Study Of Activation Of Epidermal Growth Factor Receptor In Tumor-associated Macrophage And Epithelial Ovarian Cancer Malignant Behavior

Epithelial ovarian cancer (EOC, referred to as ovarian cancer in this study) is one of the most lethal gynecologic malignancy in the world. Despite recent advances in chemotherapeutic treatments that have improved the initial responses, the5-year survival rate for women with advanced stage ovarian cancer is only about30%after initial diagnosis. Pessimistically, more than70%of EOC patients appeared the first specific symptoms and are diagnosed only during advanced disease stage. Collective data have proved that tumor-associated macrophages (TAMs) play an important role in EOC progression. TAMs, derived from circulating monocyte, are recruited into tumors and stromal tissues by chemokines and cytokines. In special microenvironments, monocytes (MOs) can be polarized toward M1or M2differentiation, which is very similar to the Th1/Th2dichotomy. TAMs display the M2macrophage phenotype and promote tumor progression by producing growth factors, as well as inflammatory cytokines, chemokines, and immunosuppressive mediators.Additionally, emerging studies have demonstrated that EGFR signaling could promote cancer invasion and metastasis in many solid tumors. Moreover, the function and activation of EGFR in TAMs cause more and more attention. Our study aimed to explore the relationship between the activation of EGFR in TAMs and EOC. Our conclusions were as followed:1. The study consisted of67primary EOC patients with ascites no less than200ml, diagnosed and treated at the Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital from January2007to December2008. We proved that high TAMs count in primary ovarian cancer tissues and percent in ascites were related to EOC patients with advanced FIGO stage and platinum resistant and refractory (P<0.05) by using, of Immunohistochemistry (IHC) and Fluorescence-activated cell sorting (FACS), respectively. In the Cox proportional hazard mode, TAMs count in primary ovarian cancer tissues was the independent indicators of progression-free survival (PFS) and overall survival (OS) for EOC patients.2. We investigated the phenotype and cytokine/chemokine expression of EGF-treated peripheral blood monocytes (MOs). It was found that the phenotype of MOs was altered toward a TAM-like macrophage CD163highIL-10highTGF-phighIL-8high after EGF stimulation. By Matrigel invasion assay, MTT proliferation assay, and wound healing assay, the conditioned medium of EGF-stimulated MOs accelerated remarkable invasion, proliferation, and migration of human ovarian cancer cell line SKOV3, which was similar to the results of conditioned medium from TAMs stimuli (P<0.05). This study provided insight the role of EGF in the regulation of EOC malignant behaviors via "educating" MOs.3. We found that EGF could directly stimulate IL-10production of TAMs through the activation of EGFR-PI3K/AKT and EGFR-ERK signal pathways by using of the inhibitors of EGFR, PI3K, and ERK. Furthermore, our data indicated that IL-10enhanced the invasion, proliferation and migration of human ovarian cancer cell line SKO V3via the up-regulation of vascular epithelial growth factor (VEGF) and matrix metalloproteinase-9(MMP-9) in SKOV3.