Yoshida Mitsuyo, Taguchi Ayumi, Kawana Kei, Adachi Katsuyuki, Kawata Akira, Ogishima Juri, Nakamura Hiroe, Fujimoto Asaha, Sato Masakazu, Inoue Tomoko, Nishida Haruka, Furuya Hitomi, Tomio Kensuke, Arimoto Takahide, Koga Kaori, Wada-Hiraike Osamu, Oda Katsutoshi, Nagamatsu Takeshi, Kiyono Tohru, Osuga Yutaka, Fujii Tomoyuki
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Division of Virology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
PLoS One. 2016 Aug 2;11(8):e0160330. doi: 10.1371/journal.pone.0160330. eCollection 2016.
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.
癌基因最常见的特性是促进恶性细胞的增殖并防止其凋亡，进而导致肿瘤的形成和扩散。然而，癌基因对肿瘤微环境（TME）的影响尚未得到详细研究。伴有慢性炎症和血管内皮生长因子（VEGF）浓度升高的腹水积聚是卵巢癌进展的一个标志。我们在此展示了癌基因调控卵巢癌微环境的机制。将c-MYC和KRAS转导至小鼠卵巢癌细胞系ID8中。然后将ID8、ID8-c-MYC或ID8-KRAS细胞注射到C57/BL6小鼠的腹腔中，并评估腹水的产生情况。ID8-c-MYC和ID8-KRAS在体内均显著加速了卵巢癌的进展，而在体外增殖活性方面未观察到显著差异。特别是ID8-KRAS诱导产生腹水，其在注射后约两到三周开始积聚，比ID8和ID8-c-MYC更快（分别在九到十周和六到七周开始积聚）。在c-MYC诱导的卵巢癌中，腹水中VEGF浓度显著升高，而在KRAS诱导的卵巢癌中，腹水中炎性细胞因子浓度显著升高，并伴有腹水中中性粒细胞数量增加。细胞因子阵列显示，KRAS显著诱导ID8细胞中粒细胞巨噬细胞集落刺激因子（GM-CSF）的表达。这些结果表明，癌基因通过调节肿瘤微环境促进癌症进展，有利于癌症的发展。
