Page 83 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

inhibitory effect of Patched on another membrane receptor, Smoothened. The alleviation of Patched inhibition is probably caused by internalization of Patched following binding of Hedgehog, but the signaling mechanisms involved remain obscure at best[2, 17]. Following removal of Patched-mediated repression Smoothened translocates to the primary cilium in a microtubule and kinesin- dependent process, that is essential for Smoothened to initiate further signaling as evident from the potential from pharmacological inhibitors of this process to counteract canonical Hedgehog signaling[18, 19]. Subsequently, Smoothened mediates the activation of the latent transcription factor glioma-associated oncogene (Gli) via a process which is still largely unresolved but involves the kinase Fused (Fu) and the Suppressor of Fused protein (Su(Fu))[20, 21] . Gli proteins are the final transcriptional effectors of Hedgehog signaling, both in normal vertebrate development as well as oncological disease[22, 23]. Together this signalling cascade may be termed the canonical hedgehog pathway. It is obvious that enhanced knowledge of the signaling elements involved in this pathway should prove exceeding useful in defining novel rational therapy directed at disease emanating from aberrant activation of canonical Hedgehog signaling.
Apart from canonical Hedgehog signaling, Hedgehog effects in physiology and pathophysiology also depend on so-called non-canonical signaling. For most morphogens, non-canonical signaling has been identified and effects observed are in general contrasting the effects derived from canonical signaling. An example is BMP signaling. In the colon BMP generally acts as a tumor suppressor[24]. In presence of canonical BMP-signaling abrogating SMAD4 mutations, however, a non-canonical BMP-induced signaling pathway becomes evident that stimulates epithelial-to-mesenchymal transition and metastasis via activation of Rho and ROCK and furthers the colon cancer process[25]. Likewise, non-canonical Wnt signal transduction mediates important aspects of the action of this morphogen in the body through activation of small GTPases like Rac, Rho and Cdc42 to regulate the activity of ROCK, MAPK and JNK as well as Ca++ signaling, also an effect important for colon cancer metastasis[26-28] . For Hedgehog also various modes of non-canonical signaling have been described, both downstream of Patched and independent of Smoothend as well as downstream of Smoothened. The most prominent example of the former concerns colorectal cancer stem cells[29]. Whereas canonical Gli-dependent Hedgehog signaling negatively regulates Wnt signaling in the normal intestine in and intestinal tumors[7, 30], Hedgehog signaling in colon cancer stem cells activates a non-canonical Patched-dependent but
Noncanonical Hedgehog signaling
Noncanonical Hedgehog signalling
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