Escape from reactive oxygen species cause of cancer metastasis: Hopes for development of inhibitor

Cancer is the leading cause of death among Japanese. However, most of cancer-related deaths are not attributed to primary tumors but to metastases. Why does cancer metastasize? What benefits does cancer get from this? In fact, no one really knew the answers. A research group led by Associate Professor Nobuaki Takahashi, Researcher Yoshifumi Ueda, and Professor Yasuo Mori of the Graduate School of Engineering at Kyoto University, and Professor Shigeki Kiyonaka of Nagoya University has discovered the regions in cancer tissue where hydrogen peroxide, a reactive oxygen species (ROS), is accumulated at high concentrations (hotspots). The research group has revealed that cancer cells take the first step toward metastasis to escape from the hotspots. Takahashi said, "As we now know that an ROS is a trigger for the first step in metastasis, we hope to develop a metastasis inhibitor that targets the hydrogen peroxide hotspots." The study was published in Nature Cell Biology.

These findings were a serendipitous discovery made while advancing research on oxidative stress and cancer. Although oxidative stress is cytotoxic and is considered to cause various diseases, no previous studies had demonstrated the presence of ROS in the body because they are not encoded in DNA. The research group developed an antibody-fluorescent sensor complex (T-AP1) to visualize ROS at the single-cell level. This complex consists of an antibody targeting cancer-specific molecules, modified with a green, fluorescent molecule that enhances fluorescence upon detecting hydrogen peroxide and a red fluorescent molecule whose fluorescence intensity remains unchanged in the presence of hydrogen peroxide.

They found the hotspots by administering this ROS probe, which selectively accumulates in tumors, to mouse models of cancer. Detailed observations revealed that tumor budding, in which cancer cells are separated from the tumor mass and migrate toward the tumor stroma, was occurring at a high frequency in the hotspots. Furthermore, the ROS was found to trigger activation of the oncogene MYC.

The probe system is expected to enable ROS detection in various in vivo environments where it has been challenging, advancing research on the role of ROS in physiological phenomena and diseases. The research group has also begun experiments to inhibit metastasis with membrane-impermeable antioxidants that selectively remove extracellular ROS. This research may lead to the development of a completely new cancer treatment strategy for metastasis suppression.

Journal Information
Publication: Nature Cell Biology
Title: Intratumour oxidative hotspots provide a niche for cancer cell dissemination
DOI: 10.1038/s41556-025-01617-w