Chemotherapy induces stemness in osteosarcoma cells through activation of Wnt/β-catenin signaling

Area of Science:

• Oncology
• Cancer Biology
• Stem Cell Research

Background:

• Drug resistance is a significant challenge in osteosarcoma treatment, often linked to cancer stem-like cells.
• Non-stem cells can acquire stemness under specific microenvironmental conditions, enhancing stress tolerance.

Purpose of the Study:

• To investigate if conventional chemotherapeutics induce a stem-like phenotype in osteosarcoma cells.
• To explore the underlying molecular mechanisms and therapeutic strategies to overcome this induced resistance.

Main Methods:

• Utilized osteosarcoma cell lines and a mouse xenograft model.
• Analyzed phenotypic cell transitions, Wnt/β-catenin signaling, pluripotency factors, and detoxification systems.
• Assessed the efficacy of combining doxorubicin with Wnt/β-catenin inhibition.
• Correlated stemness marker expression with chemotherapy response using public microarray data.

Main Results:

• Exposure to chemotherapeutics induced a stem-like cell phenotype in osteosarcoma.
• This transition was associated with Wnt/β-catenin activation, pluripotency factor upregulation, and enhanced detoxification.
• Combined doxorubicin and Wnt/β-catenin inhibition prevented stem-like state transition and factors linked to it.
• Public data analysis confirmed a correlation between stemness markers and poor chemotherapy response in osteosarcoma patients.

Conclusions:

• Conventional chemotherapy can induce an adaptive, stem-like phenotype in osteosarcoma, contributing to treatment failure.
• Inhibition of Wnt/β-catenin signaling presents a potential strategy to overcome chemotherapy-induced adaptive resistance in osteosarcoma.