Translational Research in Personalized Medicine with Special References to Gastric Cancer and Obesity

Translational research in personalized medicine with special references to gastric cancer and obesity Background: Translational research in medical science is essential because the rapid progression of science and technology has led to “the valley of death” between basic science and clinical practice. Cancer is one of the main leading causes of morbidity and mortalityworldwide, and gastric cancer is mthe 5th most common cancer and the 3rd leading cause of cancer mortality (8.2% of all cancer deaths). Over the past decades, early diagnosis and minimal invasive surgery have been successfully applied in gastric cancer patients, however the treatment of patients with advanced gastric cancer still remains a challenging, as the current standard treatment such as chemotherapy is effective only in a small proportion of the patients due to high heterogeneity of gastric cancer. Thus, the development of new and personalized therapy for gastric cancer is needed. Several reports have demonstrated the importance of crosstalk between tumor cells and nerves, and vagus nerve is well-known to play an important role in the regulation of gastrointestinal function and gastric epithelial cell proliferation, indicating the potential role of vagus nerve in gastric tumorigenesis. Obesity is one of the risk factors to develop gastric cancer and the bariatric surgery is effective treatment for weight loss as well as reducing the cancer risk in obese patients, however the mechanisms underlying various bariatric procedures remain unclear, and thus it is important to elucidate the underlying mechanisms for personalized bariatric surgery. Aims: Overall aim of this thesis is to conduct translational research with attempt to develop personalized therapies for gastric cancer (Part I) and obesity (Part II). The specific objectives included: (i) to investigate the role of vagus nerve on gastric tumorigenesis, and to develop new treatment based on the elucidated underlying mechanism, (ii) to elucidate the mechanisms of bariatric surgeries such as vagotomy with pyloroplasty (VTPP), sleeve gastrectomy (SG), duodenal switch (DS) and gastric bypass (GB). Methods: In Part I, pathological evaluation, immunohistochemical analyses and gene expression profiling were performed using three different mouse models of gastric cancer (i.e., genetically-, chemically- or infection-induced gastric cancer models). Mice underwent denervation by VTPP (including unilateral vagotomy, UVT) or local injection of botulinum toxin type A (Botox). In vitro gastric organoids were also used. Three cohort studies were performed on human primary gastric cancer and gastric stump cancer. In Part II, rats were subjected to VTPP, PP, SG, DS, SG+DS, GB and laparotomy (as controls), and monitored by comprehensive laboratory animal monitoring system (CLAMS). Results: In Part I, denervation of the stomach markedly inhibited gastric cancer initiation and progression, particularly in the denervated portion of the stomach (such as after UVT and unilateral Botox injection), in all three independent mouse models of gastric cancer. Denervation also enhanced the anti-tumor effects of chemotherapy and prolonged survival. Denervation-induced suppression of tumorigenesis was associated with suppression of the stem cell expansion by inhibiting Wnt signaling via muscarinic acetylcholine receptor M3 (M3R). In gastric cancer patients, tumor stage and lymph node metastasis correlated with neural density and activated Wnt signaling, whereas vagotomy reduced the risk of gastric cancer. In Part II, VTPP did not affect body weight, eating behavior and metabolic parameters. SG reduced body weight in short-term but not long-term, and transiently increased energy expenditure without reduction of food intake. DS regardless of whether it was accompanied by SG caused remarkable and continuous body weight loss, which was associated with increased energy expenditure, reduction of food intake and malabsorption. GB induced persistent body weight loss which was associated with increased energy expenditure without altered eating behavior and malabsorption. Conclusions: In Part I, denervation suppresses gastric cancer initiation as well as progression through inhibition of the cancer stem cell niche by down-regulation of Wnt signaling pathway via M3R. These findings could be translated to clinical trials using endoscopic Botox injection, and the therapy should be personalized depending on Wnt signaling expression on each gastric cancer patient. In Part II, weight loss after each bariatric surgical procedure differs in terms of degree, duration and the underlying mechanisms, pointing to the need of personalized bariatric surgery