Researchers at the Cancer Research Institute and Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, have discovered a critical mechanism that allows stomach cancer to spread to distant organs. Their study shows that cancer cells stimulate Wnt signaling in the surrounding stromal fibroblasts to produce hyaluronan, creating a supportive microenvironment that promotes metastasis.
These findings provide new insight into how metastatic tumors establish and suggest promising strategies to prevent gastric cancer progression.
A major challenge in gastric cancer
Stomach cancer remains one of the leading causes of cancer-related deaths worldwide, mainly because it often spreads to other organs such as the liver. While the genetic mutations that cause tumors have been extensively studied, the biological mechanisms that allow cancer cells to colonize new tissues remain poorly understood.
“Wnt signaling”—a pathway essential for stem cell maintenance and tissue regeneration—is often activated in gastric cancer through external ligand stimulation rather than genetic mutation. This study further identifies that Wnt signaling in the tumor microenvironment also plays a critical role in disease progression.
Cancer cells remodel their environment to allow spread
Using advanced mouse and organelle models, team leader Masanobu Oshima and colleagues investigated how stomach cancer spreads to the liver.
They discovered that:
• Wnt ligand expression promotes gastric cancer metastasis to the liver.
• Wnt ligands secreted by tumor cells activate surrounding stromal fibroblasts.
• Wnt signaling cooperates with TGF-β signaling to activate these fibroblasts.
• Activated fibroblasts express Has2, producing hyaluronan that accumulates at metastatic sites.
• Hyaluronan deposition creates a supportive niche that allows cancer cells to survive and grow in the liver.
• Degradation of hyaluronan dramatically suppressed metastatic tumor formation.
Importantly, activation of Wnt signaling within tumor cells alone was not sufficient to induce metastasis, demonstrating that stromal Wnt activation is necessary.
Hyaluronan creates a supportive metastatic niche
The researchers observed a significant accumulation of hyaluronan in the tumor microenvironment during the early stages of metastasis.
When hyaluronan was degraded using hyaluronidase expression, liver metastasis was significantly reduced, demonstrating that stromal hyaluronan plays a key role in metastatic tumor development.
Implications for future treatments
This study highlights the importance of ligand-dependent Wnt signaling in tumor-stroma interactions in cancer progression.
The results suggest promising therapeutic strategies, including:
• ligand-dependent targeting of Wnt signaling
• inhibition of hyaluronan production
• disturbance of the formation of metastatic sites
These approaches may help prevent or limit gastric cancer metastasis.
To better prevent metastatic disease
By revealing how cancer cells create a supportive metastatic microenvironment, this research provides a new framework for understanding gastric cancer progression and developing therapies aimed at preventing metastatic spread. Future studies will focus on validating these mechanisms in human metastatic tumors and investigating therapeutic interventions targeting the tumor microenvironment.
Our study shows that metastasis is not only driven by the cancer cells themselves, but also by how they remodel the surrounding tissue. By creating a supportive environment in distant organs, tumors can survive and grow. “Rather than targeting cancer cells alone, our findings suggest that disrupting the environment that supports metastasis could be a powerful new therapeutic approach.”
Masanobu Oshima, WPI Nano Life Science Institute (NanoLSI), Kanazawa University
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