A step further in understanding the biology of the folate receptor in ovarian carcinoma
A step further in understanding the biology of the folate receptor in ovarian carcinoma
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DOI：
10.1006/gyno.2002.6705
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发表时间：
2003-01-01
影响因子：
4.7
通讯作者：
Miotti, S
中科院分区：
文献类型：
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作者：
Bagnoli, M;Canevari, S;Miotti, S
卵巢癌治疗策略的部分疗效依赖于对潜在病理生理学的不完全理解。卵巢癌被认为是通过异常分化过程从卵巢表面上皮（OSE）中产生的，该过程包括获得高度分化的苗勒管上皮的特性和新基因（如E-钙粘蛋白和CA 125）的表达[1]。我们过去的研究将叶酸受体（FR）的α亚型确定为卵巢恶性转化的标志物，FR是一种38 kDa的GPI锚定蛋白，我们发现其在90%的非粘液性卵巢癌中以高水平组成性表达，而在少数其他正常上皮组织中以低水平存在[2]。该受体被描述为当与富含胆固醇和鞘糖脂的专门膜微结构域（称为小窝）相关时，为叶酸内化至正常猴肾上皮细胞提供高亲和力途径[3]。然而，我们发现FR仅部分负责卵巢癌细胞系中的叶酸内化[4]。FR表达赋予FR转染细胞生长优势以及FR表达水平与卵巢癌患者肿瘤进展相关的发现[5，六、最近的一些研究表明，由质膜内脂质和脂质修饰蛋白的不均匀分布所产生的膜微区与细胞增殖密切相关，受体信号传导、细胞间相互作用和细胞粘附事件[7]。通过从微区的Vantage角度重新审视通过FR进行信号传导的假设，我们发现FR在低密度微区中与src-激酶林恩和异源三聚体G蛋白相关，但没有小窝蛋白-1（cav-1）[8]。Cav-1是一种21至24 kDa的蛋白质，最初被鉴定为RSV转化的成纤维细胞中的主要酪氨酸磷酸化底物，是小窝的主要结构组分（综述见[9]）。这些结构不仅参与囊泡运输（内吞作用，转胞吞作用），而且也被认为是受调控的位点。
The partial efficacy of therapeutic strategies for ovarian carcinoma relies on a still incomplete understanding of the underlying pathophysiology. Ovarian carcinoma is thought to arise from the ovarian surface epithelium (OSE) by an aberrant differentiation process which encompasses the acquisition of properties of the highly differentiated Müllerian epithelium and the expression of new genes as E-cadherin and CA125 [1]. Our past studies identified as a marker of the malignant transformation in the ovary the alpha isoform of the folate receptor (FR), a 38-kDa GPI-anchored protein that we found to be constitutively expressed at high levels in 90% of nonmucinous ovarian carcinoma, while it is present at low levels in few other normal epithelial tissues [2]. The receptor was described to provide a high-affinity route for folate internalization into normal monkey kidney epithelial cells when associated with specialized membrane microdomains enriched in cholesterol and glycosphingolipids named caveolae [3]. However, we found that FR is only partially responsible for folate internalization in ovarian cancer cell lines [4]. The finding that FR expression confers a growth advantage in FR-transfected cells and that FR expression levels correlate with tumor progression in ovarian cancer patients [5, 6] suggested an involvement of the receptor in the control and maintenance of cell proliferation.Several recent studies demonstrate that membrane microdomains created by unequal distribution of lipids and lipidmodified proteins within the plasma membranes are intimately involved in cell receptor signaling, cell-to-cell interaction, and cell adhesion events [7]. By revisiting the hypothesis of signaling via FR from the vantage point of microdomains, we found that FR partitioned in low-density microdomains in association with src-kinase lyn and heterotrimeric G proteins but devoid of caveolin-1 (cav-1)[8]. Cav-1, a 21-to 24-kDa protein initially identified as the major tyrosine phosphorylated substrate in RSV-transformed fibroblast, is the main structural component of caveolae (see [9] for a review). These structures not only are involved in vescicular trafficking (endocytosis, transcytosis) but are also considered sites where regulated