Development and characterization of a preclinical model of breast cancer lung micrometastatic to macrometastatic progression.
Development and characterization of a preclinical model of breast cancer lung micrometastatic to macrometastatic progression.
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DOI：
10.1371/journal.pone.0098624
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ihnat MA
中科院分区：
文献类型：
--
作者：
Bailey-Downs LC;Thorpe JE;Disch BC;Bastian A;Hauser PJ;Farasyn T;Berry WL;Hurst RE;Ihnat MA
大多数癌症患者死于转移性疾病，因此，重现自然转移过程（包括微转移细胞的休眠期）的良好模型将有助于制定治疗策略。在此，我们报告了一种自然转移模型，该模型平衡了完成实验的时间与合理的休眠期，可用于更好地研究转移进展。该模型的基础是未切除原发肿瘤的 4T1 三阴性同基因乳腺癌模型。将 500 个 GFP 标记的 4T1 细胞植入免疫良好的八周雌性 BALB/cJ 小鼠的四号脂肪垫中，进行细胞滴定，优化了模型的速度，同时具有包括休眠和重新激活开始在内的转移过程。在植入 500-1500 个细胞的动物中，原发性肿瘤的发生率低于 50%。虽然植入超过 10,000 个细胞导致 100% 原发性肿瘤发展，但形成的肿瘤和大转移瘤具有高度侵袭性，缺乏休眠性，并且不提供治疗机会。植入 7,500 个细胞后 10 天，肿瘤切除率超过 90%；植入后两周，肺部出现 30-60 个微转移（许多动物也有 2-30 个脑部微转移），第一个小转移在五周时出现；许多动物在植入后五周内表现出巨大转移，并且动物在植入后六周内变得垂死。使用 7,500 个细胞的最佳值，测试了以最大耐受剂量（MTD；每周 1 mg/kg）给予的乳腺癌化疗剂阿霉素对转移的影响。阿霉素治疗显着减少原发肿瘤生长和肺微转移，但实验结束时大转移的数量没有显着影响。该模型对于开发靶向转移的药物和研究转移的生物学应该是有用的。
Most cancer patients die with metastatic disease, thus, good models that recapitulate the natural process of metastasis including a dormancy period with micrometastatic cells would be beneficial in developing treatment strategies. Herein we report a model of natural metastasis that balances time to complete experiments with a reasonable dormancy period, which can be used to better study metastatic progression. The basis for the model is a 4T1 triple negative syngeneic breast cancer model without resection of the primary tumor. A cell titration from 500 to 15,000 GFP tagged 4T1 cells implanted into fat pad number four of immune proficient eight week female BALB/cJ mice optimized speed of the model while possessing metastatic processes including dormancy and beginning of reactivation. The frequency of primary tumors was less than 50% in animals implanted with 500–1500 cells. Although implantation with over 10,000 cells resulted in 100% primary tumor development, the tumors and macrometastases formed were highly aggressive, lacked dormancy, and offered no opportunity for treatment. Implantation of 7,500 cells resulted in >90% tumor take by 10 days; in 30–60 micrometastases in the lung (with many animals also having 2–30 brain micrometastases) two weeks post-implantation, with the first small macrometastases present at five weeks; many animals displaying macrometastases at five weeks and animals becoming moribund by six weeks post-implantation. Using the optimum of 7,500 cells the efficacy of a chemotherapeutic agent for breast cancer, doxorubicin, given at its maximal tolerated dose (MTD; 1 mg/kg weekly) was tested for an effect on metastasis. Doxorubicin treatment significantly reduced primary tumor growth and lung micrometastases but the number of macrometastases at experiment end was not significantly affected. This model should prove useful for development of drugs to target metastasis and to study the biology of metastasis.
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影响因子：
46.9
作者：
Ma L;Reinhardt F;Pan E;Soutschek J;Bhat B;Marcusson EG;Teruya-Feldstein J;Bell GW;Weinberg RA
通讯作者：
Weinberg RA
影响因子：
6
作者：
Grippo, PJ;Sandgren, EP
通讯作者：
Sandgren, EP
影响因子：
4.8
作者：
Heimburg, Jamie;Yan, Jun;Rittenhouse-Olson, Kate
通讯作者：
Rittenhouse-Olson, Kate
DOI：
10.1186/bcr2345
发表时间：
2009
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Das Roy L;Pathangey LB;Tinder TL;Schettini JL;Gruber HE;Mukherjee P
通讯作者：
Mukherjee P
通过预防新血管形成，体内肿瘤休眠。
影响因子：
15.3
作者：
Gimbrone, M A Jr;Leapman, S B;Cotran, R S;Folkman, J
通讯作者：
Folkman, J