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Mesenchymal Cancer Stem Cells: Role in tumour development and radiotherapy resistance

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We have access to a highly useful sarcoma model consisting of immortalized mesenchymal stem cells and several sub clones. These will strengthen the research in both the basal and the translational areas of cancer research and likely give results with prognostics value, as well as insight into tumour evolution. A healthy population of mesenchymal stem cells was immortalized by retroviral insertion of human telomerase subunit TERT and after several population doublings the cell line (hMSC-TERT20) became tumourigenic. Xenografts of hMSC-TERT20 and its sub cell lines (BB3, BC8, BD6, BD11, CE8 and DB9) all showed different latency times and different morphology, even though all had the same common origin (Burns 2005).

All clones but one were as tumourigenic as the origin; only 3 out of 10 mice with BC8 cells injected had tumours, all with very long latency time (Burns 2005 and own data). Using an in-vitro radiosensitivity assay, based on Survival Fraction at 2Gy (SF2), we found CE8 to be significantly different from the 5 other clones (p<0.1 for all 5 t-tests, n=12) and least radiosensitive (SF2 0.40±0.01). BB3 and BC8 were nearly equal and the most radiosensitive (SF2 0.26±0.03 and 0.23±0.02). Hypoxia measurement (Eppendorf pO2 probe) divided the cell lines into 3 groups of oxygenation levels (n=5 in all groups, except BD6 where n=4). Relative high for BC8 and BD6 (median of 5.5mmHg; fraction with 0≤5mmHg 52%), intermediate for BB3 and DB9 (4mmHg; 60%), and low for BD11 and CE8 (1.5mmHg; 75%). Preliminary data on in-vivo radiation sensitivity, based on a tumour growth-time assay after 10Gy irradiation, indicates different radiation responses; BD6 being significantly different from BD11 (p<0.005) and different from CE8 (p<0.2) (n=4 in all groups).

Access to both a pre-tumourigenic and a tumourigenic version of the same cell line, as well as sub clones, makes comparable studies at various levels feasible. Both studies of tumourigenic evolution and radiation therapy are possible due to the model's strength as a CSC family of differentiated clones. Comparing the in-vivo and in-vitro data, could separate the intrinsic and the microenvironmental effects on tumour radiosensitivity.
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Document Type: Abstract

Affiliations: Afd. for Eksperimentel Klinisk Onkologi, Aarhus Universitetshospital, Århus Sygehus, Nørrebrogade 44, bygn. 5, 8000 Århus C

Publication date: May 1, 2008

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