Modification of the Tumor Microenvironment in KRAS or c-MYC-Induced Ovarian Cancer-Associated Peritonitis.
Modification of the Tumor Microenvironment in KRAS or c-MYC-Induced Ovarian Cancer-Associated Peritonitis.
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DOI：
10.1371/journal.pone.0160330
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Fujii T
中科院分区：
文献类型：
--
作者：
Yoshida M;Taguchi A;Kawana K;Adachi K;Kawata A;Ogishima J;Nakamura H;Fujimoto A;Sato M;Inoue T;Nishida H;Furuya H;Tomio K;Arimoto T;Koga K;Wada-Hiraike O;Oda K;Nagamatsu T;Kiyono T;Osuga Y;Fujii T
癌基因最常见的特性是细胞增殖和阻止恶性肿瘤细胞的凋亡，从而导致肿瘤的形成和扩散。然而，癌基因对肿瘤微环境(TME)的影响尚未被详细研究。腹水积聚伴随慢性炎症和血管内皮生长因子浓度升高是卵巢癌进展的标志。在此，我们展示了癌基因调节卵巢癌微环境的机制。将c-myc和KRAS基因导入小鼠卵巢癌细胞株ID8。然后将ID8、ID8-c-MYC或ID8-KRAS细胞注射到C57/BL6小鼠的腹水产生情况。ID8-c-MYC和ID8-KRAS在体内均能明显促进卵巢癌的进展，而在体外增殖活性无明显差异。ID8-KRAS尤其引起腹水的产生，在注射后大约两到三周内积累，比ID8和ID8-c-MYC(分别在九到十周和六到七周之间)更快地积累。C-myc诱导的卵巢癌腹水中的VEGF浓度显著升高，而KRAS诱导的卵巢癌腹水中炎性细胞因子的浓度显著升高，并伴有腹水中中性粒细胞的增多。细胞因子阵列显示KRAS可显著诱导ID8细胞表达粒细胞巨噬细胞集落刺激因子(GM-CSF)。这些结果表明，癌基因通过调节TME促进癌症进展。
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.