van Duijn Petra W, Marques Rute B, Ziel-van der Made Angelique C J, van Zoggel Hanneke J A A, Aghai Ashraf, Berrevoets Cor, Debets Reno, Jenster Guido, Trapman Jan, van Weerden Wytske M
Department of Pathology, JNI, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Urology, JNI, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
Prostate. 2018 Sep;78(13):1013-1023. doi: 10.1002/pros.23659. Epub 2018 May 29.
Prostate cancer is recognized as a heterogeneous disease demanding appropriate preclinical models that reflect tumor complexity. Previously, we established the PSA-Cre;PtenLoxP/LoxP genetic engineered mouse model (GEMM) for prostate cancer reflecting the various stages of tumor development. Prostate tumors in this Pten KO model slowly develop, requiring more than 10 months. In order to enhance its practical utility, we established a syngeneic panel of cell lines derived from PSA-Cre targeted Pten KO tumors, designated the mouse prostate cancer (MuCap) model.
Four different MuCaP epithelial cell lines were established from three independent primary Pten KO mouse prostate tumors. Tumorigenic capacity of the MuCaP cell lines was determined by subcutaneous inoculation of these cell lines in immunocompetent mice. Response to PI3K-targeted therapy was validated in ex vivo tissue slices of the established MuCaP tumors.
The MuCaP cell lines were all tumorigenic in immunocompetent mice after subcutaneous inoculation. Interestingly, these syngrafted tumors represented different tumor growth rates and morphologies. Treatment with the specific PI3K inhibitor GDC0941 resulted in responses very similar between syngeneic MuCaP and primary Pten KO prostate tumors. Finally, immunoprofiling of the different syngeneic MuCaP tumors demonstrated differential numbers of tumor infiltrating lymphocytes and distinct immune gene profiles with expression of CD8, INFy, and PD1 being inversely related to tumor aggressiveness.
Collectively, we present here a well-defined MuCaP platform of in vitro and in vivo mouse prostate cancer models that may support preclinical assessment of (immune)-therapies for prostate cancer.
前列腺癌是一种异质性疾病，需要合适的临床前模型来反映肿瘤的复杂性。此前，我们建立了PSA-Cre;PtenLoxP/LoxP基因工程小鼠模型（GEMM）用于前列腺癌研究，该模型可反映肿瘤发展的各个阶段。在这个Pten基因敲除模型中，前列腺肿瘤发展缓慢，需要超过10个月的时间。为了提高其实际应用价值，我们建立了一组源自PSA-Cre靶向Pten基因敲除肿瘤的同基因细胞系，即小鼠前列腺癌（MuCap）模型。
从三个独立的原发性Pten基因敲除小鼠前列腺肿瘤中建立了四种不同的MuCaP上皮细胞系。通过将这些细胞系皮下接种到免疫功能正常的小鼠体内来确定MuCaP细胞系的致瘤能力。在已建立的MuCaP肿瘤的离体组织切片中验证对PI3K靶向治疗的反应。
皮下接种后，MuCaP细胞系在免疫功能正常的小鼠中均具有致瘤性。有趣的是，这些移植瘤表现出不同的肿瘤生长速度和形态。用特异性PI3K抑制剂GDC0941治疗后，同基因MuCaP肿瘤与原发性Pten基因敲除前列腺肿瘤的反应非常相似。最后，对不同同基因MuCaP肿瘤的免疫分析表明，肿瘤浸润淋巴细胞数量不同，免疫基因谱也不同，CD8、INFγ和PD1的表达与肿瘤侵袭性呈负相关。
总体而言，我们在此展示了一个定义明确的MuCaP体外和体内小鼠前列腺癌模型平台，该平台可能支持前列腺癌（免疫）治疗的临床前评估。
