Singla Arvind K, Downey Charlene M, Bebb Gwyn D, Jirik Frank R
Department of Biochemistry and Molecular Biology, The McCaig Institute for Bone and Joint Health, Alberta, Canada.
Tom Baker Cancer Centre, and Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
Oncoscience. 2015 Feb 9;2(3):263-71. doi: 10.18632/oncoscience.117. eCollection 2015.
Despite successful preclinical testing carried out through the use of subcutaneous xenografted tumors, many anti-cancer agents have gone on to fail in human trials. One potential factor accounting for this discrepancy may relate to the inadequacy of the commonly employed preclinical models to recapitulate the human disease, particularly when it comes to discovery of agents that are effective against advanced disease. Herein, we report the characterization of a NSCLC model and an exploration of the impact that a CXCR4 inhibitor, AMD3100, had on NCI-H1299-derived metastasis. These cells express a variety of metastasis-promoting factors, hence we selected them for a study of their metastatic colonization potential. To accomplish this, luciferase-expressing H1299 (H1299-luc2) cells were inoculated into athymic mice via the intracardiac route. This strategy produced adrenal, bone, ovarian, and pancreatic metastases, sites commonly involved in human metastatic NSCLC. Notably, micro-computed tomography and histological evaluation of the skeletal lesions revealed the presence of extensive osteolysis. To investigate the potential role of CXCR4 in mediating metastatic colonization of tissues, AMD3100 was administered to mice inoculated with H1299-luc2 cells. While this treatment did not appreciably alter the frequency of metastatic colonization, it was able to slow the growth of macrometastases. This model, recapitulating some of the events seen in late-stage human NSCLC, may prove useful in the evaluation of new therapies targeting metastatic disease.
尽管通过使用皮下异种移植肿瘤进行了成功的临床前测试，但许多抗癌药物在人体试验中仍告失败。造成这种差异的一个潜在因素可能与常用临床前模型无法重现人类疾病有关，特别是在发现对晚期疾病有效的药物方面。在此，我们报告了一种非小细胞肺癌（NSCLC）模型的特征，并探讨了CXCR4抑制剂AMD3100对源自NCI-H1299细胞的转移的影响。这些细胞表达多种促进转移的因子，因此我们选择它们来研究其转移定植潜力。为实现这一目标，将表达荧光素酶的H1299（H1299-luc2）细胞通过心内途径接种到无胸腺小鼠体内。这一策略产生了肾上腺、骨、卵巢和胰腺转移，这些部位通常是人类转移性NSCLC所累及的部位。值得注意的是，对骨骼病变的微型计算机断层扫描和组织学评估显示存在广泛的骨质溶解。为了研究CXCR4在介导组织转移定植中的潜在作用，将AMD3100给予接种了H1299-luc2细胞的小鼠。虽然这种治疗并未明显改变转移定植的频率，但它能够减缓大转移灶的生长。该模型重现了晚期人类NSCLC中所见的一些事件，可能在评估针对转移性疾病的新疗法中证明有用。
