Pro-Inflammatory Cytokines in the Formation of the Pre-Metastatic Niche.

Abstract

Simple SummaryThe formation of the pre-metastatic niche, a favorable microenvironment in an organ distant from a primary tumor, is critical for tumor metastasis. We review the role of a key player, a class of proteins named pro-inflammatory cytokines secreted from both tumor cells and other cells in tissues, in helping to build the pre-metastatic niche. Various drugs have been developed to target pro-inflammatory cytokines, and their effects on tumor metastases are under investigation. Future clinical studies should focus on combining those drugs and applying them during cancer surgery, a critical moment for the establishment of the pre-metastatic niche.In the presence of a primary tumor, the pre-metastatic niche is established in secondary organs as a favorable microenvironment for subsequent tumor metastases. This process is orchestrated by bone marrow-derived cells, primary tumor-derived factors, and extracellular matrix. In this review, we summarize the role of pro-inflammatory cytokines including interleukin (IL)-6, IL-1β, CC-chemokine ligand 2 (CCL2), granulocyte-colony stimulating factor (G-CSF), granulocyte–macrophage colony-stimulating factor (GM-CSF), stromal cell-derived factor (SDF)-1, macrophage migration inhibitory factor (MIF), and Chemokine (C–X–C motif) ligand 1 (CXCL1) in the formation of the pre-metastatic niche according to the most recent studies. Pro-inflammatory cytokines released from tumor cells or stromal cells act in both autocrine and paracrine manners to induce phenotype changes in tumor cells, recruit bone marrow-derived cells, and form an inflammatory milieu, all of which prime a secondary organ’s microenvironment for metastatic cell colonization. Considering the active involvement of pro-inflammatory cytokines in niche formation, clinical strategies targeting them offer ways to inhibit the establishment of the pre-metastatic niche and therefore attenuate metastatic progression. We review clinical trials targeting different inflammatory cytokines in patients with metastatic cancers. Due to the pleiotropy and redundancy of pro-inflammatory cytokines, combined therapies should be designed in the future.