LTA4H Expression in Human and Mice Colon Cancer Models

Trent Wang, Dr. Xiaoxin Chen Lab, Laboratory of Cancer Research

This study is carried out under Dr. Xiaoxin Chen in the Laboratory of Cancer Research. We are examining the effects of Leukotriene A4 Hydrolase and its relation to carcinogenesis. Leukotriene A4 Hydrolase (LTA4H) is a zinc enzyme twith two functions: as an epoxide hydrolase and as an aminopeptidase. It catalyzes the hydrolysis of the epoxide LTA4 to LTB4 (a chemoattractant and activator of inflammatory cells). It was found in a previous experiment that LTA44H is overexpressed in esophageal adencarcinoma of humans and in a surgical rat model. In this experiment, we extend the testing of LTA4H overexpression to colon cancer in humans as well as animal models.

First, it was necessary to establish that LTA4H was indeed overexpressed in colon cancer. This was done using immunohistochemistry and semi-quantification of expression levels with ImagePro Plus v4.5. We examined cases of archival human colon cancer, and the tissue sections of small intestinal tumors of APC mice as well as dextran sulfate sodium (DSS)-induced colon adenocarcinoma mice. The results showed that overexpression was present from 2-4 fold among different types of tissue.

Following such encouraging results, a chemoprevention study has been initiated to find out whether a LTA4H inhibitor can suppress tumorigenesis in animal models of colon cancer. The chemoprevention study is based on APC and Min mice, and modeled somewhat similarly to our esophageal adenocarcinoma study. Bestatin was used as a LTA4H inhibitor, and was applied to animals at varying time points to determine the efficacy at removing and preventing. Although results are still very preliminary, it seems that the LTA4H inhibitor is not of great efficiency in preventing colon cancer, as fatality rates are not significantly different in later weeks of colon cancer development. Further studies are needed to determine whether or not the use of Bestatin will be significant, as well as expanding experiments in multiple directions. Currently however, the best hope for progress is to catch the cancer early and treat as soon as possible.

References:

1. Chen X, Wang S. Leukotriene A4 Hydrolase as a Target for Cancer Prevention and Therapy. Current Cancer Drug Targets 2004, 4:267-83.

2. Chen X, Li N. Overexpression of Leumkotriene A4 Hydrolase in Rat and Human Esophageal Adenocarcinomas and Inhibitory Effects of Bestatin. J. Natl Cancer Inst., 2003, 95: 1053-61.

last updated Aug 24, 2005