Distinct roles for cysteine cathepsin genes in multistage tumorigenesis.
Multiple types of degradative enzymes, including cathepsins of the cysteine protease family, have been implicated in the regulation of angiogenesis and invasion during cancer progression. Several cysteine cathepsins are up-regulated in a mouse model of pancreatic islet cell carcinogenesis (RIP1-Tag2), and tumor progression is impaired following their collective pharmacologic inhibition. Using null mutations of four of the implicated cysteine cathepsins, we have now dissected their individual roles in cancer development. Mutants of cathepsins B or S impaired tumor formation and angiogenesis, while cathepsin B or L knockouts retarded cell proliferation and tumor growth. Absence of any one of these three genes impaired tumor invasion. In contrast, removal of cathepsin C had no effect on either tumor formation or progression. We have identified E-cadherin as a target substrate of cathepsins B, L, and S, but not cathepsin C, potentially explaining their differential effects on tumor invasion. Furthermore, we detected analogous increases in cathepsin expression in human pancreatic endocrine neoplasms, and a significant association between increased levels of cathepsins B and L and tumor malignancy. Thus individual cysteine cathepsin genes make distinctive contributions to tumorigenesis.
Cancer Biology and Genetics Program, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
Vasilena
V
Gocheva
Wei
W
Zeng
Danxia
D
Ke
David
D
Klimstra
Thomas
T
Reinheckel
Christoph
C
Peters
Douglas
D
Hanahan
Johanna A
JA
Joyce
D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D002403:Cathepsins / Q000235:genetics* / Q000502:physiology*; D049109:Cell Proliferation; D003433:Crosses, Genetic; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D011994:Recombinant Proteins / Q000378:metabolism; D047368:Tumor Burden; D015854:Up-Regulation
D015820:Cadherins; D015853:Cysteine Proteinase Inhibitors; D005456:Fluorescent Dyes; D007211:Indoles; D011994:Recombinant Proteins; C007293:DAPI; D002403:Cathepsins; D016650:Fluorescein-5-isothiocyanate