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Cell Cycle. 2014;13(13):2110-9. doi: 10.4161/cc.29156. Epub 2014 May 8.

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

Author information

1
AntiCancer, Inc; San Diego, CA USA; Department of Surgery; University of California, San Diego; La Jolla, CA USA; Department of Gastroenterological Surgery; Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences; Okayama, Japan.
2
AntiCancer, Inc; San Diego, CA USA.
3
AntiCancer, Inc; San Diego, CA USA; Department of Surgery; University of California, San Diego; La Jolla, CA USA.
4
Department of Gastroenterological Surgery; Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences; Okayama, Japan.
5
Center for Innovative Clinical Medicine; Okayama University Hospital; Okayama, Japan.
6
Department of Surgery; University of California, San Diego; La Jolla, CA USA.

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/G₁ phase. Similarly, approximately 75% of cancer cells far from (> 100 µm) tumor blood vessels of an established tumor are in G₀/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/G₂/M, are mostly ineffective on solid tumors. The results also suggest that drugs that target quiescent cancer cells are urgently needed.

KEYWORDS:

FUCCI; cell cycle; confocal laser microscopy; dormancy; drug resistance; fluorescent proteins; tumor; tumor blood vessels

PMID:
24811200
PMCID:
PMC4111702
DOI:
10.4161/cc.29156
[Indexed for MEDLINE]
Free PMC Article

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