Neumeister Peter, Pixley Fiona J, Xiong Ying, Xie Huafeng, Wu Kongming, Ashton Anthony, Cammer Michael, Chan Amanda, Symons Marc, Stanley E Richard, Pestell Richard G
Division of Hormone-dependent Tumor Biology, The Albert Einstein Comprehensive Cancer Center, Bronx, New York 10461, USA.
Mol Biol Cell. 2003 May;14(5):2005-15. doi: 10.1091/mbc.02-07-0102. Epub 2003 Feb 21.
The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein, thereby promoting cell-cycle progression. Cyclin D1 is overexpressed in hematopoetic and epithelial malignancies correlating with poor prognosis and metastasis in several cancer types. Because tumor-associated macrophages have been shown to enhance malignant progression and metastasis, and cyclin D1-deficient mice are resistant to oncogene-induced malignancies, we investigated the function of cyclin D1-/- bone marrow-derived macrophages. Cyclin D1 deficiency increased focal complex formation at the site of substratum contact, and enhanced macrophage adhesion, yielding a flattened, circular morphology with reduced membrane ruffles. Migration in response to wounding, cytokine-mediated chemotaxis, and transendothelial cell migration of cyclin D1-/- bone marrow-derived macrophages were all substantially reduced. Thus, apart from proliferative and possible motility defects in the tumor cells themselves, the reduced motility and invasiveness of cyclin D1-/- tumor-associated macrophages may contribute to the tumor resistance of these mice.
细胞周期蛋白D1基因编码一种全酶的调节亚基，该全酶可使视网膜母细胞瘤蛋白磷酸化并使其失活，从而促进细胞周期进程。细胞周期蛋白D1在造血系统和上皮恶性肿瘤中过度表达，与几种癌症类型的不良预后和转移相关。由于肿瘤相关巨噬细胞已被证明可促进恶性进展和转移，且细胞周期蛋白D1缺陷小鼠对癌基因诱导的恶性肿瘤具有抗性，因此我们研究了细胞周期蛋白D1基因敲除的骨髓来源巨噬细胞的功能。细胞周期蛋白D1缺陷增加了基质接触部位的粘着斑复合物形成，并增强了巨噬细胞的粘附，产生了扁平的圆形形态，膜皱褶减少。细胞周期蛋白D1基因敲除的骨髓来源巨噬细胞对伤口的迁移反应、细胞因子介导的趋化作用以及跨内皮细胞迁移均显著减少。因此，除了肿瘤细胞自身的增殖和可能的运动缺陷外，细胞周期蛋白D1基因敲除的肿瘤相关巨噬细胞运动性和侵袭性的降低可能导致这些小鼠的肿瘤抗性。
