Cathepsin B and glioma invasion.
Increased expression of cathepsin B has been reported in a number of human and animal tumors. This has also been observed in human gliomas where increases in cathepsin B mRNA, protein, activity and secretion parallel malignant progression. In the present study, we showed that cathepsin B was directly involved in glioma cell invasion. Activity of cathepsin B was an order of magnitude higher in glioma tissue than in matched normal brain. Inhibitors of cysteine proteases reduced invasion of glioma cells in two in vitro models: invasion through Matrigel and infiltration of a glioma spheroid into a normal brain aggregate. Glioma spheroids expressed higher levels of cathepsin B than did monolayers and the ability of subclones differing in cathepsin B activity to infiltrate normal brain aggregates paralleled their cathepsin B activity. We confirmed that intracellular staining for cathepsin B occurs at the cell periphery and in cell processes and observed extracellular staining on the cell surface. In addition, we demonstrated that intracellular cathepsin B located at the cell periphery and in processes was active. The cell surface cathepsin B colocalized with areas of degradation of an extracellular matrix component. We hypothesize that the increased expression of active cathepsin B in gliomas leads to increases in invasion in vitro and in vivo and have developed a xenotransplant model in which this hypothesis can be tested.
Demchik
L L
LL
Department of Pharmacology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Ml 48201, USA.
Sameni
M
M
Nelson
K
K
Mikkelsen
T
T
Sloane
B F
BF
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002401:Cathepsin B / Q000235:genetics*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009361:Neoplasm Invasiveness; D051381:Rats; D012016:Reference Values; D014183:Transplantation, Heterologous
D015853:Cysteine Proteinase Inhibitors; D002401:Cathepsin B