Colorectal cancer development is affected by the ECM molecule EMILIN-2 hinging on macrophage polarization via the TLR-4/MyD88 pathway

Journal of Experimental & Clinical Cancer Research

Marco Scarpa¹  Emma Di Carlo²  Evelina Poletto³  Paola Spessotto³  Federico Todaro³  Alice Paulitti³  Alfonso Colombatti³  Giulia Tarticchio³  Eva Andreuzzi³  Greta Carobolante³  Albina Fejza³  Maurizio Mongiat³  Lucrezia Camicia³  Alessandra Capuano³  Roberto Doliana³  Renato Cannizzaro⁴  Stefania Maiero⁴  Mara Fornasarig⁴  Maurizio Polano⁵  Vincenzo Canzonieri⁶  Melania Scarpa⁷ 

[1] Clinica Chirurgica I- Azienda Ospedaliera di Padova, Padua, Italy;Department of Medicine and Sciences of Aging, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy;Anatomic Pathology and Immuno-Oncology Unit, Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy;Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy;Division of Oncological Gastroenterology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy;Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy;Pathology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy;Ricerca Traslazionale Avanzata, Istituto Oncologico Veneto IOV – IRCCS, Padua, Italy;

关键词: Extracellular matrix;    Tumor microenvironment;    Colorectal cancer;   

DOI  :  10.1186/s13046-022-02271-y

来源: Springer

【 摘 要 】

BackgroundColorectal cancer is one of the most frequent and deadly tumors. Among the key regulators of CRC growth and progression, the microenvironment has emerged as a crucial player and as a possible route for the development of new therapeutic opportunities. More specifically, the extracellular matrix acts directly on cancer cells and indirectly affecting the behavior of stromal and inflammatory cells, as well as the bioavailability of growth factors. Among the ECM molecules, EMILIN-2 is frequently down-regulated by methylation in CRC and the purpose of this study was to verify the impact of EMILIN-2 loss in CRC development and its possible value as a prognostic biomarker.MethodsThe AOM/DSS CRC protocol was applied to Emilin-2 null and wild type mice. Tumor development was monitored by endoscopy, the molecular analyses performed by IHC, IF and WB and the immune subpopulations characterized by flow cytometry. Ex vivo cultures of monocyte/macrophages from the murine models were used to verify the molecular pathways. Publicly available datasets were exploited to determine the CRC patients’ expression profile; Spearman’s correlation analyses and Cox regression were applied to evaluate the association with the inflammatory response; the clinical outcome was predicted by Kaplan-Meier survival curves. Pearson correlation analyses were also applied to a cohort of patients enrolled in our Institute.ResultsIn preclinical settings, loss of EMILIN-2 associated with an increased number of tumor lesions upon AOM/DSS treatment. In addition, in the early stages of the disease, the Emilin-2 knockout mice displayed a myeloid-derived suppressor cells-rich infiltrate. Instead, in the late stages, lack of EMILIN-2 associated with a decreased number of M1 macrophages, resulting in a higher percentage of the tumor-promoting M2 macrophages. Mechanistically, EMILIN-2 triggered the activation of the Toll-like Receptor 4/MyD88/NF-κB pathway, instrumental for the polarization of macrophages towards the M1 phenotype. Accordingly, dataset and immunofluorescence analyses indicated that low EMILIN-2 expression levels correlated with an increased M2/M1 ratio and with poor CRC patients’ prognosis.ConclusionsThese novel results indicate that EMILIN-2 is a key regulator of the tumor-associated inflammatory environment and may represent a promising prognostic biomarker for CRC patients.

【 授权许可】

CC BY