Roles and Regulation of Growth differentiation factor-15 in the Immune and tumor microenvironment

Growth differentiation factor-15 (GDF-15), a member of the TGF-β superfamily, plays multiple roles in a wide variety of cellular processes. It is expressed at low levels under normal conditions but is highly expressed in tumor and tumor microenvironment (TME)-related cells, such as fibroblasts and immune cells. The TME consists of the noncancerous cells present in the tumor, including immune cells, fibroblasts, blood vessel signaling molecules and extracellular matrix, which play a key role in tumor development. GDF-15 affects both stromal cells and immune cells in the TME. It also acts on immune checkpoints, such as PD-1/PDL-1 that regulate stemness of cancer cells, indicating that GDF-15 plays a prominent role in cancer, exhibiting both protumorigenic and antitumorigenic effects, although the latter are reported much less often than the former. The present review addresses novel ideas regarding communication between GDF-15 and stromal cells, immune cells, and cancer cells in the TME. In addition, it discusses the possibility of GDF-15's clinical application as a diagnostic biomarker and therapeutic target in cancer.