Clinical prospects of matrix metalloproteinases and their tissue inhibitors study in blood serum of patients with endometrial cancer and benign endometrial lesions

Background: Despite comparatively favorable clinical course and satisfactory prognosis of endometrial cancer, the increase of its incidence observed in the last years both in this country and abroad requires the development of new approaches to early diagnostics, prognostic assessment and the choice of personalized postoperative management. Therefore, exploration of biological markers for fundamental tumor characteristics, such as invasion, metastasizing, proliferative activity, sensitivity to endogenous and exogenous regulators, are still on the agenda. The family of matrix metalloproteinases (MMPs) degrading the majority of extracellular matrix components and involved in all stages of tumor progression comprise a rich source of such markers.

Aim: Comparative evaluation of MMP-2, 7, 9 and their type 1 and 2 tissue inhibitors (TIMP) levels in the serum of patients with endometrial cancer and benign endometrial disease and in healthy women, and the analysis of its associations with the main clinical and pathologic characteristics of cancer for evaluation of their potential diagnostic and prognostic value.

Materials and methods: Ninety four patients with endometrial cancer and 53 women with benign endometrial lesions (28 with polyps, 25 with various degree of hyperplasia) were enrolled into the study. The age of cancer patients was 36 to 78 (median 60) years, of those with benign lesions, 20 to 79 (median 54) years. The control group involved 77 practically healthy women aged 19 to 75 (median 46) years. The concentrations of the markers studied were measured by direct enzyme immunoassay (ELISA) kits (Quantikine, R&D Systems, USA).

Results: A significant increase of MMP-7 and TIMP-2 levels was demonstrated both in cancer patients (median values 5.5 and 96.9 ng/ml, respectively) and in those with benign endometrial lesions (median values 5.7 and 73.2 ng/ml, respectively) as compared to the control (median values 2.1 and 60.7 ng/ml, respectively). The ROC curve allowed to establish a cutoff level for MMP-7 (3.5 ng/ml) with good sensitivity/specificity ratio for endometrial cancer (88% and 87% respectively); however, it did not allow for differentiating between benign and malignant endometrial lesions. On the contrary, MMP-2, MMP-9 and TIMP-1 levels were 1.2-1.3-fold decreased in patients with cancer and benign endometrial diseases as compared to the control; MMP-9 and TIMP-1 levels in cancer patients were also lower than in those with endometrial polyps and hyperplasia. There were no significant associations between the levels of the markers studied and the indices of progression, histological type and grade of endometrial cancer. Also, no differences between the marker levels in serum of patients with polyps or various endometrial hyperplasias were identified.

Conclusion: MMPs and TIMPs assessed in this study cannot be considered as potential diagnostic markers of endometrial cancer; however, they might be useful for disease monitoring, prognosis assessment and evaluation of sensitivity to targeted therapy.