Solov'eva N I, Timoshenko O S, Kugaevskaia E V, Andreeva Iu Iu, Zavalishina L E
Bioorg Khim. 2014 Nov-Dec;40(6):743-51.
A key role in tumor progression play two processes--the destruction and angiogenesis. Matrix metalloproteases (MMPs) play a leading role during tissue degradation. Tissue collagenase--MMP-1 and MT1-MMP hydrolyze fibrillar collagens, which are the basis of connective tissue matrix, and ensure the development of an invasive process. Gelatinase A and B (MMP-2 and MMP-9) hydrolyze collagen type IV, which is the basis of the basal membrane, and facilitate the development of metastasis. Endogenous tissue inhibitors TIMP-1 and TIMP-2 are involved in the regulation of MMP expression and activity. It has been established that MMP-9 release vascular endothelial growth factor (VEGF) associated with the STM--the primary inductor angiogenesis. Angiotensin-converting enzyme (ACE) participates in the induction of VEGF synthesis. ACE--a key enzyme of the renin-angiotensin system, forms angiotensin II, which interactes with the receptor ATIR and induces VEGF synthesis, as well as stimulates endothelial cell proliferation. Our experimental studies devoted to the study of particularity expression of key enzymes of destruction and angiogenesis in squamous cell carcinoma of the cervix (SCC). It was studied: MMP-1, MT1-MMP, MMP-2 and MMP-9 and their endogenous regulators: TIMP-1, TIMP-2, and as well as ACE. Work was performed on clinical specimens containing the tumor tissue, taking into account the presence or absence of metastasis to regional lymph nodes and the specimens of adjacent morphologically normal tissue. It was shown that the increase of MMP-1, MT1-MMP and MMP-9 expression and low of TIMP-1 and TIMP-2 expression makes the main contribution to the destructive (invasive) potential of SCC. The change of MMP-2 expression is not so significant and it is less influenced to the destructive potential. It was shown dramatic increasing of MMP-1 and MMP-9 activity in metastasizing tumor tissue ACE activity in a tumor in most of the samples was higher than the activity in normal tissues. It was established that the expression of key enzymes degradation and angiogenesis occurs not only in tumor but also in normal tissues. Data are important for understanding the mechanisms of tumor progression and have prognostic value and may affect the therapeutic strategy for patients.
肿瘤进展过程中的两个关键过程是组织破坏和血管生成。基质金属蛋白酶（MMPs）在组织降解过程中起主导作用。组织胶原酶——MMP-1和MT1-MMP可水解作为结缔组织基质基础的纤维状胶原蛋白，并确保侵袭过程的发展。明胶酶A和B（MMP-2和MMP-9）可水解作为基底膜基础的IV型胶原蛋白，并促进转移的发生。内源性组织抑制剂TIMP-1和TIMP-2参与MMP表达和活性的调节。已经确定MMP-9可释放与STM相关的血管内皮生长因子（VEGF）——血管生成的主要诱导因子。血管紧张素转换酶（ACE）参与VEGF合成的诱导。ACE——肾素-血管紧张素系统的关键酶，可形成血管紧张素II，其与受体ATIR相互作用并诱导VEGF合成，还可刺激内皮细胞增殖。我们的实验研究致力于研究子宫颈鳞状细胞癌（SCC）中破坏和血管生成关键酶的表达特性。研究了：MMP-1、MT1-MMP、MMP-2和MMP-9及其内源性调节剂：TIMP-1、TIMP-2以及ACE。对含有肿瘤组织的临床标本进行了研究，同时考虑到区域淋巴结转移的有无以及相邻形态学正常组织的标本。结果表明，MMP-1、MT1-MMP和MMP-9表达的增加以及TIMP-1和TIMP-2表达的降低对SCC的破坏（侵袭）潜能起主要作用。MMP-2表达的变化不太显著，对破坏潜能的影响较小。结果显示转移瘤组织中MMP-1和MMP-9活性显著增加，大多数样本中肿瘤的ACE活性高于正常组织中的活性。已经确定关键酶降解和血管生成的表达不仅发生在肿瘤中，也发生在正常组织中。这些数据对于理解肿瘤进展机制具有重要意义，具有预后价值，并可能影响患者的治疗策略。
