分子遺伝医学

Differential Associations of MMP-2 and MMP-14 with Stromal Amounts and T lymphocyte Presence in Ovarian Cancer

Abstract

M Caroline Vos, Elise Bekers, Brenda L Den Oudsten, Ella de Boed, Anneke A M van der Wurff, Toin H van Kuppevelt, Katarina Wolf and Leon F A G Massuger

Aim: Ovarian cancer prognosis is influenced by factors such as intratumoral T-lymphocyte presence and the amount of stroma formation relative to the epithelial tumor compartment. The regulation of these factors is unknown. Matrix metalloproteinases are involved in stromal remodeling and may be involved in T-cell trafficking as well. This study investigates the quantitative relationships between the matrix metalloproteinases MMP-2 and MMP-14 and both relative stroma amounts (‘stroma percentage’) and the presence of T lymphocytes in the stromal and epithelial compartments of ovarian cancer.

Patients and methods: In 86 patients with ovarian cancer, MMP-2 and MMP-14 expression and T-lymphocyte presence was determined using semi quantitative immunohistochemistry. Stroma percentage was determined by area calculation in haematoxylin eosin slides. Per slide, 3 random images at the tumor-stroma interface were investigated.

Results: Epithelial MMP-14 scoring correlated negatively with T-lymphocytes in tumor epithelium: correlation coefficient rho −0.36 (p < 0.01) for CD3, −0.30 (p < 0.01) for CD8 and −0.24 (p < 0.05) for CD45Ro. Stromal MMP-2 was positively related to stroma percentage (rho 0.29; p < 0.01). No significant correlations were found for MMP-14 with stromal amounts, or MMP-2 with T-cell presence in stroma or tumor epithelium.

Conclusion: Opposite to our hypothesis that MMPs reduce stromal amounts and permit T cell trafficking into both stromal and epithelial tumor parts, MMP expression was associated with higher relative stromal amounts and lower presence of T lymphocytes. In particular, we found that epithelial MMP-14 expression was negatively associated with T-lymphocyte presence in the tumor suggesting a role for MMP-14 in negatively regulating T-cell trafficking by other means. Stromal MMP-2 expression was associated with an increase in stromal amounts suggesting an ineffective feedback on tumor stroma volume growth of the expression of this gelatinase. More research is necessary to determine the specific actions of MMPs in ovarian cancer.