Wnt Signaling Pathway, Cancer-Associated Fibroblasts, and Extracellular Matrix Axis (Wnt/CAF/ECM Axis)

The Wnt signaling pathway is a complex network of secreted glycoproteins (Wnt ligands), membrane receptors (Frizzled family, LRP5/6), intracellular mediators (β-catenin, DVL), and nuclear factors (TCF/LEF) that govern cell fate, proliferation, migration, and tissue homeostasis[2][4][5]. Dysregulation of this pathway is a major driver of cancer development, progression, tumor microenvironment remodeling, and therapy resistance[1][2][3][5][7]. Cancer-associated fibroblasts (CAFs) are activated stromal cells in tumors that secrete extracellular matrix (ECM) components and paracrine factors, modulating tumor growth, invasion, immune evasion, and the response to therapy. The ECM components produced and remodeled by CAFs (e.g., collagen, fibronectin, proteoglycans) provide structural support, shape the biochemical microenvironment, and directly regulate pathways such as Wnt signaling via storage or presentation of ligands and antagonists (e.g., sFRP, Dickkopf, WIF-1)[4][6][8]. This triad forms a dynamic regulatory network central to cancer pathophysiology. However, this entry reflects an interconnected biology rather than a single druggable molecular target, so clinical targeting strategies often focus on specific pathway members or mediators within this axis.

Other names

Wnt/β-catenin signaling pathwayWnt signalingCanonical Wnt pathwayCancer-associated fibroblast and extracellular matrix axis

Inhibition of Wnt ligand-receptor (Frizzled-LRP5/6) interaction; Inhibition of β-catenin stabilization or nuclear translocation; Suppression of Wnt-mediated gene transcription (via TCF/LEF); Inhibition of stromal remodeling and ECM production (indirect, by CAF targeting); Modulation of tumor-stromal crosstalk