Fetal-type Glycogen Phosphorylase Expression in Intestinal Metaplasia as a Predictor of the Development of Gastric Cancer

Abstract

Glycogen phosphorylase (GP; EC 2.4.1.1) plays a central role in the mobilization of carbohydrate reserves in a wide variety of organs and tissues. There are three major isoforms of mammalian GP; i.e., the muscle, liver, and brain isoforms. The physiological roles of muscle and liver GP are to provide fuel for energy production (to produce the energy required for muscle contraction) and to ensure a constant supply of glucose to extra hepatic tissues, respectively. However, the physiological role of brain GP (BGP) is poorly understood. It has been demonstrated that BGP is the major isoform of GP found in fetal tissue and tumor tissue, and BGP is identical to fetal-type GF (FGP). We have demonstrated that the significant enzymatic activity of FGP in the gastric carcinoma and proliferating cells of particular Intestinal Metaplasia (IM). We studied 136 specimens with gastric carcinoma and the adjacent IM using specific anti-FGP antibody. FGP was expressed in 80% of the intestinal type and 19% of the diffuse type of carcinoma and in 88% and 42% in the generative zone of IM adjacent to each type of cancer foci, respectively. The proportion of the positivity of FGP expression in the cancer and IM was significantly greater in intestinal type carcinoma than in diffuse type. In addition, according to the proliferating cell nuclear antigen labeling index analysis, IM with FGP expression (FGP-IM) were significantly higher in a proliferating state than in IM without FGP, and some of them were co-expressed accumulated p53 in the generative cells. These data indicate that FGP could be one of the fetal biomarkers and FGP-IM could be a premalignant lesion of intestinal type adenocarcinoma. We conducted another study to investigate the incidence of FGP-IM in gastric biopsy specimens and to identify FGP-IM as a predictor of the coexistence of accessory carcinoma and/or metachronous carcinoma. Eight endoscopic biopsy specimens of methylene blue-positive mucosa of the stomach were obtained from the patients with multiple gastric carcinomas (n=14), a single carcinoma (n=25) and atrophic gastritis (n=20), examined the incidence of FGP-IM. FGP positivity was 93.3% in the multiple carcinomas and 80.0% in the single carcinomas. The incidences of FGP-IM in the stomachs with multiple carcinomas, single carcinoma and atrophic gastritis were 83.2 ± 22.8%, 36.5 ± 41.3% and 7.1 ± 18.0%, respectively. The incidence of FGP-IM was significantly higher in the stomachs with multiple carcinomas than in those with a single carcinoma or atrophic gastritis. It is suggested that the frequent appearance of FGP-IM reflects the high potential of carcinogenesis of intestinal type gastric carcinoma and FGP-IM could be a predictive indicator of metachronous gastric carcinoma. Recently, there are increasing opportunities where endoscopic and laparoscopic local treatments are applied for the early gastric carcinoma, therefore, it is significantly important to identify the high-risk group of metachronous recurrence of gastric carcinoma. FGP could serve as a potential predictor of the risk of the development of multiple and/or metachronous carcinomas. It might be possible to follow-up new lesions using this method, and follow-up studies would provide better information on whether FGP-IM positivity is a good predictor of metachronous recurrence after local treatment for gastric cancer.