Page 42 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

production of Shh by parietal cells and the ability of gastric endocrine cells to sense the ligand through primary cilia are consistent with a central role for Hedgehog signaling in the feedback regulation of gastric acidity
Modes of hedgehog signaling in gastric cancer
Upregulation of Hedgehog signaling pathway is involved in tumour development[36]. De Sauvage and Rubin postulated models for Hedgehog signalling in human cancer development[36]. The type I cancers are ligand-independent and involve constitutive stimulation of downstream signalling molecules (e,g, loss of Patched) and an example is basal cell carcinoma. Type II are cancers ligand- dependent were both the autocrine, or juxtacrine signaling mechanisms are involved as seen in pancreatic tumors. In type III cancers also ligand-dependency is observed but this type displays paracrine type signalling[36]. Table 1 provides information on these type of tumours in the context of stomach cancer. Remarkably, these models ignore the involvement of non-canonical signalling mechanisms. A number of studies have evaluated the role of cyclin B1 interaction with Patched, in which a Ptch1-cyclin B1 complex is formed at the plasma membrane in a cyclin kinase-1 (Cdk1)-dependent fashion[56, 57]. This results in a reduction in the mitotic index by the separation of cyclin B1/Cdk1 complex from the nuclear machinery resulting in decreased proliferation. Shh binding to patched release the complex and thus fosters cell cycle progression through G2/M phase checkpoint. Obviously Smoothened inhibitors do not affect this process. Another study documents Hedgehog- independent activation of Patched through the action of proteases and in particular Caspase 3, splitting the C-terminal from Patched[36, 58, 59]. It islikely that such non-canonical signalling
Chapter 2
Chapter 2
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