Expression of an activated Notch4(int‐3) oncoprotein disrupts morphogenesis and induces an invasive phenotype in mammary epithelial cells in vitro
Expression of an activated Notch4(int‐3) oncoprotein disrupts morphogenesis and induces an invasive phenotype in mammary epithelial cells in vitro
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DOI：
10.1002/(sici)1097-0215(20000601)86:5
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发表时间：
2000-06
影响因子：
6.4
通讯作者：
J. Soriano;H. Uyttendaele;J. Kitajewski;R. Montesano
中科院分区：
文献类型：
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作者：
J. Soriano;H. Uyttendaele;J. Kitajewski;R. Montesano
Notch4基因编码的蛋白是Notch/Lin-12跨膜受体蛋白家族的成员，已被证明在多种生物中控制细胞命运和细胞分化。Notch4(int-3)是Notch4的一种截短形式，其大部分胞外结构域被缺失，作为转基因在小鼠体内的表达，可诱导低分化乳腺癌的形成。为了确定Notch4(int-3)是否具有颠覆正常上皮结构的能力，我们观察了Notch4(int-3)的表达对TAC-2乳腺上皮细胞体外形态发生特性的影响。当在氢化可的松存在的三维胶原凝胶中生长时，野生型和LacZ转染型TAC-2细胞都形成了由围绕中央管腔的极化上皮细胞组成的肺泡样结构。相反，编程表达Notch4(int-3)的TAC-2细胞形成了致密的细胞聚集体，没有组织特异性的组织。此外，当生长在胶原凝胶表面时，表达Notch4(int-3)的TAC-2细胞侵入基质，而TAC-2 LacZ细胞严格限制在凝胶表面。Notch4(int-3)在TAC-2细胞中的表达也破坏了细胞增殖的接触抑制，导致细胞多层。我们的结果表明，Notch4(int-3)能够颠覆正常的上皮形态发生并促进细胞外基质的侵袭，这对其致癌潜力有重要作用。内部癌症杂志86：652-659,2000。©2000 Wiley-Liss Inc.
The protein encoded by the Notch4 gene is a member of the Notch/lin‐12 family of transmembrane receptor proteins, which have been shown to control cell fate determination and cell differentiation in a wide variety of organisms. Expression of Notch4(int‐3), a truncated form of Notch4 having most of its extracellular domain deleted, as a transgene in mice induces the formation of poorly differentiated mammary carcinomas. To establish whether Notch4(int‐3) has the capacity of subverting normal epithelial architecture, we assessed the effect of Notch4(int‐3) expression on the in vitro morphogenetic properties of TAC‐2 mammary epithelial cells. When grown in three‐dimensional collagen gels in the presence of hydrocortisone, both wild‐type and LacZ‐transfected TAC‐2 cells formed alveolar‐like structures composed of polarized epithelial cells surrounding a central lumen. In contrast, TAC‐2 cells programmed to express Notch4(int‐3) formed compact cell aggregates devoid of tissue‐specific organization. In addition, when grown on the surface of a collagen gel, Notch4(int‐3)‐expressing TAC‐2 cells invaded the underlying matrix, whereas TAC‐2 LacZ cells remained strictly confined to the gel surface. Expression of Notch4(int‐3) in TAC‐2 cells also disrupted contact‐inhibition of cell proliferation, resulting in cell multilayering. Our results suggest that the ability of Notch4(int‐3) to subvert normal epithelial morphogenesis and to promote invasion of the extracellular matrix contributes significantly to its tumorigenic potential. Int. J. Cancer 86:652–659, 2000. © 2000 Wiley‐Liss, Inc.