Mesenchymal Transition of High-Grade Breast Carcinomas Depends on Extracellular Matrix Control of Myeloid Suppressor Cell Activity

Cell Reports

Mariella Parenza¹  Sabina Sangaletti¹  Alessandra Santangelo¹  Paola Portararo¹  Mario P. Colombo¹  Barbara Cappetti¹  Laura Botti¹  Claudia Chiodoni¹  Nadia Castioni¹  Rosaria Orlandi²  Elda Tagliabue²  Claudio Tripodo³  Alessandro Gulino³ 

[1] Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy;Molecular Targets Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy;Tumor Immunology Unit, Human Pathology Section, Department of Health Science, Palermo University School of Medicine, 90129 Palermo, Italy;

关键词: Breast cancer;    epithelial to mesenchymal transition;    EMT;    extracellular matrix;    ECM;    myeloid-derived suppressor cells;    MDSC;    SPARC;    aminobisphosphonates;    cyclooxygenase-2;    COX-2;    granulocyte-macrophage colony-stimulating factor;    GM-CSF;    granulocyte colony-stimulating factor;    G-CSF;    CXCL12;   

DOI  :  10.1016/j.celrep.2016.08.075

来源: DOAJ

【 摘 要 】

The extracellular matrix (ECM) contributes to the biological and clinical heterogeneity of breast cancer, and different prognostic groups can be identified according to specific ECM signatures. In high-grade, but not low-grade, tumors, an ECM signature characterized by high SPARC expression (ECM3) identifies tumors with increased epithelial-to-mesenchymal transition (EMT), reduced treatment response, and poor prognosis. To better understand how this ECM3 signature is contributing to tumorigenesis, we expressed SPARC in isogenic cell lines and found that SPARC overexpression in tumor cells reduces their growth rate and induces EMT. SPARC expression also results in the formation of a highly immunosuppressive microenvironment, composed by infiltrating T regulatory cells, mast cells, and myeloid-derived suppressor cells (MDSCs). The ability of SPARC to induce EMT depended on the localization and suppressive function of myeloid cells, and inhibition of the suppressive function MDSCs by administration of aminobisphosphonates could revert EMT, rendering SPARC-overexpressing tumor cells sensitive to Doxil. We conclude that that SPARC is regulating the interplay between MDSCs and the ECM to drive the induction of EMT in tumor cells.

【 授权许可】

Unknown