Study Uncovers How Tumor Cell Clusters Invade Blood Vessels and Spread Cancer

Metastasis, the spread of cancer to different parts of the body, makes treatment significantly more challenging. A recent study published in iScience by researchers from The University of Tokyo, investigates how clusters of circulating tumor cells manage to move from primary tumors into the bloodstream and seed new tumors elsewhere.

Circulating tumor cell clusters, rather than single cells, have been detected in the blood of patients with advanced cancer and are much more likely to cause metastases. However, the process by which these clusters penetrate the blood vessel wall and enter circulation has not been well understood. As senior author Yukiko Matsunaga, explains, “Clinical observations demonstrate that metastases are induced by circulating tumor cell clusters, but it has remained unclear how these clusters cross the robust endothelial barrier of the blood vessel to enter our body’s circulation.”

To explore this, the team developed a three-dimensional in vitro culture system featuring an artificial blood vessel and intestinal tumor organoids. By positioning the organoids near the vessel and using live-imaging techniques, the researchers observed that tumor cell clusters migrated toward the vessel, disrupted the vessel wall, and then dispersed within the bloodstream. “The results were striking,” note co-lead authors Yukinori Ikeda and Makoto Kondo.

Further analysis showed that the vessel wall cells expressed high levels of transforming growth factor-β (TGF-β) and activin when exposed to migrating tumor clusters. This led to endothelial-to-mesenchymal transition, where parts of the vessel wall lost their normal characteristics, allowing the clusters to infiltrate.

“Our findings suggest that these tumor cell clusters, after detaching from primary tumors, move toward blood vessels, take over a part of the blood-vessel wall, and disperse via the bloodstream to facilitate distal metastasis,” says Matsunaga. The new 3D system may help develop therapies targeting this infiltration process, potentially improving outcomes for advanced cancer patients.