Zhang Yong, Miwa Shinji, Zhang Nan, Hoffman Robert M, Zhao Ming
AntiCancer, Inc., San Diego, CA, USA.
Department of Surgery, University of California San Diego, San Diego, CA, USA.
Oncotarget. 2015 Feb 20;6(5):2615-22. doi: 10.18632/oncotarget.2811.
Brain metastasis is a morbid, treatment-resistant, end-stage frequent occurrence in breast cancer patients. The aim of this study was to evaluate the efficacy of tumor-targeting Salmonella typhimurium A1-R on breast cancer brain metastases. High brain-metastatic variants of murine 4T1 breast cancer cells expressing red fluorescent protein (RFP) were injected orthotopically in the mammary fat pad in non-transgenic nude mice or in the left ventricle of non-transgenic nude mice and transgenic nude mice expressing nestin-driven green fluorescent protein (ND-GFP). ND-GFP mice express GFP in nascent blood vessels. In the orthotopically-injected mice, the primary tumor was surgically-resected in order to allow brain metastasis to develop. At various time points, the tumors and vasculature in the brain were imaged by confocal and stereo fluorescence microscopy. Some of the breast cancer cells that reached the brain extravasated and grew perivascularly and some of the cells proliferated within the vasculature. S. typhimurium A1-R significantly inhibited brain metastasis in both metastatic models and increased survival of the orthotopically-transplanted, primary-tumor-resected mice (p<0.05). The results of the present study suggest the clinical potential of bacterial therapy of breast cancer brain metastasis.
脑转移是乳腺癌患者中一种常见的、难治的终末期病变。本研究的目的是评估靶向肿瘤的鼠伤寒沙门氏菌A1-R对乳腺癌脑转移的疗效。将表达红色荧光蛋白（RFP）的小鼠4T1乳腺癌高脑转移变体原位注射到非转基因裸鼠的乳腺脂肪垫中，或注射到非转基因裸鼠以及表达巢蛋白驱动的绿色荧光蛋白（ND-GFP）的转基因裸鼠的左心室中。ND-GFP小鼠在新生血管中表达GFP。在原位注射的小鼠中，通过手术切除原发肿瘤以促进脑转移形成。在不同时间点，通过共聚焦和立体荧光显微镜对脑中的肿瘤和脉管系统进行成像。一些到达脑部的乳腺癌细胞渗出并在血管周围生长，一些细胞在脉管系统内增殖。鼠伤寒沙门氏菌A1-R在两种转移模型中均显著抑制脑转移，并提高了原位移植、原发肿瘤切除小鼠的生存率（p<0.05）。本研究结果提示了细菌疗法治疗乳腺癌脑转移的临床潜力。
