Abstract
In this study chemotherapy response in neuroblastoma (NB) was assessed for the first time in a transplantation model comprising non-malignant human embryonic microenvironment of pluripotent stem cell teratoma (PSCT) derived from diploid bona fide hESC. Two NB cell lines with known high-risk phenotypes; the multi-resistant BE(2)-C and the drug sensitive IMR-32, were transplanted to the PSCT model and the tumour growth was exposed to single or repeated treatments with doxorubicin, and thereafter evaluated for cell death, apoptosis, and proliferation. Dose dependent cytotoxic effects were observed, this way corroborating the experimental platform for this type of analysis. Notably, analysis of doxorubicin-resilient BE(2)-C growth in the PSCT model revealed an unexpected 1,5-fold increase in Ki67-index (p<0.05), indicating that non-cycling (G0) cells entered the cell cycle following the doxorubicin exposure. Support for this notion was obtained also in vitro. A pharmacologically relevant dose (1μM) resulted in a marked accumulation of Ki67 positive BE(2)-C cells (p<0.0001), as well as a >3-fold increase in active cell cycle (i.e. cells positive staining for PH3 together with incorporation of EdU) (p<0.01). Considering the clinical challenge for treating high-risk NB, the discovery of a therapy-provoked growth-stimulating effect in the multi-resistant and p53-mutated BE(2)-C cell line, but not in the drug-sensitive p53wt IMR-32 cell line, warrants further studies concerning generality and clinical significance of this new observation.
Highlights
Childhood cancers show fundamental differences to most common adult solid tumours in their cancer-causing genetics, cell biology, and importantly their local tissue microenvironment [1]
Besides mitotic catastrophe we were interested in investigating early apoptosis
Positive staining for c-casp3 was used as an indication of early apoptosis
Summary
Childhood cancers show fundamental differences to most common adult solid tumours in their cancer-causing genetics, cell biology, and importantly their local tissue microenvironment [1]. Neuroblastoma (NB) is the most common extracranial solid tumour during infancy, half of which are clinically manifested before the age of 18 months [2]. Evidence for early stage microscopic tumour-like NB lacking metastasis in young infants supports. Response to doxorubicin in high-risk neuroblastoma design, data collection and analysis, decision to publish, or preparation of the manuscript
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call