Heterogeneous suppression of experimentally induced colon cancer metastasis in rat liver lobes by inhibition of extracellular cathepsin B.
Metastatic rat colon cancer cells but not normal rat hepatocytes showed activity of cathepsin B on their plasma membranes. Activity was visualized in living cells with a new fluorogenic substrate, [Z-Arg]2-cresyl violet, and confocal microscopy. When these cancer cells were injected into the portal vein of rats, the animals developed tumors in the liver in a heterogeneous fashion. Three- to four-fold more tumors were found in the small caudate lobe than in the other three large lobes of the liver. Oral treatment with a selective water-soluble inhibitor of extracellular cathepsin B, Mu-Phe-homoPhe-fluoromethylketone, resulted in 60% reduction of the number of tumors and 80% reduction of the volume of tumors in the three large lobes whereas tumor development was not affected in the small caudate lobe. This study supports the conclusions that (a) extracellular cathepsin B plays a crucial but complex role in liver colonisation by rat colon carcinoma cells in vivo, (b) its selective inhibition suppresses tumor growth heterogeneously in the liver and (c) the caudate lobe of the liver is a relatively large risk factor for tumor development.
Van Noorden
C J
CJ
Academic Medical Center, University of Amsterdam, Laboratory of Cell Biology and Histology, The Netherlands. c.j.vannoorden@amc.uva.nl
Jonges
T G
TG
Van Marle
J
J
Bissell
E R
ER
Griffini
P
P
Jans
M
M
Snel
J
J
Smith
R E
RE
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000502:physiology*; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000201:enzymology*; D005260:Female; D008099:Liver / Q000201:enzymology; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D009362:Neoplasm Metastasis; D051381:Rats; D014407:Tumor Cells, Cultured
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D002401:Cathepsin B