Major IL-6 signaling pathways and their roles in cancer evolution. The classical signaling is mediated by the membrane-associated IL-6R, whereas the trans-signaling by the soluble form sIL-6R. gp130 is ubiquitously expressed on a large range of cell types, thus accounting for the pluripotent activities of IL-6 via the trans-signaling mechanism. Both classical and trans-signaling pathways activate the identical intracellular pathways including JAK1–STAT3, RAS–MAPK, and, PI3K–AKT
The proliferation and survival of tumor cells are promoted by IL-6 through both paracrine and autocrine mechanisms. After activation by IL-6, various types of cells, such as tumor-associated macrophages (TAM), myeloid derived suppressor cells (MDSCs), and endothelial cells, are involved in the development of pro-inflammatory and metastatic tumor microenvironment. In addition, IL-6 supports the generation and the survival of cancer stem cells (CSC), induces collagen production by fibroblasts, and promotes the differentiation of osteoclasts and augments angiogenesis.