The metastatic potential of ras-transfected cells has been attributed in part to significant ras induction of
proteinase expression. To determine whether primary
cancers also demonstrate higher
cysteine proteinase activities in the presence of activated ras genes or altered
ras protein expression, we have analyzed 60 primary human
colorectal carcinomas for ras gene or
protein changes together with the expression of
cathepsins B and L.
Cancers containing K-ras mutations (47% of 60
carcinomas) demonstrated greater increases in
cathepsin L activity than
cancers without K-ras mutations (p = 0.029), with particularly significant correlations for earlier stage
cancers (Dukes' A and B
carcinomas, p = 0.006). Western blots used to characterize
ras protein patterns in the same
cancer/normal pairs have demonstrated that N-
ras protein is more highly expressed in colon tissues than H- or K-
ras proteins and that N-ras overexpression occurs in almost 70% of
colorectal cancers, with or without a concurrent change in electrophoretic mobility of N-
ras protein. Our current study has now shown that N-
ras protein overexpression alone does not significantly induce
cathepsin B or L activity levels in
colon cancers. However,
carcinomas demonstrating altered N-
ras protein forms, in the absence of any K- or N-ras mutations, expressed significantly higher levels of
cathepsin B and L activities compared with
carcinomas with normal N-
ras protein banding patterns. Our data suggest that
colorectal carcinomas with either K-ras mutations or altered forms of N-
ras protein may increase their tumorigenic potential via the induction of
cathepsin L or B expression levels. Our results also confirm that ras oncogene up-regulation of
cathepsin B and L activities, previously reported in cultured cells, is a frequent event in primary human
colorectal carcinomas.