Page 170 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

success in the battle against gastric cancer will depend not only on improved therapy in these late phases of disease. Gastric cancer remains an important contributor to overall mortality and especially cancer-related mortality when viewed globally. To deal with this problem it will be necessary to improve prevention, e.g. by widening opportunities for more active screening of subjects which are predisposed to develop gastric cancer, to improve the efficacy of screening procedures involved and to better understand the gastric cancer process as to open novel avenues for the rational treatment of disease, in particular opportunities for preventive therapy when atrophic gastritis develops should exist. My thesis has tried to make contributions here. My findings will be summarized and discussed in this chapter. I shall also provide future perspectives and issues that need to be addressed in additional studies.
In chapter 2 I have prepared a comprehensive review of the relation between hedgehog signaling and (development of) gastric cancer. Some of the related aspects I also reflect on in chapter 1, Hedgehog signaling has a pivotal role in the homeostasis of the healthy stomach, whereas loss of Hedgehog signaling is an important event in neoplastic transformation of the stomach. Loss of Hedgehog production in the parietal cells during atrophic gastritis drives excessive production of gastrin (among other events) in turn resulting in excess gastrin production which is an important disease-promoting occurrence. Once cancer has been established Hedgehog signaling may support the cancer process and especially have a trophic influence on the cancer stem cell compartment. Thus modulation of Hedgehog signaling with respect to gastrointestinal cancer development is pivotal at different phases of the gastric cancer process. Although Hedgehog antagonists have been used in different cancer types, the usage of Hedgehog antagonists for gastric cancer in clinical trials is still in its infancy. New therapeutic strategies need to be explored. Such development is hampered by the lack of knowledge on the mechanistic details of Hedgehog signaling and this aspect of carcinogenesis in the stomach and elsewhere in the gastrointestinal tract will be dealt with elsewhere in this thesis.
In chapter 3 I further evaluated immunotherapy checkpoint inhibition in gastric cancer. Gastric cancer stands out amongst other cancers as particularly aggressive and as a disease in which chemotherapy alone cannot satisfactorily help to change the final outcome due to constrained efficacy. A critical factor that guides both tumorigenicity of precancerous lesions and the outcome of cancer itself, is immune signaling and how it relates to heterogeneity of gastric cancer (thus not all cells may express the same neoantigen repertoire). We still cannot, however, distinguish those
Chapter 8
Chapter 8
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