Page 44 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

Cross-Links between Hedgehog Signaling, Chronic Inflammation and Gastric Cancer
As stated, Hedgehog signalling in the stomach plays a significant role in gastric development, homeostasis, and neoplastic transformation[70]. Initially Shh was somewhat ignored in the context of gastric cancer, despite the evidence that Shh is highly expressed in gastric cancer cell lines[64]. Although increased levels of Shh have been reported in gastric cancers, its specific role in gastric transformation remains elusive but carries significance because of the availability of Hh antagonists. A link exists through the immune system; several studies show that in gastritis the phenotype of infiltrating myeloid cells changes over time to become myeloid-derived suppressor cells (MDSCs) and that this phenotypic switch requires Hedgehog signaling. More specifically, expression of GLI1, which targets Slfn4 (mice) and SLFN12L and SLFN5 (humans), is an early marker for chronic inflammation-associated myeloid cells in their transition towards the MDSC phenotype. As MDSCs are important for immune-evasion for transformed cells, Hedgehog signaling can thus favor neoplastic development.
Figure 1. A simplified model of the mammalian Hh pathway. In the ‘OFF’ state, Patch inhibits the activity of Smo. Inactive Smo is unable to inhibit Sufu, which promotes processing of the Gli transcription factors in favor of shorter, transcriptional repressor forms (GliR). In the ‘ON’ state, Hh ligands bind to and inhibit Patch, thus releasing Smo activity and in turn blocking Sufu. Gli processing is then shut down, leading to the accumulation of transcriptional activator forms (GlIA).
Chapter 2
Chapter 2
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