Page 38 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

Introduction
Hedgehog proteins are fundamental regulators of embryological development, and tissue homeostasis in adult organisms. Disturbed hedgehog signaling is associated, amongst others, with a range of congenital disabilities, oncological malignancies and immunological defects[1]. Hedgehog proteins intercellular signaling molecules of unusual and fundamental relevance as also illustrated by their substantial conservation across the animal kingdom[2-5]. Initially recognized as a segment polarity gene in Drosophila, now numerous vertebrate paralogues have been found, and in mammals, these include Sonic Hedgehog (Shh), Desert Hedgehog (Dhh), and Indian Hedgehog (Ihh), with Shh being the most comprehensively characterized[5]. Although mainly associated with organogenesis and general and embryological formation of the intestines, in particular, Hedgehog signaling remains active until death, and serves to maintain lifelong histostasis in the intestinal tract and also the immune system[6-8]. The pathophysiological importance of Hedgehog signalling is illustrated by the observation that continuous hedgehog signalling is an essential permissive factor in endodermal cancer development[9-11]. With regard to the above, especially the stomach is relevant, where the morphogen not only maintains pit-gland asymmetry, but also fosters the development of gastric cancer, homeostasis, and neoplastic transformation[12-14]. Part of this nefarious functionality is related in the initiation of gastric inflammation due to Helicobacter infection[12]. As stated, although classically associated with gestation, the role of Hedgehog pathway has also important functionality beyond embryogenesis and a potentially vicious one with respect to oncological disease. In cancer, both autocrine Hedgehog signalling and paracrine signalling (through the tumor stroma that would thus nurture the tumour cells) of Hedgehog ligands is well-established[15, 16]. Both autocrine and paracrine Hedgehog signalling should be sensitive to pharmacological inhibitors and are thus tested in clinical trials in addition to an intense preclinical research effort[15, 17]. The importance of Hedgehog signalling gastric pathophysiology has led to hopes that pharmacological inhibitors of this signalling may become useful for combating oncological disease in the stomach and this consideration prompted us to review here the detailed molecular mechanism by which Hedgehog influences gastric pathophysiology and to evaluate the evidence that anti-Hedgehog strategies will prove effective in this respect.
The physiological importance of Hedgehog signaling in the physiology of the proximal tract is illustrated by the phenotypes observed in mice with genetic loss of
Chapter 2
Chapter 2
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