Neutrophil elastase as a diagnostic marker and therapeutic target in colorectal cancers.
Neutrophil elastase (NE), a serine protease secreted by neutrophils, contributes to the progression of cancers to enhance tumor invasion and metastasis. It has been well reported that the regions surrounding the colorectal cancerous tissues usually are decorated with increased accumulation or aggregation of neutrophils coupled with a higher deposition/expression of NE. Therefore, we hypothesized that an increased expressional level of NE in patients with colorectal cancer (CRC) may represent as one of putative biomarkers for CRC. The aim of this study was to evaluate and assure our hypothesis by measurements of the expressional level of NE in the sera and tissues from CRC patients. Moreover, we also proposed a potential therapeutic strategy by blocking enzymatic activity of NE using sivelestat to inhibit the progression of tumor developments. The infiltrated numbers of neutrophils from specimen tissues of CRC patients, and the secreted forms of NE in the sera were quantitatively measured and compared. To evaluate the serum NE as one of putative biomarkers of CRC patients, the receiver operating characteristic (ROC) curve was made to determine the cut-off value of NE in sera for assurance of CRC diagnosis. To evaluate NE as therapeutic target for CRC, sivelestat, a NE inhibitor, was used and administrated into the CRC xenografts. NE expression level coupled with tumor volume were measured and compared between the control and sivelestat-treated xenografts. We found that more infiltrated neutrophils and an increased NE expression were detected in the cancerous tissues compared to the normal tissues. The serum NE concentration in CRC patients was statistically higher than that in the healthy controls (0.56 ± 0.08 μg/ml vs. 0.22 ± 0.03 μg/ml) (p<0.05), indicating that serum NE can potentially be a putative marker of CRC. To characterize the role of NE in tumorigenesis, the NE activity was detected in HCT-15-xenografts using in vivo imaging system (IVIS). Compare to normal mice, the amounts of active NE in xenografts are significantly higher than normal control animals. In the therapeutic characterizing studies, we found that sivelestat can inhibit tumor growth in the HCT-15-induced xenografts. This study suggests that NE is not only as a putative diagnostic biomarker of CRC, but also a potential therapeutic target for patients suffered with CRC.
Division of Gastroenterology, Cheng Hsin General Hospital, Taipei, Taiwan.
Ai-Sheng
AS
Ho
Chien-Hsin
CH
Chen
Chun-Chia
CC
Cheng
Chia-Chi
CC
Wang
Hua-Ching
HC
Lin
Tsai-Yueh
TY
Luo
Gi-Shih
GS
Lien
Jungshan
J
Chang
D000595:Amino Acid Sequence; D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood*; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine