FGF18 as a prognostic and therapeutic biomarker in ovarian cancer

Abstract

High-throughput genomic technologies have identified biomarkers and potential therapeutic targets for ovarian cancer. Comprehensive functional validation studies of the biological and clinical implications of these biomarkers are needed to advance them toward clinical use. Amplification of chromosomal region 5q31-5q35.3 has been used to predict poor prognosis in patients with advanced stage, high-grade serous ovarian cancer. In this study, we further dissected this large amplicon and identified the overexpression of FGF18 as an independent predictive marker for poor clinical outcome in this patient population. Using cell culture and xenograft models, we show that FGF18 signaling promoted tumor progression by modulating the ovarian tumor aggressiveness and microenvironment. FGF18 controlled migration, invasion, and tumorigenicity of ovarian cancer cells through NF-κB activation, which increased the production of oncogenic cytokines and chemokines. This resulted in a tumor microenvironment characterized by enhanced angiogenesis and augmented tumor-associated macrophage infiltration and M2 polarization. Tumors from ovarian cancer patients had increased FGF18 expression levels with microvessel density and M2 macrophage infiltration, confirming our in vitro results. These findings demonstrate that FGF18 is important for a subset of ovarian cancers and may serve as a therapeutic target.

Fibroblast growth factor 18 promotes proliferation and migration of H460 cells via the ERK and p38 signaling pathways

“…Nevertheless, the role of FGF18 has not been previously studied in the context of lung cancer. Previous studies have indicated that elevated expression of FGF18 promotes the growth of colon cancer cells in culture (23), and demonstrated the pronounced oncogenic effect of FGF18 on ovarian tumor growth and metastasis (16). These observations are in agreement with our conclusion that FGF18 promoted the proliferation and migration of H460 cells.…”

“…FGF18 has been demonstrated to serve an important role in skeletal growth and limb development, potentially through the modulation of osteoblasts, chondrocytes, and osteoclasts (12,13). Furthermore, FGF18 expression was upregulated in colon cancer and ovarian cancer, and increased expression of FGF18 mRNA and protein is associated with tumor progression and poor overall survival in patients (14)(15)(16).…”

Jagged1 DNA Copy Number Variation Is Associated with Poor Outcome in Liver Cancer

“…In the oncology field, Notch signaling abnormalities are related to carcinogenesis or tumor vessel abnormalities 22,23 . Notch has revealed that copy number changes in specific genes are associated with carcinogenesis or the aggressiveness of the cancer and correlate with patient survival 34,35 . In the hepatological field, some reports have mentioned links between genomic alterations, severity of liver cancer, and survival 36,37 .…”

AAV9 delivering a modified human Mullerian inhibiting substance as a gene therapy in patient-derived xenografts of ovarian cancer

“…In total, 416 formalin-fixed, paraffinembedded, microdissected tumor cores of 3-mm diameter with >80% tumor and <20% necrosis/stroma were collected under institutional review boardapproved protocols (MGH2007P00001918 or DFCI 02-051) from ovarian cancer patients hospitalized at Massachusetts General Hospital between 1993 and 2009 as previously described (75). TMA slides were incubated with an anti-MISRII antibody (R&D) at a concentration of 5 μg/mL (1:40) followed by incubation with a donkey anti-sheep HRP (R&D) secondary at a concentration of 1:400.…”