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

被引：14

作者：

Cortini, Margherita ^{[1
]}

Macchi, Francesca ^{[2
]}

Reggiani, Francesca ^{[3
]}

Vitale, Emanuele ^{[3
,4
]}

Lipreri, Maria Veronica ^{[2
]}

Perut, Francesca ^{[1
]}

Ciarrocchi, Alessia ^{[3
]}

Baldini, Nicola ^{[1
,2
]}

Avnet, Sofia ^{[2
]}

机构：

[1] Ist Ricovero & Cura Carattere Sci, IRCCS Ist Ortoped Rizzoli, Biomed Sci & Technol & Nanobiotechnol Lab, I-40136 Bologna, Italy

[2] Univ Bologna, Dept Biomed & Neuromotor Sci, Alma Mater Studiorum, I-40127 Bologna, Italy

[3] Ist Ricovero & Cura Carattere Sci, Azienda Unita Sanit Locale, Lab Translat Res, IRCCS Reggio Emilia, I-42123 Reggio Emilia, Italy

[4] Univ Modena & Reggio Emilia, Clin & Expt Med PhD Program, I-41125 Modena, Italy

来源：

CANCERS | 2023年 / 15卷 / 04期

关键词：

osteosarcoma; 3D models; extracellular matrix; collagen; spheroids; tumor microenvironment; drug screening; MESENCHYMAL STEM-CELLS; CANINE OSTEOSARCOMA; EXPRESSION; CHEMOTHERAPY; PROMOTES; METASTASIS; ACTIVATION; DEPOSITION; RESISTANCE; MIGRATION;

D O I：

10.3390/cancers15041221

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Simple Summary The pathogenesis of osteosarcoma relies on complex interactions between developing cancer and surrounding tissue, which includes proteins of the extracellular matrix. Mapping ECM-cell interactions and ECM composition is highly important to understand and predict cancer response to chemotherapy and potentially give rise to alternative targets for therapy. Our study aims at generating a 3D model that recapitulates interactions of cancer cells with ECM components and with non-tumor stromal cells and at elucidating the role of ECM deposition in chemotherapy response. Dissecting the contribution of the tumor environment and the role of collagenic and non-collagenic proteins of the ECM will provide additional knowledge for the development of new antitumor strategies. 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.

引用

页数：17