Slow degrading Mg-based materials induce tumor cell dormancy on an osteosarcoma-fibroblast coculture model
Philipp Globig1, Regine Willumeit-Römer1, Fernanda Martini2
1Institute of Metallic Biomaterials, Helmholtz-Zentrum Hereon, 21502, Geesthacht, Germany.
Abstract:
Osteosarcoma is one of the most common cancers in young adults and is commonly treated using surgery and chemotherapy. During the past years, these therapy approaches improved but failed to ameliorate the outcomes. Therefore, novel, targeted therapeutic approaches should be established to enhance treatment success while preserving patient's quality of life. Recent studies suggest the application of degradable magnesium (Mg) alloys as orthopedic implants bearing a potential antitumor activity. Here, we examined the influence of Mg-based materials on an osteosarcoma-fibroblast coculture. Both, Mg and Mg-6Ag did not lead to tumor cell apoptosis at low degradation rates. Instead, the Mg-based materials induced cellular dormancy in the cancer cells indicated by a lower number of Ki-67 positive cancer cells and a higher p38 expression. This dormancy-like state could be reversed by reseeding on non-degrading glass slides but could not be provoked by inhibition of the protein kinase R-like endoplasmic reticulum kinase. By investigating the influence of the disjunct surface-near effects of the Mg degradation on cell proliferation, an increased pH was found to be a main initiator of Mg degradation-dependent tumor cell proliferation inhibition.
Insights
Degradable magnesium alloys show potential against osteosarcoma by inducing cancer cell dormancy, not apoptosis. Increased pH from magnesium degradation inhibits tumor cell proliferation, offering a novel therapeutic avenue.
Area of Science:
- Biomaterials Science
- Oncology
- Orthopedic Surgery
Background:
- Osteosarcoma treatment relies on surgery and chemotherapy, with limited success in improving patient outcomes.
- Novel therapeutic strategies are needed to enhance osteosarcoma treatment efficacy and patient quality of life.
- Degradable magnesium (Mg) alloys are being explored for orthopedic implants with potential antitumor properties.
Purpose of the Study:
- To investigate the impact of Mg-based materials on osteosarcoma-fibroblast co-cultures.
- To understand the mechanisms behind Mg-induced effects on cancer cell behavior.
- To evaluate the potential of Mg alloys as a targeted therapy for osteosarcoma.
Main Methods:
- Co-culturing osteosarcoma cells with fibroblasts in the presence of Mg and Mg-6Ag alloys.
- Assessing cancer cell apoptosis, proliferation (Ki-67), and protein expression (p38).
- Investigating the role of pH and endoplasmic reticulum kinase pathways in Mg-mediated effects.
Main Results:
- Mg and Mg-6Ag alloys did not induce apoptosis in osteosarcoma cells at low degradation rates.
- Mg-based materials induced a dormancy-like state in cancer cells, marked by reduced Ki-67 and increased p38 expression.
- Increased pH due to Mg degradation was identified as a key factor inhibiting tumor cell proliferation.
Conclusions:
- Mg-based materials can induce a reversible dormancy in osteosarcoma cells, distinct from apoptosis.
- The anti-proliferative effect of Mg alloys is primarily mediated by pH changes resulting from material degradation.
- Mg alloys present a promising avenue for developing targeted therapies against osteosarcoma, potentially improving treatment outcomes.
