Proteolysis in colorectal cancer

Abstract

Background-The process of metastasis is complex, involving many interrelated stages, including proteolysis. Proteolysis occurs in both normal and pathological processes and involves the breakdown of the extracellular matrix and/or basement membrane by proteolytic enzymes. Normally, proteolysis is tightly controlled by specific endogenous proteinase inhibitors. However, in certain disease processes, including cancer, controlled but abnormal proteolysis seems to occur. Proteinases involved in tumour invasion and metastasis include the matrix metalloproteinases (MMPs) and the serine proteinases. Aims-To gain a greater understanding of the proteolytic process occurring in colorectal cancer and to determine which, if any, proteinases are upregulated. The process of metastasis is complex, involving many sequential and interrelated steps. In brief, metastasis involves detachment of a single or a group of tumour cells from the primary tumour, local invasion through the surrounding extracellular matrix (ECM), intravasation into blood or lymphatic vessels, survival in the circulation, extravasation at a secondary site, survival and proliferation at the secondary site, and finally the potential for this secondary growth to metastasise. 1 ECM turnover normally involves homeostatic control of cell division, matrix synthesis, and degradation (proteolysis), which is under the control of cytokines, growth factors, and cell-matrix interactions. ECM degradation by proteinases is involved in normal physiological processes and is a tightly controlled and regulated process. However, in certain disease states, including cancer invasion and metastasis, the balance of ECM turnover is not controlled or regulated normally and excessive proteolysis occurs. Methods-The 2Proteinases are known to be involved in tumour cell invasion and the resulting ECM degradation may occur at several stages of the metastatic cascade including angiogenesis, local invasion, intravasation, and extravasation. Several proteinases have been implicated in one or more of these processes, as well as being potential prognostic indicators of disease free survival and death; these proteinases include: cathepsin B, 3 cathepsin D, 4 and urokinase-type plasminogen activator (uPA). The ECM degradation required for tumour cell invasion is a tightly controlled process at the biochemical and cellular level. These processes are dependent not only on the total amount of secreted proenzymes, but also on the coordinated activation and inhibition of these enzymes. The cells often regulate proenzyme activation either on or close to the cell surface, permitting localised ECM degradation. 6Several proteinase classes exist including metalloproteinases, serine proteinases, aspartic proteinases, and cysteine proteinases. Within the metalloproteinase class, the matrix metalloproteinase (MMP) or matrixin family of enzymes is thought to be particularly important in ECM turnover. The serine proteinases, plasminogen activators (PAs), are also involved in ECM degradation by activatin...

Tissue levels of active matrix metalloproteinase-2 and -9 in colorectal cancer

“…By the use of a specific MMP inhibitor as a control in this activity assay and the use of a general protease inhibitor, only actual active MMPs are measured and not other proteinases or protein-inhibitor complexes. This is an important difference with assays used by others (Garbett et al, 1999b;Baker et al, 2000;McKerrow et al, 2000). The results obtained here indicate that in the tumours studied MMP (production and) activation is elevated compared to the production of TIMPs.…”

Diagnostic significance of TIMP-1 level in serum and its immunohistochemical expression in colorectal cancer patients

“…The overexpression of the TIMP-1 protein in cancer cells has also been confirmed in molecular studies [14,15]. However, the analyses of tissue homogenates obtained from the patients diagnosed with CRC with the ELISA method indicated that the level of TIMP-1 protein increased in comparison to its concentration in normal colon tissue in biological material of this type [16][17][18]. Furthermore, Baker et al [17] noted that the growth of TIMP-1 in tumor homogenates was closely connected with Duke's cancer stage, lymph node involvement and MMP-1 level.…”

Functional Proteomics Study Reveals That N-Acetylglucosaminyltransferase V Reinforces the Invasive/Metastatic Potential of Colon Cancer through Aberrant Glycosylation on Tissue Inhibitor of Metalloproteinase-

“…Treatment with gelatinase inhibitors significantly nullified the invasiveness of WiDr cells (Fig. 4B), indicating the involvement of hydrolysis of the basement membrane catalyzed by MMP-2 and/or MMP-9 (21,22). In view of the result that the cell invasion rate was nearly the same among mock cells of TIMP-1 transfectant (Fig.…”