Investigating the mechanisms of peritoneal metastasis in gastric adenocarcinoma using a novel ex vivo peritoneal explant model

Abstract

Gastric adenocarcinoma, commonly known as stomach cancer, has a predilection for metastasis to the peritoneum, which portends limited survival. The peritoneal metastatic cascade remains poorly understood, and existing models fail to recapitulate key elements of the interaction between cancer cells and the peritoneal layer. To explore the underlying cellular and molecular mechanisms of peritoneal metastasis, we developed an ex vivo human peritoneal explant model. Fresh peritoneal tissue samples were suspended, mesothelial layer down but without direct contact, above a monolayer of red-fluorescent dye stained AGS human gastric adenocarcinoma cells for 24 h, then washed thoroughly. Implantation of AGS cells within the explanted peritoneum and invasion beyond the mesothelial layer were examined serially using real-time confocal fluorescence microscopy. Histoarchitecture of the explanted peritoneum was preserved over 5 days ex vivo. Both implantation and invasion were suppressed by restoration of functional E-cadherin through stable transfection of AGS cells, demonstrating sensitivity of the model to molecular manipulation. Thus, our ex vivo human peritoneal explant model permits meaningful investigation of the pathways and mechanism that contribute to peritoneal metastasis. The model will facilitate screening of new therapies that target peritoneal dissemination of gastric, ovarian and colorectal cancer.

Activated Leukocyte Cell Adhesion Molecule (ALCAM), a Potential ‘Seed’ and ‘Soil’ Receptor in the Peritoneal Metastasis of Gastrointestinal Cancers

“…Importantly, when ALCAM were knocked down from both cancer cells and mesothelial cells, the interaction between the two cell types were greatly reduced compared to an individual knocking down, further supporting the role of ALCAM in both "seed" and "soil" receptors during the process of metastasis. This finding on ALCAM has a similar echo to a recent study by Ng et al [49] who reported that E-cadherin may have a similar property in an ex vivo gastric cancer model. Similar suggestions were indicated in the peritoneal metastasis from pancreatic cancer, although experimental data are yet to come [50].…”

Galectin-1 promotes gastric cancer peritoneal metastasis through peritoneal fibrosis

“…In short, tumor metastasis involves interaction between the primary tumor and the local microenvironment of the new metastatic site. Therefore, by providing various cytokines that promote tumor invasion and metastasis, tumors promote peritoneal changes to facilitate the adhesion of shed tumor cells to the peritoneum, which is an important basis for the occurrence of GC peritoneal metastasis [ 6 , 7 ]. This process involves interaction between the primary tumor and peritoneal mesenchymal cells and the extracellular matrix (ECM) [ 8 ].…”

Exosomes secreted by ST3GAL5high cancer cells promote peritoneal dissemination by establishing a premetastatic microenvironment

“…The omentum is the preferred early site of peritoneal metastasis of cancer cells, including gastric, pancreatic, and high‐grade serous ovarian cancer [ 17 , 18 , 19 ]. Milky spots (MS), lymphoid tissues most frequently observed in the omentum and mesentery, comprise B, T, and natural killer cells, along with MΦs, and other immune‐progenitor cells and play an essential role in cancer metastasis colonization [ 20 , 21 ].…”