Blood vessel hyperpermeability and pathophysiology in human tumour xenograft models of breast cancer: a comparison of ectopic and orthotopic tumours.
Blood vessel hyperpermeability and pathophysiology in human tumour xenograft models of breast cancer: a comparison of ectopic and orthotopic tumours.
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DOI：
10.1186/1471-2407-12-579
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发表时间：
2012-12-05
期刊：
影响因子：
3.8
通讯作者：
Shoichet MS
中科院分区：
文献类型：
--
作者：
Ho KS;Poon PC;Owen SC;Shoichet MS
人类肿瘤异种移植物在免疫受损小鼠体内被广泛用作癌症模型，因为它们易于复制并且易于用于各种临床前评估。纳米医学的发展已经导致使用肿瘤异种移植物来测试纳米级递送装置，如纳米颗粒和聚合物药物偶联物，通过增强渗透性和保留（EPR）效应来确定靶向性和有效性。为了使这些结果有意义，必须在模型中复制与肿瘤病理生理相关的高透性脉管系统和淋巴引流减少。在临床前乳腺癌异种移植模型中，细胞通常通过原位注射（乳腺脂肪垫，MFP）或异位注射（皮下，SC）引入，肿瘤细胞所经历的器官环境已被证明会影响它们的行为。为了评估EPR背景下的乳腺癌异种移植模型，对NOD scid γ (NSG)小鼠进行了原位MFP和异位SC注射MDA-MB-231-H2N细胞。通过注射高分子量葡聚糖作为模型纳米载体，对具有两种大小类别的匹配肿瘤的动物进行了测试。肿瘤被收集和切片，以评估葡聚糖积累与肝组织作为阳性对照。为了了解这些观察的细胞基础，肿瘤切片也进行了内皮细胞、基底膜、周细胞和淋巴管的免疫染色。SC肿瘤需要更长的发育时间才能变成与MFP肿瘤匹配的大小，并且在细胞注射后6周也表现出广泛的大小变异性和溃疡性皮肤病变。3周MFP肿瘤模型比5周SC肿瘤模型显示更多葡聚糖积累（P < 0.10）。免疫染色显示MFP肿瘤模型注射细胞3周后血管密度增大，基底膜变薄。MFP和SC肿瘤均显示淋巴引流不足，可见许多充满液体和iv型胶原蛋白的间隙，可能含有过量的间质液。右旋糖酐积累和免疫染色结果表明，小MFP肿瘤最能复制体内观察EPR效应所需的血管通透性。更可预测的生长特征和没有溃疡性皮肤损伤进一步表明，MFP模型是在达到目标肿瘤大小后开始的长期治疗研究的有力选择。
Human tumour xenografts in immune compromised mice are widely used as cancer models because they are easy to reproduce and simple to use in a variety of pre-clinical assessments. Developments in nanomedicine have led to the use of tumour xenografts in testing nanoscale delivery devices, such as nanoparticles and polymer-drug conjugates, for targeting and efficacy via the enhanced permeability and retention (EPR) effect. For these results to be meaningful, the hyperpermeable vasculature and reduced lymphatic drainage associated with tumour pathophysiology must be replicated in the model. In pre-clinical breast cancer xenograft models, cells are commonly introduced via injection either orthotopically (mammary fat pad, MFP) or ectopically (subcutaneous, SC), and the organ environment experienced by the tumour cells has been shown to influence their behaviour. To evaluate xenograft models of breast cancer in the context of EPR, both orthotopic MFP and ectopic SC injections of MDA-MB-231-H2N cells were given to NOD scid gamma (NSG) mice. Animals with matched tumours in two size categories were tested by injection of a high molecular weight dextran as a model nanocarrier. Tumours were collected and sectioned to assess dextran accumulation compared to liver tissue as a positive control. To understand the cellular basis of these observations, tumour sections were also immunostained for endothelial cells, basement membranes, pericytes, and lymphatic vessels. SC tumours required longer development times to become size matched to MFP tumours, and also presented wide size variability and ulcerated skin lesions 6 weeks after cell injection. The 3 week MFP tumour model demonstrated greater dextran accumulation than the size matched 5 week SC tumour model (for P < 0.10). Immunostaining revealed greater vascular density and thinner basement membranes in the MFP tumour model 3 weeks after cell injection. Both the MFP and SC tumours showed evidence of insufficient lymphatic drainage, as many fluid-filled and collagen IV-lined spaces were observed, which likely contain excess interstitial fluid. Dextran accumulation and immunostaining results suggest that small MFP tumours best replicate the vascular permeability required to observe the EPR effect in vivo. A more predictable growth profile and the absence of ulcerated skin lesions further point to the MFP model as a strong choice for long term treatment studies that initiate after a target tumour size has been reached.
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DOI：
10.1111/j.1349-7006.2000.tb00940.x
发表时间：
2000-02-01
期刊：
JAPANESE JOURNAL OF CANCER RESEARCH
影响因子：
--
作者：
Hori, K;Saito, S;Sato, Y
通讯作者：
Sato, Y
影响因子：
10.3
作者：
Dreher, MR;Liu, WG;Chilkoti, A
通讯作者：
Chilkoti, A
影响因子：
4.8
作者：
Schiffelers, RM;Metselaar, JM;Storm, G
通讯作者：
Storm, G
DOI：
10.1083/jcb.201102147
发表时间：
2012-02-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lu P;Weaver VM;Werb Z
通讯作者：
Werb Z
影响因子：
24
作者：
Rockson, Stanley G.
通讯作者：
Rockson, Stanley G.