Cathepsin B expression and survival in colon cancer: implications for molecular detection of neoplasia.
OBJECTIVE
Proteases play a critical role in tumorigenesis and are upregulated in colorectal cancer and neoplastic polyps. In animal models, cathepsin B (CTSB)-activatable imaging agents show high enzyme activity within intestinal tumors.


METHODS
We conducted a prospective cohort study of 558 men and women with colon cancer with tumors that were accessible for immunohistochemical assessment. We used Cox proportional hazards models, stratified by stage, to compute colon cancer-specific and overall mortality according to tumoral expression of CTSB.


RESULTS
Among 558 participants, 457 (82%) had tumors that expressed CTSB (CTSB positive) and 101 (18%) had tumors that did not express CTSB (CTSB negative). CTSB expression was not associated with disease stage (P = 0.19). After a median follow-up of 11.6 years, there were 254 total and 155 colon cancer-specific deaths. Compared with participants with CTSB-negative tumors, participants with CTSB-positive tumors experienced a multivariate hazard ratio for colon cancer-specific mortality of 1.99 (95% confidence interval, 1.19-3.34) and overall mortality of 1.71 (95% confidence interval, 1.16-2.50). CTSB expression was independently associated with KRAS (P = 0.01) and BRAF mutation (P = 0.04), but not microsatellite instability status, CpG island methylator phenotype status, PIK3CA mutation, LINE-1 methylation, TP53 expression, or PTGS2 (cyclooxygenase-2) expression. Among 123 individuals with adenomas, 91% expressed CTSB.


CONCLUSIONS
As assessed by immunohistochemistry, CTSB is expressed in the vast majority of colon cancers, independent of stage, and is significantly associated with higher risk of colon cancer-specific and overall mortality.


CONCLUSIONS
These results support the potential of CTSB a target for image detection of neoplastic lesions in humans.
Chan
Andrew T
AT
Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. achan@partners.org
Baba
Yoshifumi
Y
Shima
Kaori
K
Nosho
Katsuhiko
K
Chung
Daniel C
DC
Hung
Kenneth E
KE
Mahmood
Umar
U
Madden
Karen
K
Poss
Kirtland
K
Ranieri
Audrey
A
Shue
Daniel
D
Kucherlapati
Raju
R
Fuchs
Charles S
CS
Ogino
Shuji
S
D014408:Biomarkers, Tumor / Q000032:analysis* / Q000378:metabolism; D002401:Cathepsin B / Q000096:biosynthesis*; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D009367:Neoplasm Staging
D014408:Biomarkers, Tumor; D002401:Cathepsin B