Citrullination in Tumor Metastasis, Inside and Outside the Cells

Tumor metastasis remains a poor prognosis because it occurs in all tissues and is difficult to diagnose or prevent before metastatic tumor nodules form. Metastasis is a multi-step process involving tumor cells, bone marrow-derived cells, and tissue resident cells, making it a biological three-body problem. It has been shown that a pre-metastatic soil/niche (PMN) is formed in metastatic tissue before tumor cells physically appear at the metastatic site, and suppressing this PMN is key to preventing metastasis. Recent studies highlighted the importance of protein citrullination, an irreversible post-translational modification of proteins, in tumor metastasis. Peptidyl arginine deiminase (PADI) catalyzes the modification of arginine to citrulline. In this enzymatic reaction, the amino acid residue's net charge changes, inducing a structural change in the protein. This review discusses the role of protein citrullination in cancer metastasis. Intracellular citrullination regulates gene expression and genome structure by citrullinating RNA polymerase and histones, while extracellular citrullination provides a pro-metastatic environment. These factors play an important role in PMN formation. Additionally, we discuss PADI inhibitors and anti-metastatic immune cells from the viewpoint of metastasis prevention.