Page 39 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

Hedgehog paralogues. Genetic knockout of both Shh and Dhh provoke by malrotation of the gastrointestinal tract, oesophageal atresia, gastric overgrowth and other gross abnormalities[18-20]. The specific importance of Hedgehog signalling for the stomach in this respect is illustrated by the observation in mice from embryonic day 16 onwards as dichotomy occurs in that the foregut and at the level of antrum and pyloric border region which becomes dramatically more active with respect to Hedgehog signalling as compared to the adjacent duodenal tissues[21], and also is proposed to maintain pit-gland asymmetry in the stomach[7, 22]. Thus the relevance of Hedgehog signaling for gastric physiology seems evident. With regard to pathophysiology, Hedgehog signaling is suggested to be pivotal for gastric cancer progression in both of humans and animals, but a definite etiological role has not yet been shown for this pathway in gastric cancer. To further analyze the precise evidence available in this respect it is essential first to review the molecular details of the molecular signaling involved[23].
Hedgehog signaling: An overview
Hedgehog signaling in general is unusual and complicated, and an immense scientific effort has been necessary to unravel its general principles[15, 24-26]. Signaling is initiated by the different Hedgehog ligands, in casu Shh, Ihh and Dhh. In the classical Hedgehog signal pathway activation, these different ligands bind a common cognate membrane-bound receptor called Patched that has approximately 1,500 amino acids. The protein transverses the plasma membrane twelve times and thus strongly resembles abc transporter proteins. In accordance both the The N- terminal and C-terminal domains of the protein reside at cytoplasmic side of membrane, The tertiary conformational of Patched allows Hedgehog ligands to bind via the interaction with two extracellular loops[15, 27]. There are two genes encoding Patched receptors in humans; which are dominated as PTCH1 and PTCH2, and differ slightly with respect to their amino acid configuration in the N- terminal region[15, 27]. While both PTCH1 and PTCH2 receptors are associated with numerous human cancers, with respect to gastric cancer especially PTCH1 is the relevant gene product. The function of Patched is to exclude a second receptor, called Smoothed from the primary cilium and retain Smoothened in a vascular compartment/ Binding of Hedgehog to PTCH release this inhibition enabling further downstream signalling[15, 28]. Figure 1 provides a graphical representation.
Gastric cancer and the Hedgehog Signalling
Gastric cancer and Hedgehog signalling
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