Comparative Localization of Cathepsin B Protein and Activity in Colorectal Cancer

Abstract

S U M M A R YCathepsin B is a lysosomal cysteine proteinase that may participate in cancer progression. We compared localization of its protein and activity during progression of human colorectal cancer. In adenomas and carcinomas, protein expression and, particularly, activity were elevated compared with those in normal colorectal mucosa. In normal mucosa, cathepsin B protein expression was moderate in stroma and variable in epithelium, whereas activity was mainly present in distinct areas of stroma directly underneath the surface of the colon and in epithelium at the surface of the colon. Stroma in adenomas and carcinomas contained moderate to high protein levels but little activity except for areas of angiogenesis, inflammation, and necrosis, in which activity was high. In adenomas and the majority of well-differentiated carcinomas and moderately differentiated carcinomas, cathepsin B protein and activity were found in granular form in the epithelium, close to the basement membrane. Protein and activity levels were low and diffusely distributed in cancer cells in the remainder of the well-differentiated and moderately differentiated carcinomas and in all poorly differentiated carcinomas. Invasive fronts in most cancers contained moderate protein levels but high activity. We conclude that (a) activity localization is essential to understand the role of cathepsin B in cancer progression, and (b) cathepsin B activity in human colon is associated with invasion of cancer cells, endothelial cells, and inflammatory cells, and in cell death, both apoptotic and necrotic.

Caveolin-1 mediates the expression and localization of cathepsin B, pro-urokinase plasminogen activator and their cell-surface receptors in human colorectal carcinoma cells

“…Expression and redistribution of active cathepsin B to the basal plasma membrane during the progression of colon cancer are associated with a shortened patient survival (Campo et al, 1994;Hazen et al, 2000). Although the mechanism of cathepsin-B distribution to the basal plasma membrane remains to be elucidated, it occurs in late adenomas (Campo et al, 1994) coincident with the activation of K-ras (Fearon and Vogelstein, 1990).…”

“…Furthermore, translocation of cathepsin B from the apical region of the cells to the basal plasma membranes parallels malignant progression of colon cancer, occurring in late adenomas and early carcinomas (Campo et al, 1994). The cathepsin B associated with the basal plasma membrane of human colon tumors is active (Hazen et al, 2000). Increases in expression of cathepsin B and translocation of active cathepsin B to the basal membrane are also observed during the progression of adenomas in Min mice (Marten et al, 2002), a model for familial adenomatous polyposis in humans (for a review, see Dove et al, 1995).…”

Cathepsin B localizes to plasma membrane caveolae of differentiating myoblasts and is secreted in an active form at physiological pH

“…In all cells, caveolae are membrane invaginations reported to play a role in transcytosis, receptor-mediated uptake, stabilization of lipid rafts, and compartmentalization of signaling events at the cell surface (Hazen et al, 2000). It is well established that the principle component of skeletal muscle caveolae, cav-3, plays a role in signal compartmentalization (Lisanti et al, 1994).…”

RNAi-mediated inhibition of cathepsin B and uPAR leads to decreased cell invasion, angiogenesis and tumor growth in gliomas

“…In ovarian cancer cells, inhibition of cell surface cathepsin B prevents activation of pro-uPA, and subsequently, invasion of the carcinoma cells through Matrigel (Kobayashi et al, 1993). Cathepsin B activity in human colon cancer is associated with the invasiveness of cancer cells, endothelial cells and inflammatory cells as well as apoptotic and necrotic cell death (Hazen et al, 2000). Stable transfection of human cathepsin B cDNA into a murine squamous cell carcinoma resulted in a nearly three-fold increase in the level of secreted pro-cathepsin B and a 22% increase in invasiveness across a Matrigel-reconstituted basement membrane (Coulibaly et al, 1999).…”