Development of 3D culture models of plexiform neurofibroma and initial application for phenotypic characterization and drug screening
| Autor: | Janice M. Kraniak, Margaret R. Wallace, Raymond R. Mattingly, Anita Chalasani |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Neurofibromatosis 1 Cell Culture Techniques MAP Kinase Kinase 1 Bone Morphogenetic Protein 2 Antineoplastic Agents Biology Article Receptor IGF Type 1 03 medical and health sciences Developmental Neuroscience In vivo Genes Reporter Transduction Genetic Genes Neurofibromatosis 1 medicine Tumor Cells Cultured Neurofibroma Humans Molecular Targeted Therapy Protein Kinase Inhibitors Cells Cultured Podophyllotoxin Neurofibroma Plexiform Dose-Response Relationship Drug Cell growth MEK inhibitor medicine.disease Luminescent Proteins 030104 developmental biology Phenotype Pyrimidines Neurology Cell culture Drug Resistance Neoplasm Cancer research Selumetinib Picropodophyllin Pyrazoles Benzimidazoles Schwann Cells Drug Screening Assays Antitumor Immortalised cell line |
| Popis: | Plexiform neurofibromas (PNs), which may be present at birth in up to half of children with type 1 neurofibromatosis (NF1), can cause serious loss of function, such as quadriparesis, and can undergo malignant transformation. Surgery is the first line treatment although the invasive nature of these tumors often prevents complete resection. Recent clinical trials have shown promising success for some drugs, notably selumetinib, an inhibitor of MAP kinase kinase (MEK). We have developed three-dimensional (3D) cell culture models of immortalized cells from NF1 PNs and of control Schwann cells (SCs) that we believe mimic more closely the in vivo condition than conventional two-dimensional (2D) cell culture. Our goal is to facilitate pre-clinical identification of potential targeted therapeutics for these tumors. Three drugs, selumetinib (a MEK inhibitor), picropodophyllin (an IGF-1R inhibitor) and LDN-193189 (a BMP2 inhibitor) were tested with dose-response design in both 2D and 3D cultures for their abilities to block net cell growth. Cell lines grown in 3D conditions showed varying degrees of resistance to the inhibitory actions of all three drugs. For example, control SCs became resistant to growth inhibition by selumetinib in 3D culture. LDN-193189 was the most effective drug in 3D cultures, with only slightly reduced potency compared to the 2D cultures. Characterization of these models also demonstrated increased proteolysis of collagen IV in the matrix by the PN driver cells as compared to wild-type SCs. The proteolytic capacity of the PN cells in the model may be a clinically significant property that can be used for testing the ability of drugs to inhibit their invasive phenotype. |
| Databáze: | OpenAIRE |
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