What is the Impact of Endothelial-to-Mesenchymal Transition in Solid Tumours: A Qualitative Systematic Review and Quantitative Meta-Analysis.

Abstract

Endothelial-to-mesenchymal transition (EndMT) has gained increasing recognition as a crucial mechanism in the progression of solid cancers, influencing tumour heterogeneity, metastasis, and resistance to therapy. However, despite its growing importance, EndMT remains insufficiently studied within the cancer research landscape. In this study, we conduct a systematic review, adhered to the 2020 PRISMA guidelines, of the existing literature on EndMT in solid tumours, examining its functional roles, key biomarkers, underlying mechanisms, experimental models, and potential as a target for therapeutic intervention. Our objective was to identify critical areas where further research is needed. In addition, we performed a meta-analysis to evaluate the variability in the expression of EndMT-related markers and their potential links to patient prognosis. To this aim, literature searches were conducted in major databases including PubMed, Scopus, and Web of Science, covering studies published up to June 2024. The risk of bias of selected articles was evaluated using the OHAT tool, for the in vitro experiments and the SYRCLE tool for studies using animal models. Out of an initial pool of 1,197 articles, 54 studies were selected for data extraction by two independent reviewers. Selected studies were identified according to specific inclusion/exclusion criteria applied through distinct stages like "title and abstract screening", "full text article review" and "article bibliography screening". Our analysis confirms that EndMT is a key contributor to tumour progression and metastasis, but several aspects remain poorly understood, particularly regarding the induction of EndMT in specific cancer types, its role in lymphatic endothelial cells, and its interactions with other stromal elements. We observed substantial heterogeneity in the biomarkers associated with EndMT, as well as variations in the endothelial cell types studied, the functional outcomes, and the molecular mechanisms involved. Our meta-analysis revealed significant variability in the expression of EndMT biomarkers, with notable correlations between changes in the expression of specific genes and patient outcomes, particularly in lung cancer. In conclusion, it is essential for future research to focus on identifying the specific cancer and stromal cell types implicated in EndMT and to standardize endothelial cell models and protocols used for inducing EndMT. Investigating EndMT alongside well-established processes, such as epithelial-to-mesenchymal transition (EMT), and exploring its relationship with cancer-associated fibroblasts (CAFs) may provide valuable insights into its role in tumour biology and its impact on therapy resistance.