Page 21 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

atomic-bomb survivor longitudinal study involving 38,576 Nagasaki and Hiroshima citizens in Japan that were followed up between 1980 and 1999. Increased risk for gastric cancer in persons professionally exposed to ionizing radiation, e.g., astronauts has not been established. In contrast, in this thesis, I shall also reflect on the potential of space travel to convey lessons for better treatment of gastric disease.
The Hedgehog Signalling
Hedgehogs constitute a family of morphogens of pivotal importance for gestation in general and stomach development in particular. Intriguingly, gastric Hedgehog signaling remains active in the adult phase of life and where it is responsible, amongst other functions, for maintaining gastric pit-gland asymmetry. In this sense, the stomach is a beautiful example as to illustrate how morphogen signaling contributes to morphostasis in adults.
The importance of Hedgehog signaling in many forms of cancer in conjunction with its link to gastric developmental processes has prompted a substantial research effort investigating the potential usefulness of targeting Hedgehog signaling in gastric oncogenesis. As a result, in gastrin-mediated compartment expansion and viral and Helicobacter-dependent gastric carcinogenesis, the role of Hedgehog signaling is now relatively well understood. Furthermore, when the malignant disease is established, the evidence indicates that hedgehog signaling may provoke drug resistance. Now that the hedgehog inhibitor Vismodegib has come available, which has proved useful in other kinds of cancer (especially basal cell carcinoma), it is tempting to propose clinical trials using this compound for patients who have gastric cancer and accordingly various of such studies have now been initiated. In this thesis, I aim to comprehensively investigate this angle to explore the potential of targeting Hedgehog in preventing and combating gastric carcinogenesis.
Role of Hedgehog Signalling in Gastric Homeostasis
Ever since its initial detection in Drosophila, Hedgehog is associated with foregut development. The mammalian genome expresses three (3) Hedgehog ligands. In the mucosa of the embryonic foregut, Sonic Hedgehog is profoundly present[52]. All over the gut but especially in foregut-derived organs such as the lung, Sonic Hedgehog is expressed both in embryogenesis as well as in adults [53-56], while in the small intestine adjacent to the stomach expression is profoundly less marked (see
Chapter 1
General introduction
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