Intestinal Hedgehog signaling in tumors and inflammation

In this thesis we investigated the role of Hedgehog signaling in tumors and inflammation. By using an inducible Indian Hedgehog (Ihh) knockout mouse we show that Ihh signals via the mesenchyme to the proliferating cells in the crypt to attenuate proliferation. Despite its anti-proliferative role in intestinal homeostasis, we show that Ihh is mandatory for Apc mutant adenoma formation in mice. It seems that tumor epithelial cells need to secrete Ihh in order to maintain an intestinal stromal phenotype that is required for adenoma development. In the next study, we used mouse models where we can either activate or inactivate the Hedgehog pathway conditionally. Analysis of gene arrays of colons from these mice show that Hedgehog regulates the expression of the Interferon response target genes. This finding can explain why Ihh mutant mice are more prone to develop a more severe colitis. The next question is how Hedgehog regulates the interferon response? This question touches upon an issue that has been in the field for years; what cell is the Hedgehog target cell in the intestine? We exclude that the Hedgehog target cell is a myeloid cell and show by characterization of known mesenchymal markers that the Hedgehog target cell is a stromal cell. Furthermore, we show that Hedgehog’s effect on the expression of the Interferon response mediated genes, including chemokines seems to act via the stromal cells. Together, this thesis gives us more insight in the role of Hedgehog in homeostasis, inflammation and adenoma formation.