The phase of the cell cycle can determine whether a
cancer cell can respond to a given drug. We previously reported monitoring of real-time cell cycle dynamics of
cancer cells throughout a live
tumor, intravitally in live mice, using a fluorescence ubiquitination-based cell-cycle
indicator (FUCCI). Approximately 90% of
cancer cells in the center and 80% of total cells of an established
tumor are in G0/G1 phase. 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 cessation of
chemotherapy. These results suggested why most drugs currently in clinical use, which target
cancer cells in S/G2/M, are mostly ineffective on solid
tumors. In the present report, we used FUCCI imaging and Gelfoam®
collagen-sponge-gel histoculture, to demonstrate in real time, that the cell-cycle phase distribution of
cancer cells in Gelfoam® and in vivo
tumors is highly similar, whereby only the surface cells proliferate and interior cells are quiescent in G0/G1. This is in contrast to 2D culture where most
cancer cells cycle. Similarly, the
cancer cells responded similarly to toxic
chemotherapy in Gelfoam® culture as in vivo, and very differently than
cancer cells in 2D culture which were much more chemosensitive. Gelfoam® culture of FUCCI-expressing
cancer cells offers the opportunity to image the cell cycle of
cancer cells continuously and to screen for novel effective
therapies to target quiescent cells, which are the majority in a
tumor and which would have a strong probability to be effective in vivo.