New insights into Gremlin-1: A tumour microenvironment landscape re-engineer and potential therapeutic target

Abstract

Gremlin-1 (GREM1), a well-known bone morphogenetic protein (BMP) antagonist, is highly expressed in various malignant tumours. However, the specific role of GREM1 in tumours remains controversial and may be attributed to the heterogeneity and complexity of the tumour microenvironment (TME). It is currently believed that GREM1 regulates the complex landscape of the TME, primarily by antagonising BMP signalling or BMP-independent pathways. Both GREM1 and BMP play dual roles in tumour progression. Therefore, the mutual crosstalk between tumour cells and tumour-associated fibroblasts and the regulation of various secreted factors in the TME affect the secretion level of GREM1, which in turn regulates the amplitude balance between GREM1 and BMP, affecting tumour progression. The inhibition of GREM1 activity in the TME can disrupt this amplitude balance and prevent the formation of a tumour-supportive microenvironment, demonstrating that GREM1 is a potential therapeutic target. In this study, we reviewed the specific signalling pathways via which GREM1 in the TME regulates epithelial-mesenchymal transition, construction of the tumour immune microenvironment, and maintenance of tumour cell stemness via BMP-dependent and BMP-independent regulation, and also summarised the latest clinical progress of GREM1.