Abstract
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.
Highlights
Records for > 200 years have documented cancer patients going into remission after a bacterial infection
4T1-red fluorescent protein (RFP) high-brain-metastatic variant breast cancer cells were obtained by 4 cycles of in vivo section
Brain metastasis of 4T1 mouse mammary carcinoma was obtained after left cardiac ventricle injection or orthotopic injection in the mammary fat pad with highbrain-metastatic 4T1-RFP variants
Summary
Records for > 200 years have documented cancer patients going into remission after a bacterial infection. Coley at New York Cancer Hospital, the precursor of Sloan-Kettering Memorial Cancer Center, treated cancer patients with S. pyogenes. In 1891, Coley noted that a sarcoma patient had tumor regression after an infection with S. pyogenes. Coley’s first patient infected with S. pyogenes recovered from head and neck cancer. Coley injected many cancer patients with S. pyogenes and often had good results. Because of the danger of live streptococcal organisms, Coley subsequently used killed S. pyogenes with a second killed organism known as Serratia marcescens. These killed organisms became known as Coley’s Toxins [1]
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