Regulatory mechanisms of CSCs

Regulatory proteins and pathways establish a balance between a CSC's self-renewal ability and its death by apoptosis. The WNT, SHH, NOTCH, and PI3K/AKT/mTOR signaling pathways are especially important in this regulation and are often found be impaired in tumors. The WNT signaling pathway is mainly involved in cell proliferation and differentiation. A mutation in one of its components resulting either in an up-regulation or disruption of the signaling cascade can accelerate tumorigenesis; dysregulation of the WNT pathway compo nent E-cadherin can also lead to metastasis [45, 46]. Differentiation and self-renewal of adult SCs is usually controlled by the SHH pathway and disruption of it results in their aberrant differentiation and proliferation [47]. The NOTCH signaling pathway also regulates the differentiation, proliferation and self-renewal of adult SCs. Dysregulation of this pathway affects specific tissues and often leads to basal cell carcinoma, breast-, kidney- and prostate cancer [48-50]. In mouse models a significant inhibition of tumor growth could be achieved when the NOTCH signaling cascade was blocked [51]. The PTEN, a tumor suppressor protein with function in cell cycle regulation, is acting on the PI3K/AKT/mTOR signaling pathway. Inactivating mutations of PTEN can cause uncontrolled growth and cell division and are often found in tumors such as brain, bladder, prostate and kidney cancers [52-54].

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