Characterization of an animal model of hepatic metastasis
Characterization of an animal model of hepatic metastasis
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DOI：
10.1111/j.1440-1746.1996.tb00006.x
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发表时间：
1996-01-01
影响因子：
4.1
通讯作者：
OBrien, PE
中科院分区：
文献类型：
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作者：
Kuruppu, D;Christophi, C;OBrien, PE
控制肝转移瘤生长的可能疗法的实验研究需要技术上可行的模型的可用性，该模型似乎表现出与人类肿瘤相似的生长特征。我们报告的发展脾内注射模型的肝转移，并描述了组织学，生长模式和血流表现为光学显微镜，体视学和激光多普勒血流仪。通过脾内注射二甲基肼（DMH）诱导的原代结肠癌细胞（10（6）个细胞/1 mt）诱导小鼠肝转移。在预定的时间点，在3周的时间内研究转移瘤的生长和发展。第7天，通过光学显微镜在肝窦中可见肿瘤细胞。直径为0.18 +/- 0.02 cm（平均值+/- s.d.）的肉眼可见异物在第10天被发现。此时，肿瘤已经从邻近肿瘤周边的肝窦获得血液供应。随着进一步血管化，肿瘤在第22天达到0.96 +/-0.50 cm的直径。通过相对于非病变肝组织的肿瘤体积的体视学分析来定量转移性生长。正常小鼠肝脏的平均体积为1.13 +/- 0.14 cm（3）。肿瘤生长分三个阶段。在最初的缓慢阶段，转移灶的体积从第10天的0.03 +/- 0.02 cm（3）增加到第16天的0.22 +/- 0.24 cm（3）。在接下来的3天内发生的快速肿瘤生长构成了中间期，到第19天转移体积达到1.21 +/- 0.74 cm（3）（与第16天相比，P=0.0003）。这种生长之后是平台期，在第22天转移体积为1.40 +/- 0.55 cm（3）。总肝体积和肿瘤坏死体积遵循类似的生长模式。第10天首次观察到的坏死肿瘤体积为0.004 +/- 0.006 cm（3），第16天增加到0.05 +/- 0.06 cm（3），第22天增加到0.25 +/- 0.20 cm（3）（与第16天相比，P=0.0022）。激光多普勒血流仪测量的转移瘤的血流量低于非病变肝脏。肿瘤血液如何表示为正常肝血流量的百分比，在第10天为63.31 +/- 26.28%，到第22天减少到27.91 +/- 8.99%，随着肿瘤大小和年龄的增加。在第13天和第16天之间，流量显著降低（P=0.0015）。这种脾内转移瘤小鼠模型是可重复的，并应证明在治疗肝转移瘤的研究中是有用的。
The experimental study of possible therapies for control of the growth of liver metastases requires the availability of a model which is technically feasible and appears to exhibit growth characteristics similar to human tumours. We report on the development of an intrasplenic injection model of liver metastases, and describe the histology, growth pattern and blood flow demonstrated by light microscopy, stereology and laser Doppler flowmetry. The hepatic metastases were induced in mice by intrasplenic injection of dimethylhydrazine (DMH) induced primary colonic carcinoma cells (10(6) cells in 1 mt). The growth and development of metastases was studied over a period of 3 weeks at predetermined time points. Tumour cells were visible in the hepatic sinusoids by day 7 by light microscopy. Macroscopically visible rumours with a diameter of 0.18 +/- 0.02 cm (mean +/- s.d.) were seen by day 10. By this time the tumours had derived a blood supply from the hepatic sinusoids adjacent to the tumour periphery. With further vascularization the tumours reached a diameter of 0.96 +/- 0.50 cm by day 22. Metastatic growth was quantitated by stereological analysis of tumour volume in relation to non-diseased hepatic tissue. Normal mouse liver had a mean volume of 1.13 +/- 0.14 cm(3). Tumour growth occurred in three phases. During the initial slow phase the volume of metastases increased from 0.03 +/- 0.02 cm(3) at day 10 to 0.22 +/- 0.24 cm(3) by day 16. Rapid tumour growth, occurring over the next 3 days, constituted the intermediate phase with metastatic volume reaching 1.21 +/- 0.74 cm(3) by day 19 (P=0.0003 compared with day 16). This growth was followed by a plateau phase when the metastatic volume was 1.40 +/- 0.55 cm(3) at day 22. The volume of total liver and of tumour necrosis followed a similar growth pattern. A necrotic tumour volume of 0.004 +/- 0.006 cm(3) first seen on day 10 increased to 0.05 +/- 0.06 cm(3) by day 16, and to 0.25 +/- 0.20 cm(3) by day 22 (P=0.0022 compared with day 16). The blood flow in metastases measured by laser Doppler flowmetry was lower compared to the nondiseased liver. Tumour blood how expressed as a percentage of normal liver blood flow, was 63.31 +/- 26.28% at day 10 and diminished to 27.91 +/- 8.99% by day 22, with an increase in tumour size and age. The decrease in flow was significant between days 13 and 16 (P=0.0015). This intrasplenic mouse model of metastases is reproducible and should prove useful in the study of treatment of hepatic metastases.