3 in 5, TIMP-1 in 3, and TIMP-2 in I. Stromal cells of most tumors expressed all the above proteins. The normal endocervical epithelium was uniformly negative for MMP-2, MMP-3, MMP-9, and TIMP-2, and variably expressed TIMP-1. Intense signals for MMP-2, MMP-9, and TIMP-2 mRNA were less frequently detected by ISH in tumor cells and peritumoral stromal cells and were absent in normal endocervical epithelium. All tumors contained HPV DNA 16, 18, or both. MMP and TIMP expression did not correlate with tumor type, grade, or HPV type. MMPs and their inhibitors are present in most cervical adenocarcinomas, independent of tumor grade or subtype, but with the exception of TIMP-1, they are not expressed in nonneoplastic endocervical epithelium. This finding might be helpful in the diagnosis of endocervical adenocarcinomas. HPV is prevalent in cervical adenocarcinomas, but its role in determining tumor behavior remains unclear.