Endogenous Extracellular Matrix Regulates the Response of Osteosarcoma 3D Spheroids to Doxorubicin

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...

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Bibliographic Details
Published in:Cancers 2023-02, Vol.15 (4), p.1221
Main Authors: Cortini, Margherita, Macchi, Francesca, Reggiani, Francesca, Vitale, Emanuele, Lipreri, Maria Veronica, Perut, Francesca, Ciarrocchi, Alessia, Baldini, Nicola, Avnet, Sofia
Format: Article
Language:English
Subjects:
Antibodies
Antitumor agents
Biological control systems
Bone cancer
Cancer
Cancer therapies
Cell culture
Cell growth
Cell interactions
Chemotherapy
Collagen
Collagen (type I)
Collagen (type III)
Cytotoxicity
Dosage and administration
Doxorubicin
Extracellular matrix
Fibronectin
Health aspects
Interleukin 6
Mechanical properties
Mesenchyme
Metastases
Metastasis
Osteosarcoma
Patient outcomes
Peptide mapping
Proteins
Spheroids
Stromal cells
Tumor cells
Tumor microenvironment
Tumorigenesis
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Summary: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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers15041221