Cell migration in paediatric glioma; characterisation and potential therapeutic targeting

• Published in: British journal of cancer 2015-02, Vol.112 (4), p.693-703
• Main Authors: Cockle, J V, Picton, S, Levesley, J, Ilett, E, Carcaboso, A M, Short, S, Steel, L P, Melcher, A, Lawler, S E, Brüning-Richardson, A
• Format: Article
• Language: English
• Subjects: 631/67/2332; 631/80/84; 692/699/67/1059/602; 692/699/67/1922; Biomedical and Life Sciences; Biomedicine; Brain cancer; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Brain research; Cancer Research; Cancer therapies; Cell adhesion & migration; Cell Line, Tumor; Cell Movement - drug effects; Child; Collagen; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Resistance; Epidemiology; Genotype & phenotype; Glioma - pathology; Glioma - therapy; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Hospitals; Humans; Indoles - pharmacology; Kinases; Lithium; Lithium Chloride - pharmacology; Medical prognosis; Medical research; Molecular Medicine; Molecular Targeted Therapy; Neoplasm Invasiveness; Oncology; Oximes - pharmacology; Pediatrics; Protein Kinase Inhibitors - pharmacology; Spheroids, Cellular - drug effects; Spheroids, Cellular - pathology; Spheroids, Cellular - physiology; Translational Therapeutics; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2015.16

Background: Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are highly aggressive brain tumours. Their invasive phenotype contributes to their limited therapeutic response, and novel treatments that block brain tumour invasion are needed. Methods: Here, we examine the migratory characteristics and treatment effect of small molecule glycogen synthase kinase-3 inhibitors, lithium chloride (LiCl) and the indirubin derivative 6-bromoindirubin-oxime (BIO), previously shown to inhibit the migration of adult glioma cells, on two pHGG cell lines (SF188 and KNS42) and one patient-derived DIPG line (HSJD-DIPG-007) using 2D (transwell membrane, immunofluorescence, live cell imaging) and 3D (migration on nanofibre plates and spheroid invasion in collagen) assays. Results: All lines were migratory, but there were differences in morphology and migration rates. Both LiCl and BIO reduced migration and instigated cytoskeletal rearrangement of stress fibres and focal adhesions when viewed by immunofluorescence. In the presence of drugs, loss of polarity and differences in cellular movement were observed by live cell imaging. Conclusions: Ours is the first study to demonstrate that it is possible to pharmacologically target migration of paediatric glioma in vitro using LiCl and BIO, and we conclude that these agents and their derivatives warrant further preclinical investigation as potential anti-migratory therapeutics for these devastating tumours.