Mass spectrometry-based proteomics to study gastric cancer progression: pathophysiological molecular characterization and identification of potential biomarkers

Aims Gastric cancer (GC) remains a major global health disease, ranking fifth among the most common malignancies and as a cause of cancer death. The disease progresses through a multi-stage carcinogenic process known as the Correa cascade, in which the gastric mucosa develops into gastric adenocarcinoma. Most existing research predominantly focuses on established GC. This study aims to advance the understanding of the molecular alterations underlying disease progression by shedding light on the transitional stages of the disease.

Methods Exploratory study carried out within the EpiGASTRIC/EDGAR project, a collaborative multicenter study of 28 centers with more than 1,500 patients recruited. This study used a DIA-MS-based proteomic approach to investigate the proteomic landscape of gastric tissue (GT) samples. Seventy-one human GT lesioned and non-lesioned samples from patients were used for proteomic analysis (10 controls, 10 chronic gastritis, 7 intestinal metaplasia+low-grade dysplasia, 10 early gastric cancer, 9 established GC). Functional pathways were carried out using QIAGEN’s Ingenuity Pathway Analysis and Metascape. These analyses allowed us to compare differentially expressed proteins (DEPs) across the different GC stages and to identify proteins as potential biomarker candidates.

Results The analysis of 3,272 proteins quantified in the experimental groups revealed stage-specific proteomic changes in pathological and non-pathological GT. Vesicle-mediated transport and neutrophil degranulation were consistently altered in lesional and non-lesional tissues, while pathways like hemostasis and complex IV assembly expressed lesion-specific disruption. The study identified thousands of DEPs across distinct GC stages, with a balance between up- and downregulated proteins. Early stages, particularly those involving inflammation and tissue repair, showed heightened protein levels, reflecting active cellular responses. While many DEPs were unique to specific stages, some were consistently modulated across all, implicating their role in GC progression. Notably, very few DEPs were shared between lesional and non-lesional tissues, emphasizing the distinct molecular environments of these areas. Neutrophil degranulation was the only shared pathway between them, suggesting a unifying immune-related mechanism across tissue types. Functional analysis also revealed key molecular disruptions associated with intermediated stages. Among these findings, ten proteins were identified as potentially stage-specific biomarkers. Ongoing validation of these proteins aims to confirm their diagnostic and therapeutic significance.

Conclusions This study highlights the potential of proteomics to uncover novel knowledge of GC progression. Key findings include stage-specific DEPs and shared molecular mechanisms in lesional and non-lesional tissues, emphasizing their relevance in early detection and therapeutic targeting. Additionally, the research highlights unique and overlapping molecular changes across disease stages, enabling the identification of biomarkers to monitor progression. These findings pave the way for advancement in the management of GC.

Publication History

Article published online:
27 March 2025