Use of plasma MMP‐2 and MMP‐9 levels as a surrogate for tumour expression in colorectal cancer patients

Abstract

Matrix metalloproteinases, and notably the gelatinases MMP-2 and MMP-9, have important roles in tumour invasion, metastasis and angiogenesis. Our study investigates the distribution of MMP-2 and MMP-9 in colorectal cancer, the correlation with plasma levels, changes following surgical resection and whether plasma levels reflect clinical staging and disease course. MMP-2 and MMP-9 expression in 48 colorectal tumours and 13 adenomatous polyps was analysed by RT-PCR, immunohistochemistry, and quantified by ELISA of tumour lysates. Concentrations of MMP-2 and MMP-9 in plasma samples from these patients and 36 other patients who underwent curative resections were measured by ELISA prior to and 6 -12 months after surgery. MMP-2 expression was significantly increased in colorectal cancer tissues compared to matched normal colon as measured by ELISA. Active MMP-2 was localised by immunohistochemistry to regions where tumour cells invaded the muscularis with little staining in more superficial areas. Plasma MMP-2 levels were also significantly elevated in patients with colorectal cancer, with significant reductions following curative resections at all stages. Similarly, MMP-9 expression was significantly increased in colorectal cancer tissues, predominantly in the tumour stroma. Plasma levels of MMP-9 were significantly elevated at all stages in colorectal cancer patients and a significant reduction was seen following curative resections. With both MMP-2 and MMP-9, the strongest correlation with clinical staging in colorectal cancer was represented by the total plasma concentration of the enzymes, both falling to within the normal range following curative surgery. Plasma levels of these enzymes may therefore have potential as a noninvasive indicator of invasion or metastasis in colorectal cancer or as a marker of disease status during follow-up. © 2003 Wiley-Liss, Inc. colorectal cancer; metastasis; proteolysis; staging; plasma Matrix metalloproteinases are a closely related multigene family of zinc-dependent proteolytic enzymes. They have a role in normal physiological tissue remodelling and are capable of degrading all components of the extracellular matrix. There is increasing evidence that metalloproteinases play many important roles in cancer, for example, releasing and activating growth factors and other proteases and assisting tumour cells to invade the extracellular matrix. In addition, MMPs potentiate neovascularisation of tumour tissue, 1-4 with both MMP-2 and MMP-9 expression being correlated with angiogenesis in colorectal cancer. 5 Several previous studies have examined MMPs and also tissue inhibitors of MMPs (TIMPs) in colorectal cancer and in some cases a relationship between expression and tumour characteristics or metastasis has been found. 2,6 -9 Other studies have measured serum or plasma levels of MMPs and stated that they are raised in various cancers; 10 -14 however few studies have been reported in colorectal cancer, and it is not clear whether circulating MMP levels reflect tumour expression....

Serum matrix metalloproteinase‐9 in head and neck squamous cell carcinomais a prognostic marker

“…The positive immunostaining for MMP-9 did not, however, show any significant association with plasma concentrations of MMP-9. Tutton et al 40 have also reported that MMP-9 expression is significantly increased in colorectal cancer tissues, predominantly in the stroma of the tumor, and that plasma levels of MMP-9 are significantly elevated at all stages in colorectal cancer patients, but any correlation between tissue and circulating levels of MMP-9 was not reported. A statistically significant difference was found in this study between the mean values of serum MMP-9 immunoreactive protein in HNSCC patients and healthy controls.…”

Serum levels of matrix metalloproteinase-2 and -9 and conventional tumor markers (CEA and CA 19-9) in patients with colorectal and gastric cancers

“…The role of MMP-2 and MMP-9 has been confirmed in colorectal cancer (3)(4)(5) and gastric cancer (6)(7)(8). Increased levels of MMP-2 and MMP-9 in patients with colorectal and gastric cancer were detected in serum (9,10), plasma (3,9), and tissue (3,11,12).…”

“…Increased levels of MMP-2 and MMP-9 in patients with colorectal and gastric cancer were detected in serum (9,10), plasma (3,9), and tissue (3,11,12). Different techniques were utilized for the determination of MMP-2 and MMP-9 including gelatin zymography (11,13), enzyme linked immunosorbant assay (ELISA) (3,14), immunohistochemical techniques (15), in situ hybridization (2) and reverse transcriptasepolymerase chain reaction (3).…”

Serum Matrix Metalloproteinase-2, -7 and -9 (MMP-2, MMP-7, MMP-9) levels as Prognostic Markers in Patients with Colorectal Cancer

“…Th ey wanted to discover whether plasma levels are a refl ection of the clinical staging and the development of the disease. Th eir results showed that MMP-2 plasma levels were considerably elevated in patients with CRC; they considerably decreased aft er surgical resection of the tumour, and MMP-9 serum levels were considerably elevated in all stages of the disease in CRC patients, while they decreased aft er the surgical resection of the neoplasm (21). On the contrary, the Ruokolainen's investigation for the prognostic role of the MMP-2 and Maurel, Nadal, Garcia-Albeniz et al examined the MMP-7 serum levels in 87 healthy patients and in 120 CRC patients in order to determine the serum level prognostic signifi cance of this enzyme.…”