Identification and characterization of compounds that block heterocellular adhesion between diffuse-type gastric cancer cells and cancer-associated fibroblasts

The phenotypes of cancer cells are profoundly influenced by reciprocal interaction with the tumor stroma within the tumor microenvironment. Among stromal components, cancer-associated fibroblasts (CAFs) are the most abundant and play pivotal roles in shaping the tumor milieu. CAFs promote cancer progression through the secretion of pro-tumorigenic factors and remodeling of the extracellular matrix. In addition to these paracrine effects, recent studies have emphasized the critical role of direct heterocellular adhesion between cancer cells and CAFs in tumor progression. Diffuse-type gastric cancer (DGC) is the most aggressive subtype of gastric cancer with an extremely poor prognosis. DGC is characterized by rapid infiltrative growth and frequent peritoneal metastasis. DGC is commonly accompanied by desmoplastic stroma, which results from the extensive proliferation of CAFs. We previously demonstrated that direct interactions with CAFs are essential for the invasion and peritoneal metastasis of DGC cells. To further elucidate the biological significance of this interaction, we established a high-throughput screening system to identify molecules that disrupt DGC cell-CAF adhesion. Using this screening system, we successfully obtained monoclonal antibodies that block this heterocellular adhesion and suppress peritoneal metastasis of DGC in vivo. In the present study, we aimed to identify small-molecule compounds that inhibit heterocellular adhesion between DGC cells and CAFs. High-throughput screening of a chemical library led to the identification of several hit compounds. Notably, one compound not only inhibited DGC cell-CAF adhesion but also suppressed the proliferation of DGC cells. Furthermore, this compound markedly reduced peritoneal metastasis of DGC in a mouse xenograft model. These findings suggest that targeting the heterocellular adhesion between cancer cells and CAFs represents a promising therapeutic strategy, and that small molecules disrupting this interaction may serve as novel anti-cancer agents.