Page 97 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

Implications of Patched-dependent Smoothened-independent non-canonical Hedgehog signaling
Literature data indicate that the final effect of Hedgehog in physiology and pathophysiology is resultant from the integration of canonical and non-canonical Hedgehog signaling[29, 46]. Aberrant Hedgehog signaling is an important factor in human disease and accordingly inhibiting Hedgehog signaling has received substantial attention and various trials employing pharmacological inhibitors of Hedgehog signaling have been developed. Especially Vismodegib and Sonidegib have met with success in diseases driven by canonical Hedgehog signaling, in particular dermatological cancer[53]. Despite the evidence, however, that Hedgehog signaling is important for many gastrointestinal cancers[54], trials in this type of disease have not yet proven successful. In view of our data presented above that Patched and not Smoothened is a major mediator of non-canonical Hedgehog signaling and the momentum-gaining notion that especially non-canonical Hedgehog signaling may be important for maintaining gastrointestinal cancer[29], this may not be surprising. Vismodegib and Sonidegib target Hedgehog signaling at the level of Smoothened and leave Patched-dependent non-canonical Hedgehog signaling unaffected. Especially in view of the Patched-dependent Smoothened- independent Wnt signaling, one can easily imagine that especially the non-canonical branch of Hedgehog signaling is important in supporting growth in the gastrointestinal compartment. An implication of our results is thus that future Hedgehog-based therapy with respect to gastrointestinal cancer should be directed at counteracting the interaction of Patched with Hedgehog rather than the current strategy of targeting Smoothened.
Conclusion
Here we characterize the non-canonical aspect of Hedgehog signaling. We observe that such non-canonical signaling mainly involves Patched-dependent Smoothened- independent signaling, with especially mTOR signaling, the activation of cytoskeletal remodeling and the activation of Wnt signaling being prominent elements. Thus, for efficient targeting of Hedgehog-dependent signaling, it may prove essential to target such signaling at the level of Patched and not Smoothened.
Noncanonical Hedgehog signaling
Noncanonical Hedgehog signalling
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