The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. The present report describes technology to monitor real-time cell cycle dynamics of cancer cells throughout a live tumor in vivo using a fluorescence ubiquitination cell cycle indicator (FUCCI). In nascent tumors in nude mice, approximately 30% of the cells in the center of the tumor are in G0/G1 and 70% in S/G2/M. In contrast in an established tumor, approximately 90% of cancer cells in the center are in G0/G1 phase. Similarly, approximately 75% of cancer cells far from (>100 µm) tumor blood vessels are in G0/G1. Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface of tumors and, in contrast, had little effect on quiescent cancer cells that are the vast majority of an established tumor. Moreover resistant quiescent cancer cells that moved to the tumor surface restarted cycling after the cessation of chemotherapy. Most drugs currently in clinical use target cancer cells in S/G2/M which our results show are a small minority in established tumors, thereby accounting, at least in part, for poor efficacy of cytotoxic drugs in solid cancer. Our results also suggest that drugs that target quiescent cancer cells are urgently needed.

Citation Format: Shuya Yano, Yasunori Tome, Yong Zhang, Yukihiko Hiroshima, Shinji Miwa, Fuminari Uehara, Atsushi Suetsugu, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Toshiyoshi Fujiwara, Robert M. Hoffman. Real-time FUCCI imaging of cell cycle phase in tumors demonstrates why cancer chemotherapy is not effective in solid cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5095. doi:10.1158/1538-7445.AM2014-5095