Page 23 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

The relationship between Sonic Hedgehog and both physiology and pathophysiology call for further studies investigating the usefulness of targeting Sonic Hedgehog signaling for combating gastric cancer and delineating the mechanistic details of its signaling as to obtain better insight in the fundamental mechanisms underlying the action of Sonic Hedgehog.
Regulation of Gastrin and Gastric Acidity by Hedgehog ligands
This notion is further supported by studies examining the impact of Hedgehog signaling on gastric physiology in vivo. An example is a transgenic mouse that secretes an endogenous inhibitor of Hedgehog ligands called Hedgehog-IP under control of the H+, K+-ATPase β subunit promoter, which is specific for parietal cells(48). The results show reduced secretion of gastric acid by the parietal cells. Hypochlorhydria, in general, stimulates gastrin gene expression through a decrease in somatostatin production by the enterochromaffin-like cells of the stomach (49). Accordingly, the Hedgehog-IP model displays increased plasma gastrin with concurrent decreased somatostatin production. Hence the loss of Hedgehog signaling is sufficient to activate the standard feedback mechanisms associated with loss of parietal cells that are typically attributed to gastrin and somatostatin and are linked to oncological transformation in the stomach(50). Furthermore, both antral G and D cells possess primary cilia, organelles protruding from the plasma membrane, which are intimately linked with transduction of Hedgehog signals and it is thus likely that these cells are subject to Hedgehog effects(51, 52). In apparent agreement, transgenic overexpression of GLI2, a transcription factor active in canonical Hedgehog signaling, suppresses gastrin gene expression(53). It would thus be interesting to study the cilium-specific effects of Hedgehog signaling (i.e., those effects of Hedgehog that do not involve the first Hedgehog receptor Patched but do involve the second Hedgehog receptor Smoothened –see later this thesis) as these may provide further insight into the link between Hedgehog and gastric physiology. In the present thesis, I aim to do so, albeit in an artificial model system.
Cross-Links between Hedgehog Signaling, Chronic Inflammation leading to Gastric Cancer
The further imperative for studying Hedgehog signaling in the context of this thesis comes from the significant role of this morphogen not only in gastric development and homeostasis but also from its role in neoplastic transformation(54). Although
Chapter 1
General introduction
16
21
1