Patient-derived mouse models of cancer need to be orthotopic in order to evaluate targeted anti-metastatic therapy.
Patient-derived mouse models of cancer need to be orthotopic in order to evaluate targeted anti-metastatic therapy.
复制标题
DOI：
10.18632/oncotarget.12322
复制
发表时间：
2016-11-01
期刊：
影响因子：
--
通讯作者：
Hoffman RM
中科院分区：
文献类型：
--
作者：
Hiroshima Y;Maawy A;Zhang Y;Zhang N;Murakami T;Chishima T;Tanaka K;Ichikawa Y;Bouvet M;Endo I;Hoffman RM
患者来源的异种移植（PDX）小鼠癌症模型正在成为个性化精确癌症治疗的重要组成部分。然而，目前提供给患者的大多数模型都将肿瘤皮下移植到免疫缺陷小鼠中，很少转移。相比之下，原位移植患者来源的模型，称为患者来源的原位异种移植物（PDOX），通常如在患者中那样转移。在本报告中，我们证明了原位模型对患者如此重要的原因，因为原位模型中产生的原发性和转移性肿瘤可能具有不同的化疗敏感性，在标准皮下肿瘤模型中无法检测到。表达HER-2的宫颈癌的皮下裸鼠模型对恩替司他（一种苯甲酰胺组蛋白脱乙酰酶抑制剂）不敏感，恩替司他在相同肿瘤的PDOX模型中也不抑制原发性肿瘤生长。然而，在PDOX模型中，与对照相比，单独的恩替司他显著降低了转移性肿瘤负荷。因此，仅PDOX模型可用于发现恩替司他对该患者的抗转移活性。本报告的结果表明，使用小鼠模型，可以重现转移性癌症的精确个性化的癌症治疗的重要性。
Patient-derived xenograft (PDX) mouse models of cancer are emerging as an important component of personalized precision cancer therapy. However, most models currently offered to patients have their tumors subcutaneously-transplanted in immunodeficient mice, which rarely metastasize. In contrast, orthotopic-transplant patient-derived models, termed patient-derived orthotopic xenografts (PDOX), usually metastasize as in the patient. We demonstrate in the present report why orthotopic models are so important for the patient, since primary and metastatic tumors developed in an orthotopic model can have differential chemosensitivity, not detectable in standard subcutaneous tumor models. A subcutaneous nude mouse model of HER-2 expressing cervical carcinoma was not sensitive to entinostat (a benzamide histone deactylase inhibitor), which also did not inhibit primary tumor growth in a PDOX model of the same tumor. However, in the PDOX model, entinostat alone significantly reduced the metastatic tumor burden, compared to the control. Thus, only the PDOX model could be used to discover the anti-metastatic activity of entinostat for this patient. The results of the present report indicate the importance of using mouse models that can recapitulate metastatic cancer for precisely individualizing cancer therapy.