癌症研究
血管生成
癌相关成纤维细胞
癌症
肿瘤进展
肿瘤微环境
癌细胞
结直肠癌
新生血管
生物
成纤维细胞
细胞培养
肿瘤细胞
遗传学
作者
Yoshito Hayashi,Masahiko Tsujii,Takahiro Kodama,Tomofumi Akasaka,Jumpei Kondo,Hayato Hikita,Takuya Inoue,Yoshiki Tsujii,Akira Maekawa,Shunsuke Yoshii,Shinichiro Shinzaki,Kenji Watabe,Yasuhiko Tomita,Masahiro Inoue,Tomohide Tatsumi,Hideki Iijima,Tetsuo Takehara
出处
期刊:Carcinogenesis
[Oxford University Press]
日期:2016-08-12
卷期号:37 (10): 972-984
被引量:41
标识
DOI:10.1093/carcin/bgw085
摘要
Cancer-associated fibroblasts (CAFs) create a microenvironment that contributes to tumor growth; however, the mechanism by which fibroblasts are phenotypically altered to CAFs remains unclear. Loss or mutation of the tumor suppressor p53 plays a crucial role in cancer progression. Herein, we analyzed how the p53 status of cancer cells affects fibroblasts by investigating the in vivo and in vitro effects of loss of p53 function in cancer cells on phenotypic changes in fibroblasts and subsequent tumor progression in human colon cancer cell lines containing wild-type p53 and in cells with a p53 functional deficiency. The growth of p53-deficient tumors was significantly enhanced in the presence of fibroblasts compared with that of p53-wild-type tumors or p53-deficient tumors without fibroblasts. p53-deficient cancer cells produced reactive oxygen species, which activated fibroblasts to mediate angiogenesis by secreting vascular endothelial growth factor (VEGF) both in vivo and in vitro. Activated fibroblasts significantly contributed to tumor progression. Deletion of fibroblast-derived VEGF or treatment with N-acetylcysteine suppressed the growth of p53-deficient xenograft tumors. The growth effect of blocking VEGF secreted from cancer cells was equivalent regardless of p53 functional status. Human colon cancer tissues also showed a significant positive correlation between p53 cancer cell staining activated fibroblasts and microvessel density. These results reveal that fibroblasts were altered by exposure to p53-deficient epithelial cancer cells and contributed to tumor progression by promoting neovascularization. Thus, p53 acts as a modulator of the tumor microenvironment.
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