Key enzymes of degradation and angiogenesis as factors of tumor progression for squamous-cell cervical carcinoma

Abstract

Destruction of the connective tissue matrix (CTM) and angiogenesis are the two processes playing a key role in tumor progression. Matrix metalloproteinases (MMPs) play a leading role in processes of tissue destruction. Tissue collagenases MMP-1 and MT1-MMP hydrolyze fibrillar collagens constituting the base of CTM and enable tumor invasion. Gelatinases A and B (MMP-2 and MMP-9) hydrolyze type IV collagen which is the main component of basal membranes and contribute to the development of metastases. Endogenous activators and inhibitors are involved in the regulation of expression and activity of these enzymes. MMP-9 was shown to release vascular endothelial growth factor (VEGF), the principal inductor of angiogenesis, bound to CTM. Angiotensin-converting enzyme (ACE) is involved in the induction of VEGF synthesis and stimulation of endothelial cell proliferation mediated by angiotensin II (AII) and its type 1 receptor (AT1R). Experiments reported in the present article addressed the distinctive features of expression of key degradation and angiogenesis enzymes in squamous cell carcinoma (SCC) of the cervix. MMP-1, MT1-MMP, MMP-2, and MMP-9 and their endogenous regulators TIMP-1 and TIMP-2, as well as ACE, were the objects of research. Experiments were performed with clinical specimens including tumor tissue samples, for which presence or absence of metastasis to regional lymph nodes was taken into account, and morphologically normal tissue samples. Increased expression of MMP-1, MT1-MMP, and MMP-9 and decreased expression of TIMP-1 and TIMP-2 were shown to make the principal contribution to the destructive (invasive) potential of cervical carcinomas; the effect of changes in MMP-2 expression was less pronounced. Dramatically increased expression of MMP-1 and MMP-9 was evident in metastasizing tumors. ACE activity in tumor samples was generally higher than activity in normal tissue. Substantial expression of MMP-1, MMP-2, MMP-9, and ACE was detected in morphologically normal tissue adjacent to the tumor; this can contribute to increased destructive potential of a tumor. The data reported are important for understanding the mechanisms of tumor progression, have prognostic value, and may affect the choice of individual therapeutic strategy for the patients.