Abstract
The purpose of this study is to link both numeric and structural chromosomal aberrations to the effectiveness of radiotherapy in chemotherapy refractory tumor cells. Neuroblastoma (LAN-1) and 79HF6 glioblastoma cells derived from patients and their chemoresistant sublines were artificially cultured as neurospheres and irradiated by X-rays and heavy ions sources. All the cell lines were irradiated by Carbon-SIS with LET of 100 keV/μm. However, 79HF6 cells and LAN-1 cells were also irradiated by Carbon-UNILAC with LET of 168 keV/μm and Nickel ions with LET of 174 keV/μm, respectively. The effect of radiation on the survival and proliferation of cells was addressed by standard clonogenic assays. In order to analyze cell karyotype standard Giemsa staining, multicolor fluorescence in situ hybridization (mFISH) and multicolor banding (mBAND) techniques were applied. Relative biological effectiveness values of heavy ion beams relative to X-rays at the D10 values were found between 2.3 and 2.6 with Carbon-SIS and Nickel for LAN-1 and between 2.5 and 3.4 with Carbon-SIS and Carbon-UNILAC for 79HF6 cells. Chemorefractory LAN-1(RETO) cells were found more radioresistant than untreated LAN-1(WT) cells. 79HF6(RETO) glioblastoma cells were found more radiosensitive than cytostatic sensitive cells 79HF6(WT). Sphere formation assay showed that LAN-1(RETO) cells were able to form spheres in serum-free culture, whereas 79HF6 cells could not. Most of 79HF6(WT) cells revealed a number of 71-90 chromosomes, whereas 79HF6(RETO) revealed a number of 52-83 chromosomes. The majority of LAN-1(WT) cells revealed a number of 40-44 chromosomes. mFISH analysis showed some stable aberrations, especially on chromosome 10 as judged by the impossibility to label this region with specific probes. This was corroborated using mBAND analysis. Heavy ion irradiation was more effective than X-ray in both cytostatic naive cancer and chemoresistant cell lines. LAN-1(RETO) chemoresistant neuroblastoma cells were found to be more radioresistant than the cytostatic naive cells (LAN-1(WT)), whereas this effect was not found in 79HF6 cells.
Highlights
There is convincing evidence that many solid and hematological malignancies are organized hierarchically and contain a small population of cancer stem cells (CSCs) that possess the capacity to self-renew and to cause the heterogeneous lineages of cells that form the tumor [1]
Cell Lines and Culture Conditions. Two parental and their subtypes highly chemotherapy refractory cell lines LAN-1WT, LAN-1RETO neuroblastoma and 79HF6WT, 79HF6RETO glioblastoma multiforme derived from human tumors were used in this investigation
To explore how LAN-1 neuroblastoma and glioblastoma 79HF6 cell lines growth, we cultured these cells under optimal conditions for propagation in serum-free neurobasal A medium
Summary
There is convincing evidence that many solid and hematological malignancies are organized hierarchically and contain a small population of cancer stem cells (CSCs) that possess the capacity to self-renew and to cause the heterogeneous lineages of cells that form the tumor [1]. There is growing evidence that CSCs are inherently resistant to radiation and perhaps other conventional anticancer treatments, i.e., chemotherapy [2,3,4] These intrinsic mechanisms of resistance are responsible for a significant number of tumor recurrences [2, 3]. Contemporaneous studies have consistently shown that CSC phenotypes are triggered after chemotherapy courses with an accompanied radioresistance of cancer cells both in vitro and in vivo probably by preferential activation of the DNA damage response [5]. This indicates the urgent necessity for reevaluation of conventional therapies and searching for new ones that focus on CSCs to enhance the efficacy of cancer treatments
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