Abstract
The most common properties of oncogenes are cell proliferation and the prevention of apoptosis in malignant cells, which, as a consequence, induce tumor formation and dissemination. However, the effects of oncogenes on the tumor microenvironment (TME) have not yet been examined in detail. The accumulation of ascites accompanied by chronic inflammation and elevated concentrations of VEGF is a hallmark of the progression of ovarian cancer. We herein demonstrated the mechanisms by which oncogenes contribute to modulating the ovarian cancer microenvironment. c-MYC and KRAS were transduced into the mouse ovarian cancer cell line ID8. ID8, ID8-c-MYC, or ID8-KRAS cells were then injected into the peritoneal cavities of C57/BL6 mice and the production of ascites was assessed. ID8-c-MYC and ID8-KRAS both markedly accelerated ovarian cancer progression in vivo, whereas no significant differences were observed in proliferative activity in vitro. ID8-KRAS in particular induced the production of ascites, which accumulated between approximately two to three weeks after the injection, more rapidly than ID8 and ID8-c-MYC (between nine and ten weeks and between six and seven weeks, respectively). VEGF concentrations in ascites significantly increased in c-MYC-induced ovarian cancer, whereas the concentrations of inflammatory cytokines in ascites were significantly high in KRAS-induced ovarian cancer and were accompanied by an increased number of neutrophils in ascites. A cytokine array revealed that KRAS markedly induced the expression of granulocyte macrophage colony-stimulating factor (GM-CSF) in ID8 cells. These results suggest that oncogenes promote cancer progression by modulating the TME in favor of cancer progression.
Highlights
Ovarian cancer is effectively treated with platinum-based chemotherapies
A previous study indicated that the characteristics of tumor-infiltrating lymphocytes (TIL) are influenced by the disruption of BRCA1, which is a well-known tumor suppressor gene of ovarian cancer [9]. These findings suggest that the activation of oncogenes or disruption of tumor suppressor genes is involved in modulations to the tumor microenvironment (TME)
We investigated TME modifications caused by oncogenes using a mouse in vivo model of the disseminated ovarian cancer cell lines
Summary
Ovarian cancer is effectively treated with platinum-based chemotherapies. Approximately 15–20% of ovarian cancer cases are resistant to this treatment [1]. Surgery followed by paclitaxel and carboplatin (TC) therapy is the standard initial treatment for ovarian cancer, 60% or more of patients need second-line chemotherapy. A treatment regimen for second-line chemotherapy against recurrence after TC therapy has yet to be established [2]. Therapies that target the tumor microenvironment (TME), including angiogenesis and inflammation, in ovarian cancer characterized by peritoneal dissemination accompanied by massive ascites are novel strategies [3]. Adjuvant therapy may be effective for each case by identifying a tumor-promoting factor (inflammation, angiogenesis, or immunosuppression)
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