Cancer stem cell (CSC) self-renewing and drug resistance cause treatment failure and
tumor recurrence.
Osteosarcoma is an aggressive bone
tumor characterized by biological and molecular heterogeneity, possibly dependent on CSCs. CSC identification in
osteosarcoma and their efficient targeting are still open questions. Spontaneous canine
osteosarcoma shares clinical and biological features with the human
tumors, representing a model for translational studies. We characterized three CSC-enriched canine
osteosarcoma cultures. In serum-free conditions, these CSC cultures grow as anchorage-independent spheroids, show mesenchymal-like properties and in vivo tumorigenicity, recapitulating the heterogeneity of the original
osteosarcoma.
Osteosarcoma CSCs express stem-related factors (Sox2, Oct4, CD133) and
chemokine receptors and
ligands (CXCR4, CXCL12) involved in
tumor proliferation and self-renewal. Standard drugs for
osteosarcoma treatment (
doxorubicin and
cisplatin) affected CSC-enriched and parental primary cultures, showing different efficacy within
tumors. Moreover,
metformin, a type-2 diabetes drug, significantly inhibits
osteosarcoma CSC viability, migration and self-renewal and, in co-treatment with
doxorubicin and
cisplatin, enhances drug cytotoxicity. Collectively, we demonstrate that canine
osteosarcoma primary cultures contain CSCs exhibiting distinctive sensitivity to
anticancer agents, as a reliable experimental model to assay drug efficacy. We also provide proof-of-principle of
metformin efficacy, alone or in combination, as pharmacological strategy to target
osteosarcoma CSCs.