title: p53 functional deficiency in human colon cancer cells promotes fibroblast-mediated angiogenesis and tumor growth.
abstract: 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.
authors: Yoshito
authors: Y
authors: Hayashi
authors: Masahiko
authors: M
authors: Tsujii
authors: Takahiro
authors: T
authors: Kodama
authors: Tomofumi
authors: T
authors: Akasaka
authors: Jumpei
authors: J
authors: Kondo
authors: Hayato
authors: H
authors: Hikita
authors: Takuya
authors: T
authors: Inoue
authors: Yoshiki
authors: Y
authors: Tsujii
authors: Akira
authors: A
authors: Maekawa
authors: Shunsuke
authors: S
authors: Yoshii
authors: Shinichiro
authors: S
authors: Shinzaki
authors: Kenji
authors: K
authors: Watabe
authors: Department of Pathology and.
authors: Yasuhiko
authors: Y
authors: Tomita
authors: Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
authors: Masahiro
authors: M
authors: Inoue
authors: Tomohide
authors: T
authors: Tatsumi
authors: Hideki
authors: H
authors: Iijima
authors: Tetsuo
authors: T
authors: Takehara
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage; D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000111:Acetylcysteine