Motility is critical for effective distribution and accumulation of bacteria in tumor tissue.
Motility is critical for effective distribution and accumulation of bacteria in tumor tissue.
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运动性对于肿瘤组织中细菌的有效分布和积累至关重要。
DOI：
10.1039/c2ib00091a
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Forbes NS
中科院分区：
文献类型：
--
作者：
Toley BJ;Forbes NS
运动细菌可以克服癌症化疗药物的渗透限制，因为它们可以主动迁移到实体瘤中。尽管已证明几个属的细菌优先在肿瘤中积累，但细菌肿瘤定植的时空动态及其对细菌运动的依赖性尚不清楚。为了有效地消退肿瘤，细菌必须渗透并均匀分布在整个肿瘤中。为了测量这些动态，我们使用连续灌注肿瘤组织的体外模型来模拟鼠伤寒沙门氏菌菌株 SL1344 和 VNP20009 以及大肠杆菌菌株 K12 和 DH5α 的递送和全身清除。用每种菌株的105或107 CFU/ml悬浮液处理组织1小时，并观察细菌积累的位置和程度30小时。沙门氏菌的平均游动速度是大肠杆菌的 14.5 倍，其定植组织的剂量比大肠杆菌低 100 倍。细菌活力与组织积累程度密切相关（R2 = 99.3%）。当以 105 CFU/ml 接种时，活动沙门氏菌形成的菌落密度高于 1010 CFU/（g 组织），而活动性较低的大肠杆菌未显示出可检测到的定殖。根据时空分布以及运动和生长的数学模型，发现细菌分散对于深层渗透到组织中是必要的。细菌定植引起肿瘤细胞凋亡，细胞凋亡水平与定植密度相关（R2 = 98.6%）。这些结果表明，运动性对于细菌在肿瘤中的有效分布至关重要，并且对于设计能够克服有限肿瘤渗透障碍的癌症疗法至关重要。
Motile bacteria can overcome the penetration limitations of cancer chemotherapeutics because they can actively migrate into solid tumors. Although several genera of bacteria have been shown to accumulate preferentially in tumors, the spatiotemporal dynamics of bacterial tumor colonization and their dependence on bacterial motility is not clear. For effective tumor regression, bacteria must penetrate and distribute uniformly throughout tumors. To measure these dynamics, we used an in vitro model of continuously perfused tumor tissue to mimic the delivery and systemic clearance of Salmonella typhimurium strains SL1344 and VNP20009, and Escherichia coli strains K12 and DH5α. Tissues were treated for 1 hour with 105 or 107 CFU/ml suspensions of each strain and the location and extent of bacterial accumulation was observed for 30 hours. Salmonella had 14.5 times greater average swimming speeds than E.coli and colonized tissues at 100 times lower doses than E.coli. Bacterial motility strongly correlated (R2 = 99.3%) with the extent of tissue accumulation. When inoculated at 105 CFU/ml, motile Salmonella formed colonies denser than 1010 CFU/(g-tissue) and less motile E.coli showed no detectable colonization. Based on spatio-temporal profiles and a mathematical model of motility and growth, bacterial dispersion was found to be necessary for deep penetration into tissue. Bacterial colonization caused apoptosis in tumors and apoptosis levels correlated (R2 = 98.6%) with colonization density. These results show that motility is critical for effective distribution of bacteria in tumors and is essential for designing cancer therapies that can overcome the barrier of limited tumor penetration.