Engineered bacteria detect spatial profiles in glucose concentration within solid tumor cell masses.
Engineered bacteria detect spatial profiles in glucose concentration within solid tumor cell masses.
复制标题
工程菌可检测实体肿瘤细胞团内葡萄糖浓度的空间分布情况。
DOI：
10.1002/bit.26006
复制
发表时间：
2016-11
影响因子：
3.8
通讯作者：
Forbes, Neil S.
中科院分区：
文献类型：
--
作者：
Panteli, Jan T.;Forbes, Neil S.
肿瘤的异质性使得癌症难以治疗。许多小分子抗癌药物靶向肿瘤周围快速分裂的细胞，但难以深入肿瘤，无法有效治疗整个肿瘤。针对肿瘤快速分裂和生长缓慢的区域对于有效治疗癌症至关重要。一种能够深入肿瘤并识别代谢活动的癌症药物载体可以根据局部微环境为这些区域提供治疗。我们假设葡萄糖感应细菌可以识别实体瘤中的糖梯度。为了检验这一假设，设计了一个遗传电路，通过趋化性渗透孔蛋白融合蛋白 Trz1（一种用于感应葡萄糖和核糖的受体）触发绿色荧光蛋白 (GFP) 报告基因的表达。将配备有 Trz1-GFP 表达系统的大肠杆菌注入连续灌注肿瘤组织的体外模型中，该模型模拟细菌通过实体瘤附近血管的全身输送和清除。每个细菌表达的 GFP 水平与时间无关，并且表明葡萄糖浓度是微流体肿瘤内渗透深度的函数。测量的葡萄糖浓度与作为深度函数的肿瘤细胞活力相关（P 值 = 2.6×10−5）。数学分析预测，与全身给药的药物相比，葡萄糖感应细菌的药物递送将消除更高比例的存活肿瘤细胞群。葡萄糖感应细菌可以通过增加药物渗透和营养依赖性剂量来提供癌症治疗，以持续治疗转移扩散率较高的癌症组织的存活区域。
Tumor heterogeneity makes cancer difficult to treat. Many small molecule cancer drugs target rapidly dividing cells on the periphery of tumors but have difficulty in penetrating deep into tumors and are ineffective at treating entire tumors. Targeting both rapidly dividing and slower growing regions of tumors is essential to effectively treat cancer. A cancer drug carrier that penetrates deep into tumors and identifies metabolically activity could supply treatment to those areas based on the local microenvironment. We hypothesized that glucose sensing bacteria could identify sugar gradients in solid tumors. To test this hypothesis, a genetic circuit was designed to trigger expression of a green fluorescent protein (GFP) reporter through the chemotaxis-osmoporin fusion protein, Trz1, a receptor for sensing glucose and ribose sugars. E. coli equipped with the Trz1-GFP expression system, were administered to an in vitro model of a continuously perfused tumor tissue that mimics systemic delivery and clearance of bacteria through a blood vessel adjacent to a solid tumor. The level of GFP expressed, per bacterium, was time independent and indicated the glucose concentration as a function of penetration depth within the microfluidic tumors. The measured glucose concentration, correlated (P-value = 2.6×10−5) with tumor cell viability as a function of depth. Mathematical analysis predicted drug delivery by glucose-sensing bacteria would eliminate a higher percentage of the viable tumor cell population than a systemically administered drug. Glucose-sensing bacteria could deliver cancer therapies with increased drug penetration and nutrient-dependent dosing to continuously treat viable regions of cancer tissue that have a higher prevalence for metastatic dissemination.
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影响因子：
4.3
作者：
Cox TR;Erler JT
通讯作者：
Erler JT
影响因子：
--
作者：
Borch-Johnsen, K;Neil, A;Qiao, Q
通讯作者：
Qiao, Q
DOI：
10.1073/pnas.86.14.5385
发表时间：
1989-07-01
影响因子：
11.1
作者：
CHARY, SR;JAIN, RK
通讯作者：
JAIN, RK
影响因子：
3.2
作者：
Barnakov, AN;Barnakova, LA;Hazelbauer, GL
通讯作者：
Hazelbauer, GL
影响因子：
--
作者：
Li, YY;Reichenstein, K;Hahn, HP
通讯作者：
Hahn, HP