Cysteine proteinases and metastasis

Abstract

Cysteine proteinases are a subclass of endopeptidases which require activation by thiol reagents. A tumor cysteine proteinase which appears to be related to lysosomal cathepsin B has been implicated in the ability of tumor cells to invade the extracellular matrix and to metastasize to secondary sites. Lysosomal cathepsin B can degrade such components of the extracellular matrix as collagen, fibronectin and proteoglycans. Activity of this cathepsin B-like cysteine proteinase (CB) has been correlated with tumor malignancy in a number of tumor lines yet not in all tumor lines studied. CB activity in tumors seems to be associated with the viable tumor cells, probably with the plasma membrane of these tumor cells. CB activity has been measured in the sera, urine, ascites fluid and pancreatic fluid of tumor-bearing patients. CB is released from tumor explants and tumor cells in vitro as well as from normal subcutaneous tissue exposed to tumor-conditioned medium. Cathepsin B from normal tissues is rapidly inactivated above pH 7.0. Therefore, CB in tumor cell membranes or released from tumor cells (or from host cells in response to tumor cells) may not possess proteolytic activity at neutral pH and thus may not facilitate tumor cell invasion. However, CB exhibits enhanced stability at neutral or slightly alkaline pH's. There is not yet definitive proof that CB plays a role in tumor invasion and metastasis. There is, however, an increasing body of correlative evidence relating CB activity and tumor malignancy. This correlative evidence plus preliminary evidence that tumor CB can degrade components of the extracellular matrix in vitro suggests that CB may be one proteinase active in a proteolytic cascade resulting in tumor invasion and metastasis.

Participation of intracellular cysteine proteinases, in particular cathepsin B, in degradation of collagen in periosteal tissue explants

“…The breakdown of cartilage components may also involve cathepsin B (Van Noorden et al, 1988;Buttle and Saklatvala, 1992;Baici et al, 1995), for example in cytokine-stimulated breakdown, where it possibly acts in a proteolytic activation cascade (Buttle et al, in press). Finally, metastasis of several malignancies is associated with increased production and/or secretion of cathepsin B (Sloane and Honn, 1984;Moin et al, 1989;Keppler et al, 1994), possibly promoting extracellular matrix degradation needed for tumor cell dissemination. Under these circumstances, various cathepsin B isoforms have been detected (Page et al, 1992), some of which were shown to be active at neutral pH (Buck et al, 1992;Spiess et al, 1994).…”

Immunostained cathepsins B and L correlate with depth of invasion and different metastatic pathways in early stage gastric carcinoma

“…They are important in the catabolism of various intracellular proteins in lysosomes and are to be implicated in the direct or indirect degradation of the extracellular matrix in tumor cells. 3 Cathepsin B has been investigated in several human tumors, such as colorectal carcinoma, 4 lung carcinoma, 5,6 and others; 7,8 in addition, some studies have reported on its prognostic values. 9 -11 Cathepsin L is also a cysteine protease whose proenzyme previously was called MEP, major excreted protein of transformed murine fibroblasts, 12,13 and some studies have shown its relation to human cancer progression.…”

Gem-diamine 1-N-iminosugars as versatile glycomimetics: synthesis, biological activity and therapeutic potential

“…[49][50][51][52][53] Proteolytic enzymes (heparanase and matrix metalloproteinases) secreted by tumor cells are capable of degrading ECM and BM components, and their activities are closely related to the metastasis potential of malignant cells. [54][55][56][57][58][59][60] The inhibitory effects of uronic acid-type gem-diamine 1-N-iminosugars that have inhibitory activities against exo-uronidase, heparanase, sulfotransferase and sialyltransferase were also evaluated on tumor metastasis using the experimental and spontaneous pulmonary metastasis in mice.…”