Ovarian cancer

Abstract: OBJECTIVE. It is now recognized that ovarian cancer includes a heterogeneous group of malignant epithelial tumors originating from the ovaries, fallopian tubes, or peritoneum. This development has prompted the International Federation of Gynecology and Obstetrics (FIGO) to issue a revised staging system that can provide prognostic information and guidance on personalized management of ovarian cancer. CONCLUSION. We review the epidemiology of ovarian cancer, the new FIGO staging system, and the role of imaging in the assessment, staging, and follow-up of ovarian cancer.

Abstract: Although initially responsive to chemotherapy, many patients with ovarian cancer subsequently develop relapsed and potentially fatal metastatic disease, which is thought to develop from cancer stem cells (CSCs) that are relatively resistant to conventional therapy. Here, we show that CSCs express a type I receptor tyrosine kinase-like orphan receptor (ROR1), which is expressed during embryogenesis and by many different cancers, but not normal postpartum tissues. Ovarian cancers with high levels of ROR1 had stem cell-like gene-expression signatures. Furthermore, patients with ovarian cancers with high levels of ROR1 had higher rates of relapse and a shorter median survival than patients with ovarian cancers that expressed low-to-negligible amounts of ROR1. We found that ROR1-positive (ROR1+) cells isolated from primary tumor-derived xenografts (PDXs) also expressed aldehyde dehydrogenase 1 (ALDH1) and had a greater capacity to form spheroids and to engraft immune-deficient mice than did ROR1-negative (ROR1Neg) ovarian cancer cells isolated from the same tumor population. Treatment with UC-961, an anti-ROR1 mAb, or shRNA silencing of ROR1 inhibited expression of the polycomb ring-finger oncogene, Bmi-1, and other genes associated with the epithelial–mesenchymal transition. Moreover, shRNA silencing of ROR1, depletion of ROR1+ cells, or treatment with UC-961 impaired the capacity of ovarian cancer cells to form spheroids or tumor xenografts. More importantly, treatment with anti-ROR1 affected the capacity of the xenograft to reseed a virgin mouse, indicating that targeting ROR1 may affect CSC self-renewal. Collectively, these studies indicate that ovarian CSCs express ROR1, which contributes to their capacity to form tumors, making ROR1 a potential target for the therapy of patients with ovarian cancer.

Abstract: Purpose: Chemokine receptor CXCR2 is associated with malignancy in several cancer models; however, the mechanisms involved in CXCR2-mediated tumor growth remain elusive. Here, we investigated the role of CXCR2 in human ovarian cancer. Experimental Design: CXCR2 expression was silenced by stable small hairpin RNA in ovarian cancer cell lines T29Gro-1, T29H, and SKOV3. Western blotting, immunofluorescence, enzyme-linked immunosorbent assay, flow cytometry, electrophoretic mobility shift assay, and mouse assay were used to detect CXCR2, interleukin-8, Gro-1, cell cycle, apoptosis, DNA binding of NF-κB, and tumor growth. Immunohistochemical staining of CXCR2 was done in 240 high-grade serous ovarian carcinoma samples. Results: Knockdown of CXCR2 expression by small hairpin RNA reduced tumorigenesis of ovarian cancer cells in nude mice. CXCR2 promoted cell cycle progression by modulating cell cycle regulatory proteins, including p21 (waf1/cip1), cyclin D1, CDK6, CDK4, cyclin A, and cyclin B1. CXCR2 inhibited cellular apoptosis by suppressing phosphorylated p53, Puma, and Bcl-xS; suppressing poly(ADP-ribose) polymerase cleavage; and activating Bcl-xL and Bcl-2. CXCR2 stimulated angiogenesis by increasing levels of vascular endothelial growth factor and decreasing levels of thrombospondin-1, a process likely involving mitogen-activated protein kinase, and NF-κB. Overexpression of CXCR2 in high-grade serous ovarian carcinomas was an independent prognostic factor of poor overall survival ( P P = 0.003) in the univariate analysis. Conclusions: Our data provide strong evidence that CXCR2 regulates the cell cycle, apoptosis, and angiogenesis through multiple signaling pathways, including mitogen-activated protein kinase and NF-κB, in ovarian cancer. CXCR2 thus has potential as a therapeutic target and for use in ovarian cancer diagnosis and prognosis. Clin Cancer Res; 16(15); 3875–86. ©2010 AACR.

Abstract: Endometriosis is classically defined as the presence of endometrial glands and stroma outside of the endometrial lining and uterine musculature. With an estimated frequency of 5%–10% among women of reproductive age, endometriosis is a common gynecologic disorder. While in itself a benign lesion, endometriosis shares several characteristics with invasive cancer, has been shown to undergo malignant transformation, and has been associated with an increased risk of epithelial ovarian carcinoma (EOC). Numerous epidemiologic studies have shown an increased risk of EOC among women with endometriosis. This is particularly true for women with endometrioid and clear cell ovarian carcinoma. However, the carcinogenic pathways by which endometriosis associated ovarian carcinoma (EAOC) develops remain poorly understood. Current molecular studies have sought to link endometriosis with EAOC through pathways related to oxidative stress, inflammation and hyperestrogenism. In addition, numerous studies have sought to identify an intermediary lesion between endometriosis and EAOC that may allow for the identification of endometriosis at greatest risk for malignant transformation or for the prevention of malignant transformation of this common gynecologic disorder. The objective of the current article is to review the current data regarding the molecular events associated with EAOC development from endometriosis, with a primary focus on malignancies of the endometrioid and clear cell histologic sub-types.