Genetic deletion of 5-lipoxygenase increases tumor-infiltrating macrophages in Apc(Δ468) mice.

INTRODUCTION: The role of 5-lipoxygenase (5-LO) in colon cancer is unknown. Tumor-infiltrating macrophages, neutrophils, and mast cells have been shown to play important roles in colon tumorigenesis and are dependent on 5-LO for function. METHODS AND MATERIALS: Utilizing the APC(Δ468) polyposis model, we performed 5-LO gene knockouts and evaluated the subsequent changes in macrophage, neutrophil, and mast cell density at the tumor site. The proliferative and degranulation capacities of 5-LO-deficient mast cells were also measured, quantifying thymidine incorporation and β-hexosaminidase release, respectively.
RESULTS: APC(Δ468)/5LO(-/-) mice displayed increased tumor-infiltrating macrophages and decreased neutrophils at the polyp site. In vitro, mast cells deficient for 5-LO proliferated at a diminished rate while mast cell degranulation was unchanged. DISCUSSION: We provide evidence suggesting that 5-LO deficiency has differential effects on the infiltration of macrophages and neutrophils in adenomatous polyps, increasing and decreasing infiltration of these cells, respectively. Our observations are consistent with a protective role for tumor-infiltrating macrophages in the initiation of polyp formation. The mechanisms through which 5-LO deficiency negatively affects these cells are under investigation.
CONCLUSIONS: These results provide evidence that 5-LO plays an important role in tumorigenesis and further indicate that 5-LO-selective inhibitors can be investigated as potential therapeutic agents for colorectal polyposis and cancer.