TGF -Induced Smad Signaling Remains Intact in Primary Human Ovarian Cancer Cells

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Abstract
Disruptions in TGF signaling have been implicated in vari- ous human cancers, including ovarian cancer. Our goal was to determine whether ovarian cancer cells isolated from patient ascites fluid were growth inhibited by TGF1 treatment and further characterize the expression and activity profile of TGF/Smad signaling components in human ovarian cancer cells. We found that 9 of 10 primary cultures of ovarian cancer cells (OC2-10) were growth inhibited by 16 pM TGF1. One primary ovarian cancer sample (OC1) and the established ovarian cancer cell lines CaOV3 and SkOV3 continued to grow in the presence of TGF1. All cells expressed components of the TGF/Smad signaling pathway including TGF1, TRI, TRII, Smad2, -3, -4, and Smad anchor for receptor activation. Although OC1, CaOV3, and SkOV3 are not growth inhibited by TGF1, they can transmit the TGF1 signal to turn on a trans- fected TGF/Smad reporter gene, p3TP.lux. In addition, all cells up-regulate the endogenous TGF target genes Smad7 and PAI-1. p15Ink4B mRNA is also up-regulated with TGF1 treatment in OC2-9, whereas the p15Ink4B gene has been de- leted in OC1, CaOV3, and SkOV3 cells. Homozygous deletion of p15Ink4B may account for TGF resistance in some popula- tions of ovarian cancer cells. Our data demonstrate that the TGF/Smad signaling pathway remains functional in human ovarian cancer cells and suggest that if abnormalities exist in the cellular response of TGF signals, they must lie down- stream of the Smad proteins. (Endocrinology 143: 1174 -1181, 2002) VARIAN CANCER HAS the second highest incidence in gynecological cancers, ranks first in gynecologic cancer-related mortality (5-yr survival rate is 20%), and is the fifth leading cause of cancer death among women (1, 2). If ovarian cancer is detected early, more than 93% of patients survive 5 yr; however, more than 75% of cases are diagnosed at advanced stages with a poor prognosis for survival (Amer- ican Cancer Society). Most ovarian cancers are believed to arise from the ovarian surface epithelium (OSE), a modified peritoneal mesothelium derived embryologically from the coelomic epithelium (3). Characterizing the pathways that regulate the growth of OSE cells is a necessary first step toward understanding the events that lead to uncontrolled cellular proliferation and the development of ovarian cancer. Human OSE cells express many of the receptors for hor- mones and growth factors produced by the ovarian surface epithelial, follicular, and stromal cells, leading to the sug- gestion that epithelial cell activity may be modified by au- tocrine and paracrine signals (4 - 6). OSE cells often form inclusion bodies within the ovarian cortex, and these are the predominant sites of epithelial dysplasia and cancer forma- tion (3, 7, 8). It remains unclear what factors influence the transformation of the OSE in the inclusion cysts. Under cir- cumstances in which women have reduced ovulation, such as with multiparity, lactation, and use of oral contraceptives, there is a decreased risk of developing ovarian cancer. The molecular basis for this phenomenon is unknown; however, recent research suggests that oral contraceptives may pro- vide protection against development of ovarian cancer be-
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