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TJ-14 (Hangeshashinto) Impedes the Development of Reflux-Induced Esophageal Cancer in a Surgical Rat Model
Tomoharu Miyashita^*1, Daisuke Matsui¹, Ryohei Takei¹, Ali K. Ahmed², John W. Harmon², Sachio Fushida¹, Tetsuo Ohta^1
1Department of Gastroenterologic Surgery, Kanazawa University Hospital, Kanazawa, Japan; ²Department of Surgery, Johns Hopkins Bayview Medical Center, Baltimore, MD

Background: Hangeshashinto (TJ-14), a Japanese Kampo medicine, has been reported to be effective in preventing chemotherapy-induced oral mucositis through the reduction of prostaglandin E2 (PGE2). TJ-14 has also been shown to affect cyclooxygenase activity. M2 phenotype macrophages contribute to tumor development in the immunosuppressive microenvironment. Therefore, targeting the immunosuppressive network in tumor tissues, by inhibiting PGE2, may provide an effective preventive strategy. We evaluated the effectiveness of TJ-14 as a chemoprevention agent in a surgical rat reflux model of esophageal cancer.
Methods: The rat reflux model was created by performing an end-to-side esophagojejunostomy on Sprague Dawley rats. The surgery promoted the reflux of gastro-duodenal contents into the esophagus. The rats were divided into 2 groups. One group was given commercial chow (control group), and the other was given experimental chow, containing TJ-14 (TJ-14 group). All surviving animals were sacrificed 40 weeks after surgery and their esophagi were examined. The primary antibody against CD163(M2; AbD Serotec) was used for immunohistochemistry.
Results: Twenty two rats survived 40 weeks post-surgery and were included in the study. Of these, 12 were included in the control group (Figure 1a), and the remaining 10 received TJ-14 administration (Figure 1b). 67% (8/12) of the controls developed esophageal cancer (Figure 1c), but animals that received TJ-14 had a cancer incidence of 10% (1/10) (p=0.007, Chi-squared) (Table 1). Barrett’s metaplasia (Figure 1d) was found in 83% (10/12) of the rats in the control group. However, only 50% (5/10) of the rats in the TJ-14 group displayed signs of Barrett’s metaplasia, indicating a protective tendency of TJ-14. All of the rats in the TJ-14 and control groups developed proliferative hyperplasia. M2 phenotype macrophage (Figure 1e) decreased in the TJ-14 group compared to the control group.
Conclusions: TJ-14 protected against the development of esophageal cancer in a clinically relevant surgical reflux model. Further investigation is required regarding the potential clinical use of TJ-14 as a chemopreventive agent.
Histological findings

Histology/Group	Control group (n=12) No.of rats (%)	TJ-14 group (n=10) No. of rats (%)	p value
Proliferative hyperplasia	12 (100)	10 (100)	n.s.
Squamous dysplasia	9 (75)	6 (60)	n.s.
Barrett	10 (83)	5 (50)	p=0.095
Carcinoma	8 (67)	1 (10)	p=0.007

Fig. 1a, Macroscopic findings. The distal portion of the esophagus is notably thickened in a representative control group rat. The epithelium was rough, and a transparent tumor is visible near the anastomosis, indicated by (→). 1b, While the esophagus of a representative rat from the TJ-14 group exhibited a slightly uneven surface, no tumors were visualized. 1c, Microscopic findings. Representative photomicrographs of esophageal adenocarcinoma that resulted from surgically induced gastro-duodenal reflux. 1d, Barrett’s metaplasia, indicated by (→). 1e, Immunohistological images for CD163＋ macrophages, indicated by (→).

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