Page 22 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

Chapter 1
General introduction
Table.1)[52, 57]. Functionally, Sonic Hedgehog controls maturation and differentiation of epithelial cells in the adult stomach[57-59].
During the progression from the inflamed stomach to gastric cancer, an important step is the loss of acid-production by the parietal cells followed by replacement of these parietal cells by mucus-secreting cells that express spasmolytic polypeptide (SP) or trefoil factor 2.[60]. This process is named, especially in mice but also in human subjects, SP-expressing mucosa (SPEM) and this is a type of oxyntic gland atrophy[61, 62]. Together with the atrophy of parietal cells in SPEM[56]. Sonic Hedgehog expression diminishes in parietal cells as well[63, 64]. The expanding SPEM compartment that replaces the parietal cell compartment also produces Sonic Hedgehog, but this remains inactive as the SPEM compartment fails to convert the unprocessed full-length 45-kilodalton preform of Sonic Hedgehog to its cleaved 19 kD mature form that is capable of eliciting morphogenetic signaling.[65][59, 63] ,[64, 66].
Recent insight as to why gastritis may reduce processing of Sonic Hedgehog to its active form has been gained and has been linked to the absence of gastric acid under atrophic conditions[67, 68]. The hypochlorhydria associated with atrophy of parietal and zymogenic (chief cell) lineages affects the production of the zymogens. Especially reduced serum levels of pepsinogen I (or pepsinogen A) (when compared to pepsinogen II (or pepsinogen C)) are noted in patients with atrophic gastritis [69- 75] and assessment of the levels of the two zymogens in serum is clinically useful for indicating pre-neoplastic changes in the stomach[75]. Pepsinogen A is produced primarily in the mouse corpus by parietal cells, whereas pepsinogen C produced by both mucous neck and chief cells throughout the stomach, which may account for the differential sensitivity of the two pepsinogens for gastric atrophy[67]. In the stomach, upon acidification Pepsinogens A and C are converted to the enzymatically active aspartic proteinases, pepsin A and pepsin C, through intramolecular self- cleavage[75, 76]. Pepsin A prefers to cleave proteins at hydrophobic and aromatic amino acid residues, particularly at phenylalanine (F), when the pH is less than two. By contrast, pepsin C act on a broader range of substrate peptides and is less pH sensitive when compared to pepsin A[76, 77]. Experiments employing site-directed mutagenesis show that pepsin A cleaves the nascent 45-kilodalton Sonic Hedgehog polypeptide at residue 200 (SGGCF200|P) to generate the active 19-kilodalton form, whereas pepsin C does not cleave Sonic Hedgehog[67]. This provides a mechanistic explanation as to why SPEM is associated with reduced Sonic Hedgehog signaling.
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