We previously demonstrated that quiescent
cancer cells in a
tumor are resistant to conventional
chemotherapy as visualized with a fluorescence ubiquitination cell cycle
indicator (FUCCI). We also showed that proliferating
cancer cells exist in a
tumor only near nascent vessels or on the
tumor surface as visualized with FUCCI and
green fluorescent protein (GFP)-expressing
tumor vessels. In the present study, we show the relationship between cell-cycle phase and
chemotherapy-induced
tumor angiogenesis using in vivo FUCCI real-time imaging of the cell cycle and
nestin-driven GFP to detect nascent blood vessels. We observed that
chemotherapy-treated
tumors, consisting of mostly of quiescent
cancer cells
after treatment, had much more and deeper
tumor vessels than untreated
tumors. These newly-vascularized
cancer cells regrew rapidly after
chemotherapy. In contrast, formerly quiescent
cancer cells decoyed to S/G2 phase by a
telomerase-dependent adenovirus did not induce
tumor angiogenesis. The present results further demonstrate the importance of the
cancer-cell position in the cell cycle in order that
chemotherapy be effective and not have the opposite effect of stimulating
tumor angiogenesis and progression.