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Updated: Aug 9, 2025
Three-Dimensional Bone Extracellular Matrix Model for Osteosarcoma
Published on: April 12, 2019
Endogenous Extracellular Matrix Regulates the Response of Osteosarcoma 3D Spheroids to Doxorubicin
Margherita Cortini1, Francesca Macchi2, Francesca Reggiani3
1Biomedical Science and Technology and Nanobiotechnology Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.
Abstract:
The extracellular matrix (ECM) modulates cell behavior, shape, and viability as well as mechanical properties. In recent years, ECM disregulation and aberrant remodeling has gained considerable attention in cancer targeting and prevention since it may stimulate tumorigenesis and metastasis. Here, we developed an in vitro model that aims at mimicking the in vivo tumor microenvironment by recapitulating the interactions between osteosarcoma (OS) cells and ECM with respect to cancer progression. We long-term cultured 3D OS spheroids made of metastatic or non-metastatic OS cells mixed with mesenchymal stromal cells (MSCs); confirmed the deposition of ECM proteins such as Type I collagen, Type III collagen, and fibronectin by the stromal component at the interface between tumor cells and MSCs; and found that ECM secretion is inhibited by a neutralizing anti-IL-6 antibody, suggesting a new role of this cytokine in OS ECM deposition. Most importantly, we showed that the cytotoxic effect of doxorubicin is reduced by the presence of Type I collagen. We thus conclude that ECM protein deposition is crucial for modelling and studying drug response. Our results also suggest that targeting ECM proteins might improve the outcome of a subset of chemoresistant tumors.
Insights
Extracellular matrix (ECM) deposition in osteosarcoma (OS) influences drug response. Targeting ECM proteins may improve outcomes for chemoresistant tumors.
Area of Science:
- Biomedical Engineering
- Cancer Biology
- Extracellular Matrix Research
Background:
- Extracellular matrix (ECM) dysregulation is implicated in cancer progression, including tumorigenesis and metastasis.
- Understanding the tumor microenvironment is crucial for developing effective cancer therapies.
- Osteosarcoma (OS) is a primary bone cancer with significant metastatic potential.
Purpose of the Study:
- To develop an in vitro model mimicking the in vivo tumor microenvironment for osteosarcoma.
- To investigate the role of ECM deposition in OS progression and drug response.
- To explore potential therapeutic strategies targeting the ECM in osteosarcoma.
Main Methods:
- Long-term culture of 3D osteosarcoma spheroids co-cultured with mesenchymal stromal cells (MSCs).
- Confirmation of ECM protein deposition (Type I collagen, Type III collagen, fibronectin) using immunofluorescence.
- Assessment of doxorubicin's cytotoxic effect in the presence and absence of ECM components.
- Investigation of the effect of anti-IL-6 antibody on ECM secretion.
Main Results:
- The in vitro model successfully recapitulated tumor-ECM interactions relevant to cancer progression.
- Mesenchymal stromal cells deposited key ECM proteins at the tumor-stromal interface.
- ECM secretion was found to be inhibited by a neutralizing anti-IL-6 antibody.
- Type I collagen in the ECM significantly reduced the cytotoxic effect of doxorubicin.
- ECM protein deposition is critical for modeling and studying drug response in osteosarcoma.
Conclusions:
- ECM protein deposition plays a crucial role in modulating drug response in osteosarcoma.
- Targeting ECM proteins presents a potential therapeutic strategy to overcome chemoresistance in a subset of osteosarcoma patients.
- Interleukin-6 (IL-6) signaling may regulate ECM deposition in the osteosarcoma microenvironment.
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