Background: Milk fat globule-epidermal growth factor 8 (MFG-E8) promotes phagocytic clearance of apoptotic cells to maintain normal tissue homeostasis. However, its functions in intestinal inflammation and carcinogenesis are unknown.
Methods: Experimental colitis was induced in MFG-E8 knockout (KO) and wild-type (WT) mice by dextran sodium sulfate (DSS) administration. Colon tissues were used for assessments of colitis activity and epithelial proliferation. A mouse colitis-associated cancer (CAC) model was induced by intraperitoneal injection of azoxymethane (AOM) and then the animals were given a single administration of DSS. A sporadic colon cancer model was established by repeated intraperitoneal injections of AOM. The role of MFG-E8 in epithelial proliferation with or without treatment of siRNA targeting α(v)-integrin was examined in vitro using a WST-1 assay.
Results: The severity of colitis in KO mice was greater than that in WT mice, while the proliferative potential of colonic epithelial cells in KO mice was lower during the regenerative phase. In both CAC and sporadic models, tumor size in KO was lower as compared to WT mice, while decreased tumor incidence was only found in the CAC model. In vitro findings showed that MFG-E8 promotes epithelial cell proliferation, and treatment with a siRNA targeting α(v)-integrin reduced the proliferation of Colon-26 cells stimulated with recombinant MFG-E8.
Conclusions: MFG-E8 promotes tumor growth regardless of the presence or absence of colonic inflammation, whereas colon tumor development is initiated by MFG-E8 under inflammatory conditions. These MFG-E8 functions may be dependent on integrin-mediated cellular signaling.