Page 40 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

Following binding of Hedgehog to Patched. Smo translocates to the the primary cilium in the cell membrane. The subsequent signalling culminates in altered transcription through Gli transcription factors. The molecular details of Smoothened signalling to Gli is still partly obscure but involves the microtubule transport proteins[15, 29]. The Gli family are members of the Kruppel family of zinc finger transcription factors and a role for three different Gli proteins in Hedgehog signalling has been identified, Gli1, Gli2, and Gli3, each with a distinctive role[15], In the absence of Smoothened activation, GLI1 and GLI2 are transcriptional repressors, but following activation of the pathway these proteins are converted to transcriptional activators[15, 30]. The role Gli3 appears to be mainly as a negative regulator of Hedgehog signalling. It is thus possible to interfere with Hedgehog signalling at different levels, although clinically the use of Smoothened inhibitors has gained most attention.
Role of Hedgehog Signalling in Gastric Homeostasis
Ever since its initial detection in Drosophila, Hedgehog has long been associated with foregut development. Of the three mammalian Hedgehogs (3) Shh levels are most highly expressed h, in the mucosa of the embryonic foregut[31]. Also in other foregut-derived organs such as the lung, Shh expression is prominent, reflecting the embryonal situation[32-35]. Table 1 lists expression patterns in physiology and pathology. Interestingly high Shh expression in the stomach is lost upon development of intestinal metaplasia (Table.1), suggesting that gastric epithelium- specific effects of the morphogen[12, 36]. Indeed Shh controls gastric epithelial cell maturation and differentiation in the adult stomach[7, 36, 37].
During progression from the inflamed stomach to gastric cancer the epithelium goed through defined series of morphological transitions. First, the acid-producing parietal cells are lost and are replaced by mucus-secreting cells that express spasmolytic polypeptide (SP) or trefoil factor 2.7 [38]. Mostly in mice, but also in human subjects, the presence of SP-expressing mucosa (SPEM) defines gland atrophy[39, 40]. Together with atrophy of the parietal cells[35] Shh expression diminishes[41, 42] Although Shh expression diminishes along with the loss of parietal cells [16] the expanding mucous cell compartment or SPEM continues to produce Shh in both human subjects [37, 41] and rodents[42, 43] but appears to remain as the unprocessed pre-morphogen. Thus functionally expression is lost. Studies suggest that aberrant Hh signaling in cancer functions mainly as either
Chapter 2
Chapter 2
34
38