The following is a summary of “Clustering status of detached gastric cancer cells inhibits anoikis-induced ferroptosis to promote metastatic colonization,” published in the February 2024 issue of Oncology by Sun et al.
Ferroptosis, a novel form of regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as a potential player in cancer metastasis. Yet, its specific role in gastric cancer (GC) metastasis remains elusive. In this study, the researchers aimed to shed light on this aspect by employing a multifaceted approach integrating in vitro experimentation and clinical analysis.
Initially, the study group conducted in vitro experiments utilizing various GC cell lines, including AGS, MKN45, and HGC27, to explore the involvement of ferroptosis in both single and clustered cells subjected to extracellular matrix (ECM) detachment. Their findings revealed intriguing insights into the differential response of these cells to detachment-induced stress. While single-detached cells exhibited reduced viability compared to adherent cells, the formation of cell clusters significantly enhanced their survival under matrix-detached conditions. Importantly, the investigators observed distinct molecular alterations associated with ferroptosis in these cellular states. Single detached cells displayed elevated levels of iron-dependent reactive oxygen species (ROS), depletion of glutathione (GSH), increased lipid peroxidation, and upregulation of ferroptosis-associated genes such as ACSL4, TFRC, and HO-1. In contrast, clustered detached cells demonstrated suppression of ferroptosis markers and upregulation of ferroptosis suppressors, notably glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11).
To corroborate their in vitro findings, they performed immunohistochemical staining on tumor tissues obtained from GC patients, focusing on 54 cases with and without lymphatic metastasis. This clinical analysis provided further evidence supporting their in vitro observations, as the study group observed a correlation between lymphatic metastasis and the inhibition of ferroptosis along with the induction of epithelial-mesenchymal transition (EMT) markers. Furthermore, they evaluated the prognostic significance of GPX4 expression in a larger cohort of 178 GC patients using Kaplan-Meier survival analysis. Strikingly, high expression of GPX4 was associated with decreased overall survival, highlighting its potential as a prognostic biomarker in GC.
Overall, the study underscores the importance of ferroptosis inhibition as a mechanism facilitating GC metastasis, with GPX4 emerging as a promising prognostic indicator. These findings offer valuable insights into the interplay between ferroptosis and metastasis in GC and suggest the potential therapeutic relevance of targeting ferroptosis pathways in mitigating metastatic progression.
Source: cancerci.biomedcentral.com/articles/10.1186/s12935-024-03260-1