Paracrine Regulation of Cancer Stem Cell Populations

Stratified epithelial stem cells are responsible for skin and mucosal renewal and play an important role in homeostasis and wound healing. Lgr6 is a marker for a unique stem cell population giving rise to the different lineages in stratified epithelia. Keratin 15 expression marks a separate population of stem cells in stratified epithelia. CXC family chemokine receptors (Cxcr) are expressed as transmembrane proteins in mammalian epidermal cells. They recognize and specifically bind to chemokines of the CXC family. Recent studies have reported roles for chemokines in inflammation, tumor growth, angiogenesis, invasion, and metastasis in cancer. Selective depletion of the small K15+ stem cell fraction resulted in dramatic reduction of Lgr6+ cells and inhibition of oral tumorigenesis via senescence. Gene expression studies revealed that K15+ cancer stem cells regulate Lgr6+ cancer stem cell expansion via chemokine signaling. Genetic ablation of the chemokine receptor Cxcr2 inhibited cancer stem cell expansion and tumorigenesis via senescence. The effects of chemokines were primarily mediated by PI3K signaling, which is a candidate for targeted therapy in head and neck cancer.