Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, and Department of Pathology, State University Hospital, Rigshospitalet, Copenhagen, Denmark.
Am J Pathol. 2010 Mar;176(3):1229-40. doi: 10.2353/ajpath.2010.090648. Epub 2010 Feb 4.
Tumor cells can activate stroma, yet the implication of this activation in terms of reciprocal induction of gene expression in tumor cells is poorly understood. Epithelial Stromal Interaction 1 (EPSTI1) is an interferon response gene originally isolated from heterotypic recombinant cultures of human breast cancer cells and activated breast myofibroblasts. Here we describe the first immunolocalization of EPSTI1 in normal and cancerous breast tissue, and we provide evidence for a role of this molecule in the regulation of tumor cell properties and epithelial-mesenchymal transition. In general, no EPSTI1 staining was observed in normal breast epithelial cells from reduction mammoplasties (n=25). However, in carcinomas, staining was positive in 22 of 40 biopsies and inversely correlated with the level of differentiation. To address the function of EPSTI1, we expressed EPSTI1 ectopically in one cell line and silenced endogenous EPSTI1 by RNA interference in another. Irrespective of the experimental approach, EPSTI1 expression led to an increase in tumorsphere formation-a property associated with breast stem/progenitor cells. Most remarkably, we show that EPSTI1, by conveying spread of tumor cells, can replace peritumoral activated fibroblasts in a tumor environment assay. These observations implicate EPSTI1 as a hitherto unappreciated regulator of tumor cell properties.
肿瘤细胞可以激活基质，但肿瘤细胞中这种激活在基因表达的相互诱导方面的意义还知之甚少。上皮-间质相互作用 1（EPSTI1）是一种干扰素反应基因，最初从人乳腺癌细胞的异型重组培养物和激活的乳腺成肌纤维细胞中分离出来。在这里，我们描述了 EPSTI1 在正常和癌性乳腺组织中的首次免疫定位，并提供了证据表明该分子在调节肿瘤细胞特性和上皮-间充质转化中起作用。一般来说，在减少乳房成形术的正常乳腺上皮细胞中（n=25）未观察到 EPSTI1 染色。然而，在癌中，40 个活检中有 22 个呈阳性，并且与分化程度呈负相关。为了研究 EPSTI1 的功能，我们在一个细胞系中外源表达 EPSTI1，并通过 RNA 干扰在另一个细胞系中沉默内源性 EPSTI1。无论采用哪种实验方法，EPSTI1 的表达都导致肿瘤球形成的增加——这是与乳腺干细胞/祖细胞相关的特性。最值得注意的是，我们表明 EPSTI1 通过传播肿瘤细胞的扩散，可以在肿瘤环境测定中替代肿瘤周围激活的成纤维细胞。这些观察结果表明 EPSTI1 是一种迄今为止尚未被认识到的肿瘤细胞特性调节剂。
