Department of Anatomy and Experimental Morphology, University Cancer Center Hamburg, Hamburg, Germany.
Clin Cancer Res. 2012 Mar 1;18(5):1364-73. doi: 10.1158/1078-0432.CCR-11-2900. Epub 2012 Jan 18.
To establish xenograft mouse models of metastatic and nonmetastatic human prostate cancer and to apply these models to the search for aberrant glycosylation patterns associated with tumor progression in vivo and in patients.
Prostate cancer cells (LNCaP, PC-3, LuCaP 23.1, and DU-145) were xenografted subcutaneously into immunodeficient pfp(-/-)/rag2(-/-) mice. Tumor growth and metastasis formation were quantified and as altered glycosylation patterns have been associated with metastasis formation in several other malignancies, prostate cancer cells were profiled by a quantitative real-time PCR (qRT-PCR) glycosylation array and compared with normal human prostate cells. The activity of upregulated glycosyltransferases was analyzed by their sugar residues end products using lectin histochemistry on primary tumors and metastases in the animal experiments and on 2,085 clinical samples.
PC-3 cells produced the largest number of spontaneous lung metastases, followed by LNCaP and LuCaP 23.1, whereas DU-145 was nonmetastatic. qRT-PCR revealed an upregulation of β1,6-N-acetylglucosaminyltransferase-5b (Mgat5b) in all prostate cancer cell lines. Mgat5b products [β(1,6)-branched oligosaccharides] were predominantly detectable in metastatic xenografts as shown by increased binding of Phaseolus vulgaris leukoagglutinin (PHA-L). The percentage of prostate cancer patients who were PHA-L positive was 86.5. PHA-L intensity correlated with serum prostate-specific antigen and a cytoplasmic staining negatively affected disease-free survival.
We show a novel xenograft mouse model for human prostate cancer respecting the complete metastatic cascade. Specific glycosylation patterns reveal Mgat5b products as relevant markers of both metastatic competence in mice and disease-free survival in patients. This is the first description of Mgat5b in prostate cancer indicating a significant biologic importance of β(1,6)-branched oligosaccharides for prostate cancer progression.
建立转移性和非转移性人前列腺癌的异种移植小鼠模型，并将这些模型应用于体内和患者中寻找与肿瘤进展相关的异常糖基化模式的研究。
将前列腺癌细胞（LNCaP、PC-3、LuCaP 23.1 和 DU-145）皮下移植到免疫缺陷 pfp(-/-)/rag2(-/-) 小鼠中。定量检测肿瘤生长和转移形成，并对前列腺癌细胞进行定量实时 PCR（qRT-PCR）糖基化阵列分析，与正常人类前列腺细胞进行比较。在动物实验和 2085 例临床样本中，通过凝集素组织化学分析原发肿瘤和转移灶中上调的糖基转移酶的糖基末端产物来分析其活性。
PC-3 细胞产生了最多的自发性肺转移，其次是 LNCaP 和 LuCaP 23.1，而 DU-145 则无转移。qRT-PCR 显示所有前列腺癌细胞系中β1,6-N-乙酰氨基葡萄糖基转移酶-5b（Mgat5b）的上调。如用菜豆属植物白细胞凝集素（PHA-L）结合增加所显示，Mgat5b 产物[β（1,6）-支链寡糖]主要在转移性异种移植瘤中可检测到。PHA-L 阳性的前列腺癌患者百分比为 86.5。PHA-L 强度与血清前列腺特异性抗原相关，细胞质染色呈阴性，与无病生存相关。
我们展示了一种新型的尊重完整转移级联的人前列腺癌异种移植小鼠模型。特定的糖基化模式揭示了 Mgat5b 产物作为小鼠中转移能力和患者无病生存的相关标志物。这是前列腺癌中 Mgat5b 的首次描述，表明β（1,6）-支链寡糖对前列腺癌进展具有重要的生物学意义。
