The Stem Cell Niche as the Tumor Microenvironment

Normal adult tissue specific stem cells reside in a local microenvironment called "niche" [158]. Via adhesive molecules, cadherins and integrins, stem cells anchor in the basement membrane that separates niche cells from stem cells. Extracellular and intrinsic factors, e.g. cytokines, growth factors, neural inputs or physical stimuli, regulate self-renewal, cell division and daughter cell fate, proliferation, and migration of stem cells [159]. Secretion of certain growth factors, such as fibroblast growth factor (FGF), and mobilization of matrix molecules by niche cells stimulates activity and growth of stem cells [121]. The niche cells also release growth inhibitory molecules, such as TGF-P, bone morphogenic proteins (BMPs) and cell cycle inhibitors to suppress stem cell differentiation [160], [161]. Vascular endothe-lial cells may also provide external signals and growth factors. For normal tissue development the number of niches may vary in response to the developmental needs, e.g. the expansion of the stem cell pool or stromal cells after injury [162]. In addition, niches can modify their regulatory properties in response to stem cell activity [163]. Deregulation of the complex signaling pathways within the niche (cells) may lead to significant changes in stem cell number and stem cell fates, including remodeling the niche to favor malignant transformation. By the same token, malignant transformation of the stem cells can change completely their niche by affecting secretion of cytokines and growth factors through aberrant expression of cell surface molecules leading to uncontrolled cell signaling. Change in the intensity and nature of infiltrating immune cells and release of inflammatory cytokines may contribute to further alteration of the niche and progression of the tumor to a more mature state [144].

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