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半乳糖凝集素作为小鼠乳腺癌侵袭性的标志物:迈向人乳腺癌的凝集素靶向治疗

Galectins as markers of aggressiveness of mouse mammary carcinoma: towards a lectin target therapy of human breast cancer.

作者信息

Moiseeva E V, Rapoport E M, Bovin N V, Miroshnikov A I, Chaadaeva A V, Krasilshschikova M S, Bojenko V K, Bijleveld Caspaar, van Dijk J E, Den Otter W

机构信息

Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia.

出版信息

Breast Cancer Res Treat. 2005 Jun;91(3):227-41. doi: 10.1007/s10549-005-0289-8.

Abstract

Galectins, beta-galactoside binding proteins, expressed selectively in human breast carcinoma are attractive targets to employ lectin-aimed therapeutics. We examined beta-galactoside binding potency of neoplastic cells using fluorescein-labelled synthetic glycoconjugates as probes for flow cytometry. As a result, surface beta-galactoside binding proteins/galectins were discovered on mouse mammary carcinoma cells in vitro and in vivo unlike non-malignant cells from the several tissues; and asialo-GM1 ganglioside carbohydrate part--containing probe was the most specific one. However, in liver and lung metastatic cells galectins seem to be expressed within cytoplasm and/or nuclei. Galectin expression correlated directly with aggressive tumour potential in the A/Sn transplantable model similar to findings in several human breast carcinoma cell lines. However, galectin expression was reduced during tumour progression in more aggressive forms of spontaneous BLRB mammary carcinomas like it was shown for human breast carcinoma specimens. Analysis of the histopathological data led, however, to the conclusion that galectin expression hardly might be a suitable marker of aggressiveness of heterogeneous mammary carcinomas as the observed level of galectin expression is influenced by the amount of the stroma in a tumour sample and/or probably, galectin expression inversely correlates with tumour aggressiveness during the initial and advanced steps of mammary tumour progression. We conclude that surface beta-galactoside binding proteins/galectins that are selectively expressed during mouse mammary carcinoma progression, similarly to human breast carcinomas, seem to be proper targets for asialo-GM1-vectored cytotoxics and our mouse model system might be a relevant instrument to further test novel modes of anti-breast cancer therapy.

摘要

半乳糖凝集素,即β-半乳糖苷结合蛋白,在人类乳腺癌中选择性表达,是采用凝集素靶向疗法的有吸引力的靶点。我们使用荧光素标记的合成糖缀合物作为流式细胞术的探针,检测了肿瘤细胞的β-半乳糖苷结合能力。结果发现,与来自多个组织的非恶性细胞不同,小鼠乳腺癌细胞在体外和体内均存在表面β-半乳糖苷结合蛋白/半乳糖凝集素;而含唾液酸GM1神经节苷脂碳水化合物部分的探针是最具特异性的。然而,在肝和肺转移细胞中,半乳糖凝集素似乎在细胞质和/或细胞核内表达。在A/Sn移植模型中,半乳糖凝集素的表达与肿瘤的侵袭性直接相关,这与在几种人类乳腺癌细胞系中的发现相似。然而,在更具侵袭性的自发性BLRB乳腺癌中,肿瘤进展过程中半乳糖凝集素的表达降低,就像在人类乳腺癌标本中所显示的那样。然而,对组织病理学数据的分析得出结论,半乳糖凝集素的表达几乎不可能是异质性乳腺癌侵袭性的合适标志物,因为观察到的半乳糖凝集素表达水平受肿瘤样本中基质数量的影响,和/或可能在乳腺肿瘤进展的初始和晚期阶段,半乳糖凝集素的表达与肿瘤侵袭性呈负相关。我们得出结论,在小鼠乳腺癌进展过程中选择性表达的表面β-半乳糖苷结合蛋白/半乳糖凝集素,与人类乳腺癌相似,似乎是唾液酸GM1载体细胞毒素的合适靶点,并且我们的小鼠模型系统可能是进一步测试新型抗乳腺癌治疗模式的相关工具。

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