Glucagon-like petide-2 acts on colon cancer myofibroblasts to stimulate proliferation, migration and invasion of both myofibroblasts and cancer cells via the IGF pathway.


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Marianne Shawe-Taylor1
1Queen's Hospital Romford

Abstract

Background

Glucagon-like peptide (GLP)-2 stimulates proliferation of intestinal epithelial cells and is being investigated for therapeutic treatment of intestinal insufficiency. Epithelial cells appear not to express GLP-2 receptors and instead it is hypothesised that the main targets of GLP-2 are myofibroblasts that in turn release epithelial growth factors. We have investigated the role of insulin-like growth factor (IGF) in mediating the effects of GLP-2.

Method

We studied the action of GLP-2 on myofibroblasts from colon cancer and adjacent tissue, and the effects of conditioned medium from these cells on epithelial cell proliferation, migration and invasion. 

Results

GLP-2 stimulated proliferation, migration and invasion of myofibroblasts and the proliferative and invasive responses of cancer-associated myofibroblasts were greater than those of myofibroblasts from adjacent tissue. The responses were inhibited by an IGF receptor inhibitor, AG1024. Conditioned medium from GLP-2 treated myofibroblasts increased proliferation, migration and invasion of SW480, HT29, LoVo epithelial cells and these responses were inhibited by AG1024; GLP-2 alone had no effect on these cells. In addition, when myofibroblasts and epithelial cells were co-cultured in Ibidi chambers there was mutual stimulation of migration in response to GLP-2. The latter increased both IGF-1 and IGF-2 transcript abundance in myofibroblasts. Moreover, a number of IGF binding proteins (IGFBP-4, -5, -7) were identified in myofibroblast medium; in the presence of GLP-2 there was increased abundance of the cleavage products of IGBBP-4 and IGFBP-5 suggesting activation of a degradation mechanism that might increase IGF bioavailability. 

Conclusion

GLP-2 stimulates proliferation of myofibroblasts by a direct action and stimulates proliferation of colon cancer cells indirectly be release of IGF from myofibroblasts. The data suggest that GLP-2 stimulates cancer myofibroblast proliferation, migration and invasion; GLP-2 acts indirectly on epithelial cells partly via increased IGF expression in myofibroblasts and partly, perhaps, by increased bioavailability through degradation of IGFBPs.