Spatial-temporal FUCCI imaging of each cell in a tumor demonstrates locational dependence of cell cycle dynamics and chemoresponsiveness

Shuuya Yano, Yong Zhang, Shinji Miwa, Yasunori Tome, Yukihiko Hiroshima, Fuminari Uehara, Mako Yamamoto, Atsushi Suetsugu, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. We report here on the results of monitoring of real-time cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI) before, during, and after chemotherapy. 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, approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G0/G 1 phase. Similarly, approximately 75% of cancer cells far from (>100 ìm) tumor blood vessels of an established tumor are in G 0/G1. Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, had little effect on quiescent cancer cells, which are the vast majority of an established tumor. Moreover, resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Our results suggest why most drugs currently in clinical use, which target cancer cells in S/G 2/M, are mostly ineffective on solid tumors. The results also suggest that drugs that target quiescent cancer cells are urgently needed.

Original languageEnglish
Pages (from-to)2110-2119
Number of pages10
JournalCell Cycle
Volume13
Issue number13
DOIs
Publication statusPublished - Jul 1 2014

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Keywords

  • Cell cycle
  • Confocal laser microscopy
  • Dormancy
  • Drug resistance
  • Fluorescent proteins
  • FUCCI
  • Tumor
  • Tumor blood vessels

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology
  • Medicine(all)

Cite this

Yano, S., Zhang, Y., Miwa, S., Tome, Y., Hiroshima, Y., Uehara, F., Yamamoto, M., Suetsugu, A., Kishimoto, H., Tazawa, H., Zhao, M., Bouvet, M., Fujiwara, T., & Hoffman, R. M. (2014). Spatial-temporal FUCCI imaging of each cell in a tumor demonstrates locational dependence of cell cycle dynamics and chemoresponsiveness. Cell Cycle, 13(13), 2110-2119. https://doi.org/10.4161/cc.29156