Radiation-induced Cancer Cell Repopulation: A Possible Mechanism Implied by Experiments Using Transplantable Mouse-derived Sarcoma Cell Line

Abstract

ABSTRACT. Purpose: Treatment with any cytotoxic agent can trigger surviving cells in a tumor to divide faster than before. This phenomenon is widely recognized as "repopulation". To better clarify the mechanism, gene expression profiling and pathological experiments were performed. Materials and Methods: A mouse fibrosarcoma cell line, QRsP, was used. Cells were irradiated with 10 Gy. Colony assay and cloning were performed. Six clones were established. cDNA analysis was performed on the clone that showed the largest number of colonies on the 2nd 10 Gy irradiation. Mouse transplantation experiment was then carried out. Results: cDNA analysis showed that cyclin-dependent kinase inhibitors, p16 and p57 were down-regulated; 14.8-and 12.0-fold, respectively for the tolerant clone. Matrix metalloproteinase 3 and 13 were up-regulated; 22.5-and 25.8-fold, respectively. Transplantation ratio was 100% (5/5) for the tolerant clone whereas it was 40% (2/5) for the parent. Under light microscope, the mean mitotic cell number was 4.0+/-3.9 for the parent, and 12.8+/-3.4 for the tolerant clone (p<0.01, Student's t-test). Conclusions: This study implies that repopulation is not a temporary reaction to irradiation. It is caused probably by "clonal" gene-expression changes, though it remains unknown whether the changes are attributable to tolerant cell selection or to gene mutation/modification.

Activating transcription factor 5 enhances radioresistance and malignancy in cancer cells

“…Cancer cells that survive after irradiation acquire malignant phenotypes [2–5]. We previously reported that P cells that survive after irradiation (IR cells) are more invasive than non-irradiated P cells [6–8].…”

“…However, some cancer cells survive after irradiation and repopulate tumors with highly malignant phenotypes, such as high proliferative ability and invasiveness, which correlate with poor prognosis [2–5]. As shown in our previous studies, lung cancer cells that survive irradiation acquire invasive ability that is dependent on cell-matrix adhesion regulated by integrin β1, cellular contractile force modulated by myosin regulatory light chain (MRLC), and molecular signaling mediated by epidermal growth factor receptor and other molecules [6–8].…”

Sonic Hedgehog Signaling Pathway Supports Cancer Cell Growth during Cancer Radiotherapy

“…Tumor cell repopulation is a key process causing tumor relapse during cancer chemotherapy or radiotherapy [13]. Repopulation of surviving tumor cells can occur between dose fractions of either radiation or chemotherapy and can lead to treatment failure [14].…”

Lysyl Oxidase: From Basic Science to Future Cancer Treatment

“…Tumor necrosis Factor-α (TNF-α) also stimulates LOX expression (Voloshenyuk et al, 2011b). It is interesting that our irradiation-surviving cells expressed higher IL6-(36.0-fold) and LOX-mRNA (4.8-fold) compared to un-irradiated parental cells in vitro (Nishioka et al, 2011). IL6 might have an influence on LOX expression.…”