Gera Sakshi, Kumar S Sandeep, Swamy Shalini N, Bhagat Rahul, Vadaparty Annapurna, Gawari Ramesh, Bhat Ramray, Dighe Rajan R
Department of Molecular Reproduction Development and Genetics, Indian Institute of Science, Bengaluru, India.
Department of Biochemistry, Kidwai Cancer Institute, Bengaluru, India.
J Endocr Soc. 2018 Dec 12;3(2):340-357. doi: 10.1210/js.2018-00272. eCollection 2019 Feb 1.
The association between the upregulated Notch and FSH signaling and ovarian cancer is well documented. However, their signaling has been investigated independently and only in the primary tumor tissues. The aim of this study was to investigate the interactive effects of FSH and Notch signaling on ovarian cancer proliferation, formation, and maintenance of disseminated ovarian cancer cells. The roles of Notch and FSH in ovarian cancer pathogenesis were investigated with ovarian cancer cell lines and specific antibodies against Notch and FSH receptor (FSHR). FSH upregulated Notch signaling and proliferation in ovarian cancer cells. High levels of FSH were detected in the ascites of patients with serous ovarian adenocarcinoma. Spheroids from the patients' ascites, as well as the spheroids from ovarian cancer cell lines under low attachment culture conditions, expressed subunit mRNA and secreted the hormone into the medium. In contrast, primary ovarian tumor tissues and cell line monolayers expressed very low levels of . Ovarian cancer cell spheroids also exhibited higher expression of FSH receptor and Notch downstream genes than their monolayer counterparts. A combination of FSHR and Notch antagonistic antibodies significantly inhibited spheroid formation and cell proliferation . This study demonstrates that spheroids in ascites express and secrete FSH, which regulates cancer cell proliferation and spheroidogenesis through Notch signaling, suggesting that FSH is an autocrine regulator of cancer metastasis. Furthermore, Notch and FSHR are potential immunotherapeutic targets for ovarian cancer treatment.
Notch信号和促卵泡激素（FSH）信号上调与卵巢癌之间的关联已有充分记录。然而，它们的信号传导仅在原发性肿瘤组织中被独立研究。本研究的目的是探讨FSH和Notch信号对卵巢癌增殖、播散性卵巢癌细胞形成及维持的交互作用。利用卵巢癌细胞系以及针对Notch和FSH受体（FSHR）的特异性抗体，研究了Notch和FSH在卵巢癌发病机制中的作用。FSH上调卵巢癌细胞中的Notch信号和细胞增殖。在浆液性卵巢腺癌患者的腹水中检测到高水平的FSH。来自患者腹水的球状体以及在低附着培养条件下来自卵巢癌细胞系的球状体，表达β亚基mRNA并将该激素分泌到培养基中。相比之下，原发性卵巢肿瘤组织和细胞系单层表达的β水平极低。卵巢癌细胞球状体也比其单层对应物表现出更高的FSH受体和Notch下游基因表达。FSHR和Notch拮抗抗体的联合显著抑制球状体形成和细胞增殖。本研究表明，腹水中的球状体表达并分泌FSH，其通过Notch信号调节癌细胞增殖和球状体形成，提示FSH是癌症转移的自分泌调节因子。此外，Notch和FSHR是卵巢癌治疗的潜在免疫治疗靶点。
