Abstract
Osteosarcoma, the most common bone malignancy with a peak incidence at adolescence, had no survival improvement since decades. Persistent problems are chemo-resistance and metastatic spread. We developed in-vitro osteosarcoma models resistant to chemotherapy and in-vivo bioluminescent orthotopic cell-derived-xenografts (CDX). Continuous increasing drug concentration cultures in-vitro resulted in five methotrexate (MTX)-resistant and one doxorubicin (DOXO)-resistant cell lines. Resistance persisted after drug removal except for MG-63. Different resistance mechanisms were identified, affecting drug transport and action mechanisms specific to methotrexate (RFC/SCL19A1 decrease, DHFR up-regulation) for MTX-resistant lines, or a multi-drug phenomenon (PgP up-regulation) for HOS-R/DOXO. Differential analysis of copy number abnormalities (aCGH) and gene expression (RNAseq) revealed changes of several chromosomic regions translated at transcriptomic level depending on drug and cell line, as well as different pathways implicated in invasive and metastatic potential (e.g., Fas, Metalloproteinases) and immunity (enrichment in HLA cluster genes in 6p21.3) in HOS-R/DOXO. Resistant-CDX models (HOS-R/MTX, HOS-R/DOXO and Saos-2-B-R/MTX) injected intratibially into NSG mice behaved as their parental counterpart at primary tumor site; however, they exhibited a slower growth rate and lower metastatic spread, although they retained resistance and CGH main characteristics without drug pressure. These models represent valuable tools to explore resistance mechanisms and new therapies in osteosarcoma.
Highlights
Osteosarcoma is the first primary malignant bone tumor that predominantly occurs during adolescence [1,2]
In order to establish resistant cell lines, a panel of six osteosarcoma cell lines was exposed to increasing concentrations of methotrexate (MTX) or doxorubicin (DOXO)
Parental and resistant lines were assessed for their response to chemotherapy in terms of cell viability, migration ability, and resistance index
Summary
Osteosarcoma is the first primary malignant bone tumor that predominantly occurs during adolescence [1,2]. Standard treatment combines neoadjuvant and post-operative chemotherapy with complete surgery of all primary and metastatic sites. Treatment failure is usually due to metastatic relapse. The presence of metastases at diagnosis and poor histological response to neoadjuvant chemotherapy are risk factors of relapse [1,3,4,5]. Resistance to therapy, both intrinsic (phenomenon present prior to chemotherapy administration) and acquired (revealed after chemotherapy administration) contributes to treatment failure and recurrence. The link between resistance to chemotherapy and metastatic phenotype remains unclear
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