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. Author manuscript; available in PMC: 2015 Mar 6.
Published in final edited form as: Cell Stem Cell. 2014 Mar 6;14(3):306–321. doi: 10.1016/j.stem.2014.02.002

Figure 7. Pathway amplifiers and paracrine loops for MetSC support.

Figure 7

Many of the known traits that promote metastatic seeding involve gene products (red) that the cancer cells express to amplify their own responsiveness to vital stromal cues. The cues that activate these pathways include receptor tyrosine kinase (RTK) growth factor ligands (GF), chemokines like CXCL12, and Wnt, and Notch ligands. Examples amplifiers include cell adhesion receptors like the VCAM1-Ezrin complex that is engaged by tumor leukocyte integrins; the tyrosine kinase Src that amplifies PI3K-AKT activation by CXCR4 and IGF1R (not shown); the cancer cell- and myofibroblast-derived ECM components tenascin C (TNC) and periostin that enhance Wnt access to their receptors (periostin) or amplify signaling by the Wnt and Notch pathways (TNC); and, the collagen crosslinking enzymes LOX and PLOD2 that stiffen the ECM for integrin/focal adhesion kinase (FAK) mediated amplification of RTK signaling. Various cancer cell-derived cytokines (bottom, red) provide additional support by recruiting stromal cells that secrete activators of AKT, MAPK and STAT3 in incipient metastatic lesions. MetSC-derived BMP blockers like Coco protect self-renewal by inhibiting Smad1 signaling.