p53 functional deficiency in human colon cancer cells promotes fibroblast-mediated angiogenesis and tumor growth

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 fibroblast...

Source: Carcinogenesis - September 23, 2016 Category: Cancer & Oncology Authors: Hayashi, Y., Tsujii, M., Kodama, T., Akasaka, T., Kondo, J., Hikita, H., Inoue, T., Tsujii, Y., Maekawa, A., Yoshii, S., Shinzaki, S., Watabe, K., Tomita, Y., Inoue, M., Tatsumi, T., Iijima, H., Takehara, T. Tags: Original Manuscript Source Type: research