Matrix Metalloproteinases, Tissue Inhibitors of Matrix Metalloproteinases and Angiogenic Cytokines in Peripheral Blood of Patients with Thyroid Cancer

Abstract

Stimulation of growth of endothelial cells from preexisting blood vessels, i.e., angiogenesis, is one of the essential elements necessary to create a permissive environment in which a tumor can grow. During angiogenesis, the matrix metalloproteinase (MMP) family of tissue enzymes contributes to normal (embriogenesis or wound repair) and pathologic tissue remodeling (chronic inflammation and tumor genesis). The proposed pathogenic roles of MMPs in cancer are tissue breakdown and remodeling during invasive tumor growth and tumor angiogenesis. Tissue inhibitors of metalloproteinases (TIMPs) form a complex with MMPs, which in turn inhibits active MMPs. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are unique among mediators of angiogenesis with synergistic effect, and both can also be secreted by thyroid cancer cells. The goal of the study was to evaluate the plasma blood concentration of VEGF, bFGF, MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, TIMP-1, and TIMP-2 in patients with cancer and in normal subjects. Twenty-two patients with thyroid cancers (papillary cancer, 11; partly papillary and partly follicular cancer, 3; anaplastic cancer, 5; medullary cancer, 3) and 16 healthy subjects (controls) were included in the study. VEGF, bFGF MMPs, and TIMPs were evaluated by enzyme-linked immunosorbent assay (ELISA). In patients with thyroid cancer, normal VEGF concentrations (74.29 +/- 13.38 vs. 84.85 +/- 21.71 pg/mL; p > 0.05) and increased bFGF (29.52 +/- 4.99 vs. 6.05 +/- 1.43 pg/mL; p < 0.001), MMP-2 (605.95 +/- 81.83 vs. 148.75 +/- 43.53 ng/mL; p < 0.001), TIMP-2 (114.19 +/- 6.62 vs. 60.75 +/- 9.18 ng/mL; p < 0.001), as well as lower MMP-1 (0.70 +/- 0.42 vs. 3.87 +/- 0.53; p < 0.001) levels have been noted. Increased plasma levels of MMP-3 and MMP-9 were also found in patients with medullary carcinoma. In conclusion, predominance of MMP-2 over TIMP-2 and TIMP-1 over MMP-1 as well as increased concentration of bFGF in peripheral blood are common features in patients with thyroid cancer.

Clinical significance of serum MMP-2 and MMP-7 in patients with ovarian cancer

“…Although these levels were slightly higher than healthy controls and slightly lower than patients with malign ovarian tumors, there was no significant difference among these. We know that MMPs may also increase in nonmalignant disease such as cardiovascular disease [28][29][30]. In a study, woman with polycystic ovary syndrome had significantly higher concentrations of MMP-2 and MMP-9 compared to healthy women [31].…”

Altered Metastatic Behavior of Human Breast Cancer Cells after Experimental Manipulation of Matrix Metalloproteinase 8 Gene Expression

“…Therefore, in addition to the differential expression of MMP-8 in these tumor cell lines, activation of the procollagenase could be an important regulatory step in its inhibitory effect on metastasis. With the exception of two publications reporting the collagenase as a potential tumor marker in patients with head and neck cancer (39,40) and one showing its expression in several melanoma cell lines (14), most of the papers describing MMP expression in different types of cancers failed to observe any correlation between MMP-8 and invasion or metastasis (41)(42)(43)(44)(45)(46). In breast cancer, Duffy et al (47) did not find any relationship, but we have described previously that down-regulation of the enzyme in NM2C5-ASM8 breast cancer cells in vitro by gene transduction experiments significantly increased their ability to invade through Matrigel-coated membranes (3).…”

Lesional Overexpression of Matrix Metalloproteinase-9 Promotes Intraplaque Hemorrhage in Advanced Lesions But Not at Earlier Stages of Atherogenesis

“…Because MMP-9 exerts pleiotropic effects including ECM degradation, release of matrix-bound factors and adhesion molecule shedding, 30,31,32 we speculate that various stages of atherogenesis feature a different aspect from this wide array of physiological capacities. Depending on its context, source and abundance MMP-9 could, directly or indirectly, by activating other proteases or releasing matrix-bound effectors, affect matrix homeostasis, cell recruitment, and apoptosis.…”