Cell-cycle-dependent drug-resistant quiescent cancer cells induce tumor angiogenesis after chemotherapy as visualized by real-time FUCCI imaging

Abstract

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 cellcycle 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/G 2 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.

Identification of cell cycle dependent methotrexate resistance in placenta site trophoblastic tumors

“…4C]. As previously reported, cell cycle disorder is an important mechanism underlying the increased malignancy of tumor cells (22) , and alterations in the cell cycle have been considered responsible for drug resistance (23) . Therefore, we propose that loss of control of the G1/S transition may explain why PSTT is resistant to MTX in vivo and in vitro compared to MTX-sensitive choriocarcinoma cell lines.…”

“…Defective cell cycle events result in uncontrolled cell proliferation, which is considered as one of the hallmarks of cancer (22) . Oncogenic processes exhibit their greatest effects by targeting G1 phase progression (15) and alternations in cell cycle have also been considered responsible for drug resistance (23) . Many studies have verified that cell cycle disorders are related to MTX-resistant in some solid tumors (36,37) , therefore, we decided to focus our study of MTX-resistance on dysregulated cell cycle.…”

Inhibitory effect of fermented selected barley extracts with Lactobacillus plantarum dy‑1 on the proliferation of human HT‐29 Cells

“…Cell cycle includes G 0 /G1 phase (DNA presynthetic phase), S phase (DNA synthesis phase), and G2/M phase (DNA postsynthetic and mitosis phases) (Yano et al, ). Different from ours, Zhang et al () showed that extracts of fermented wheat germ attenuated the progression in the G0/G1 phase, same with Anduix's (Comín‐Anduix et al, ) finding which revealed that fermented extract of wheat germ halted in the S cycle phase while there was a notable accumulation of the G0/G1 cycle phase.…”

Synthesis, structure-activity relationship and in vitro pharmacodynamics of A-ring modified caged xanthones in a preclinical model of inflammatory breast cancer

“…5; Ki67 column). This impartial cancer cell targeting is clearly advantageous over the effect of various FDAapproved anticancer drugs that mainly target proliferating cells [40,41,73,74] .…”