Figure 4.

Inflammatory responses of CRP in the extracellular matrix and tumor microenvironment. 1) Platelet recruitment to damaged tissue and fibrin accumulation represent acute phase inflammatory responses that, if injury remains unresolved, will contribute to excessive chronic immunoreactivity. 2) Continuous oxidative stress (reactive oxygen species; ROS) and cytokine production by activated macrophages and neutrophils promote tumorigenicity in epithelial cells, which can promote epithelial-to-mesenchymal transition (EMT) as a result. 3) Deposition of the extracellular matrix (ECM) components, including fibronectin, collagen, laminin, and fibrin, in the tumor microenvironment (TME) by fibroblasts and activated immune cells modulate tumor cell proliferation and invasion. 4) Bidirectional crosstalk in the TME promotes further proliferation of tumor and stromal cells, as well as deposition and remodeling of ECM to promote tumor growth and motility. 5) Excessive cytokine release (e.g., IL-6) from the TME increases systemic circulating levels that promote hepatocyte pCRP production. pCRP secretion and subsequent mCRP-dependent inflammatory signaling (e.g., in involved endothelial cells and neutrophils), as well as its direct action on the ECM, contribute to tumor progression through ROS and cytokine signaling in the TME.