FUCCI Real-Time Cell-Cycle Imaging as a Guide for Designing Improved Cancer Therapy: A Review of Innovative Strategies to Target Quiescent Chemo-Resistant Cancer Cells

Abstract

Progress in chemotherapy of solid cancer has been tragically slow due, in large part, to the chemoresistance of quiescent cancer cells in tumors. The fluorescence ubiquitination cell-cycle indicator (FUCCI) was developed in 2008 by Miyawaki et al., which color-codes the phases of the cell cycle in real-time. FUCCI utilizes genes linked to different color fluorescent reporters that are only expressed in specific phases of the cell cycle and can, thereby, image the phases of the cell cycle in real-time. Intravital real-time FUCCI imaging within tumors has demonstrated that an established tumor comprises a majority of quiescent cancer cells and a minor population of cycling cancer cells located at the tumor surface or in proximity to tumor blood vessels. In contrast to most cycling cancer cells, quiescent cancer cells are resistant to cytotoxic chemotherapy, most of which target cells in S/G2/M phases. The quiescent cancer cells can re-enter the cell cycle after surviving treatment, which suggests the reason why most cytotoxic chemotherapy is often ineffective for solid cancers. Thus, quiescent cancer cells are a major impediment to effective cancer therapy. FUCCI imaging can be used to effectively target quiescent cancer cells within tumors. For example, we review how FUCCI imaging can help to identify cell-cycle-specific therapeutics that comprise decoy of quiescent cancer cells from G1 phase to cycling phases, trapping the cancer cells in S/G2 phase where cancer cells are mostly sensitive to cytotoxic chemotherapy and eradicating the cancer cells with cytotoxic chemotherapy most active against S/G2 phase cells. FUCCI can readily image cell-cycle dynamics at the single cell level in real-time in vitro and in vivo. Therefore, visualizing cell cycle dynamics within tumors with FUCCI can provide a guide for many strategies to improve cell-cycle targeting therapy for solid cancers.

Osmotic pressure modulates single cell cycle dynamics inducing reversible growth arrest and reactivation of human metastatic cells

“…Quantitative and real-time tracking of the cell cycle dynamics is possible using the fluorescent ubiquitination-based cell cycle indicator 2 (FUCCI2). This tool developed by Miyawaki et al 22 , 23 , depicts with fluorescence the different phases of the cell cycle in real-time and is increasingly used to detect non-dividing cells in the context of cancer therapies 24 .…”

Real-Time Fluorescence Image-Guided Oncolytic Virotherapy for Precise Cancer Treatment

“…FUCCI in vivo tumor imaging also demonstrated that conventional cytotoxic chemotherapy killed only proliferating cancer cells, and quiescent cancer cells were resistant to currently-used cytotoxic chemotherapy and restarted proliferation after cessation of chemotherapy [ 44 , 45 ]. This is one of the reasons why currently-used chemotherapy has limited efficacy against solid cancers [ 46 , 47 ]. OBP-301 was shown to decoy quiescent cancer cells within tumors to cycle with the decoyed tumors becoming sensitive to chemotherapy [ 40 ].…”

“…The above results showed that an oncolytic adenovirus can decoy quiescent cancer stem and non-stem cells, sensitize them to conventional chemotherapy, whereby they are killed by oncolysis and chemotherapy. FUCCI cell-cycle imaging guides the precise timing for chemotherapy to be administered to effectively eradicate the decoyed cancer cells [ 46 , 47 ] ( Figure 2 B).…”

Bioinformatics prediction of differential miRNAs in non-small cell lung cancer

“…RNA polymerase II is related to the cell cycle. Most of the cell cycle of cancer cells is static, and a few are dynamic [26,27]. Static cancer cells are the main obstacle to the treatment of cancer [28].…”