Iwama Takuya, Fujiya Mikihiro, Konishi Hiroaki, Tanaka Hiroki, Murakami Yuki, Kunogi Takehito, Sasaki Takahiro, Takahashi Keitaro, Ando Katsuyoshi, Ueno Nobuhiro, Kashima Shin, Moriichi Kentaro, Tanabe Hiroki, Okumura Toshikatsu
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Hokkaido, 078-8510, Asahikawa, Japan.
Department of Legal Medicine, Asahikawa Medical University, Asahikawa, Japan.
Cancer Cell Int. 2021 Jan 6;21(1):21. doi: 10.1186/s12935-020-01723-9.
Colorectal cancers develop through several pathways, including the adenoma-carcinoma sequence and colitis-associated carcinogenesis. An altered intestinal microflora has been reported to be associated with the development and progression of colorectal cancer via these pathways. We identified Lactobacillus casei-derived ferrichrome as a mediator of the bacterial anti-tumor effect of colorectal cancer cells through the upregulation of DDIT3. In this study, we investigated the anti-tumor effects of ferrichrome on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer.
SRB and MTT assays were performed to assess growth inhibition in vitro. Eighteen organoids were prepared from biopsy specimens obtained by colonoscopy. An AOM-DSS carcinogenesis model and xenograft model of colorectal cancer cells were generated for the assessment of the tumor suppressive effect of ferrichrome in vivo.
Ferrichrome inhibited the cell growth of colorectal cancer cells in vitro and in in vivo xenograft models. Ferrichrome exerted a strong tumor-suppressive effect that was superior to that of currently available anti-tumor agents, including 5-FU and cisplatin, both in vitro and in vivo. The tumor-suppressive effect of the combination of ferrichrome and 5-FU was superior to that of single treatment with either drug. The tumor suppressive effects of ferrichrome were confirmed through the upregulation of DDIT3 in patient-derived organoids of adenoma and carcinoma. Ferrichrome inhibited the tumor progression in the AOM-DSS model while exhibiting no anti-inflammatory effect in the DSS-colitis model, suggesting that ferrichrome inhibited cancer cells, but not a precancerous condition, via the colitis-associated pathway.
Ferrichrome exerts a tumor suppressive effect on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. The anti-tumor effect of ferrichrome was mediated by the upregulation of DDIT3, and was superior to that of 5-FU or cisplatin. These results suggest that Lactobacillus brevis-derived ferrichrome may be a candidate anti-tumor drug for the treatment of colorectal neoplasms.
结直肠癌通过多种途径发展，包括腺瘤-癌序列和结肠炎相关致癌作用。据报道，肠道微生物群改变通过这些途径与结直肠癌的发生和发展相关。我们鉴定出干酪乳杆菌衍生的铁载体蛋白通过上调DDIT3作为结直肠癌细胞细菌抗肿瘤作用的介质。在本研究中，我们研究了铁载体蛋白对与散发性以及结肠炎相关结直肠癌相关的癌前病变和癌细胞的抗肿瘤作用。
进行SRB和MTT试验以评估体外生长抑制。从结肠镜检查获得的活检标本中制备了18个类器官。建立了AOM-DSS致癌模型和结直肠癌细胞异种移植模型，以评估铁载体蛋白在体内的肿瘤抑制作用。
铁载体蛋白在体外和体内异种移植模型中均抑制了结直肠癌细胞的生长。铁载体蛋白发挥出强大肿瘤抑制作用，在体外和体内均优于目前可用的抗肿瘤药物，包括5-氟尿嘧啶和顺铂。铁载体蛋白与5-氟尿嘧啶联合使用的肿瘤抑制作用优于单一药物治疗。通过在腺瘤和癌的患者来源类器官中上调DDIT3证实了铁载体蛋白具有肿瘤抑制作用。铁载体蛋白在AOM-DSS模型中抑制肿瘤进展，而在DSS-结肠炎模型中未表现出抗炎作用，这表明铁载体蛋白通过结肠炎相关途径抑制癌细胞，而非癌前病变。
铁载体蛋白对与散发性以及结肠炎相关结直肠癌相关的癌前病变和癌细胞具有肿瘤抑制作用。铁载体蛋白的抗肿瘤作用是由DDIT3上调介导的，并且优于5-氟尿嘧啶或顺铂。这些结果表明，短乳杆菌衍生的铁载体蛋白可能是治疗结直肠肿瘤的候选抗肿瘤药物。
