Page 82 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

Introduction
Cell fate in the developing or adult body is determined by morphogens, molecules whose non-uniform distribution governs the pattern of tissue development often by providing positional information[1, 2]. Notable examples of morphogens include the Hedgehog-, Wingless-related integration site- (Wnt) and Bone morphogenetic protein- (BMP) dependent signals[3-6]. The intracellular signaling resulting from engagement of morphogens with their cognate receptors is involved in virtually all physiological and pathophysiological processes in the body, including embryogenesis, tissue regeneration, and carcinogenesis and thus understanding morphogen signaling is a scientific question of utmost importance[7, 8]. Unfortunately, morphogen-provoked signal transduction is often complex, and a special case to the point is signal transduction initiated by Hedgehogs[9].
Hedgehog proteins are a highly conserved family of intercellular signalling molecules. Originally identified as a Drosophila segment polarity gene required for embryonic patterning, several vertebrate homologues have now been discovered— Indian (Ihh), Desert (Dhh) and Sonic Hedgehog (Shh), the most extensively characterised[10]. Hedgehog signals are fundamental regulators of embryological development, as illustrated by the dramatic embryological malformations seen when accurate timing of Hedgehog signals during gestation is corrupted[11]. Hedgehog remains active in the post-embryonic period, maintaining histostasis in a variety of tissues, including the gastrointestinal tract and the immune system[12]. Continuous hedgehog signalling is an essential permissive factor for many cancers and causative in basal cell carcinoma of the skin amongst others[13]. In humans, one-allelic loss of the inhibitory hedgehog receptor Patched is sufficient to produce the so-called Gorlin syndrome [14], associated with multiple basal cell carcinomas. Despite the importance of hedgehog signalling for human physiology and pathophysiology, the molecular details underlying this signalling remain only partly characterised.
Hedgehog signal transduction is highly unusual, containing many features unique to this signaling system[15]. After synthesis, Hedgehog undergoes autocatalytic cleavage followed by lipid modifications resulting in the only protein in the animal kingdom that is sterolated and both secreted and palmitoylated[16]. The primary receptor for Hedgehogs is Patched, an intriguing receptor, as it does not convey the Hedgehog signal to the intracellular components of the pathway itself like a conventional receptor. Rather, binding of Hedgehog to Patched alleviates the
Chapter 4
Chapter 4
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