Researchers from the Cancer Research Institute and the Nano Life Science Institute (WPI-NanoLSI) at Kanazawa University have identified a key process that enables gastric cancer to spread to other organs, such as the liver. Their work demonstrates that cancer cells stimulate Wnt signaling in nearby stromal fibroblasts, leading these cells to produce hyaluronan, which then creates an environment supportive of metastasis.
According to the research team, this mechanism offers new understanding into how metastatic tumors establish themselves and points toward potential strategies for preventing the progression of gastric cancer.
Gastric cancer is a major cause of cancer-related deaths globally, mainly because it often spreads beyond its original site. While much is known about genetic mutations that initiate tumors, less is understood about how cancer cells colonize new tissues.
"Wnt signaling"—a pathway vital for stem cell maintenance and tissue regeneration—is frequently activated in gastric cancer through external ligand stimulation rather than by genetic mutation. The study further clarifies that Wnt signaling within the tumor microenvironment plays a significant role in disease progression.
The team led by Masanobu Oshima used advanced mouse and organoid models to examine how gastric cancer metastasizes to the liver. They found that Wnt ligand expression encourages liver metastasis of gastric cancer. Tumor-secreted Wnt ligands activate surrounding stromal fibroblasts, with Wnt signaling working together with TGF-β signaling to trigger these fibroblasts. Once activated, fibroblasts express Has2 and produce hyaluronan, which accumulates at metastatic sites. This buildup forms a niche that helps cancer cells survive and grow in the liver.
Crucially, simply activating Wnt signaling inside cancer cells was not enough to drive metastasis; activation within stromal cells was necessary.
The researchers observed considerable accumulation of hyaluronan in the tumor microenvironment during early metastatic stages. When they degraded hyaluronan using hyaluronidase expression, there was a marked reduction in liver metastasis. This result indicates that stromal hyaluronan is critical for developing metastatic tumors.
The findings emphasize the importance of ligand-dependent Wnt signaling in interactions between tumors and stroma during cancer progression. Potential therapeutic approaches suggested by this research include targeting ligand-dependent Wnt signaling, inhibiting hyaluronan production, or disrupting formation of the metastatic niche—all strategies aimed at limiting or preventing gastric cancer spread.
By detailing how cancer cells create a supportive environment for metastasis, this study provides a basis for future therapies designed to prevent or limit metastatic spread. The researchers plan further studies to confirm these mechanisms in human tumors and investigate treatments targeting the tumor microenvironment.
