Signaling Pathways that Control Cancer Stem Cell Function

Many important regulatory signaling pathways have been identified that contribute to stem cell survival and proliferation, malignant transformation as well as cell-cell and cell-matrix communication. For example, Wnt, a secreted highly hydrophobic signaling molecule controls stem cell activity and daughter cell fate through regulation of P-catenin [164-166]. In the absence of Wnt signaling, phosphorylated P-catenin is degraded by a complex of adenomatous polyposis coli (APC), Axin and glycogen synthase kinase-3P proteins via the ubiquitin pathway. Abnormal activation of Wnt signaling and accumulation of nuclear P-catenin in cancer stem cells can lead to a continuous targeting of a large number of downstream genes, such as the proto-oncogene c-myc, which allows undefined expansion of stem cells through inhibition of p21cip-1/ WAF, a cell-cycle inhibitor [167], as well as their migration out of the niche and accumulation of mutations that result in tumor progression [168, 169].

Another example is overexpression of membrane-associated ABC-transporters as regulators in stem and cancer stem cell survival. MDR1, the multidrug resistance P-glycoprotein (P-gp), also called ABCB1, was the first identified drug transporter that effluxes a wide range of diverse substrates [170]. Among the large family of ABC-transporters, the breast cancer resistance protein (BCRP or ABCG2) has been characterized as a novel stem cell-related transporter [171]. ABC transporters can also protect cells from apoptosis induced by a variety of factors, such as TNF-alpha or UV-irradiation, as well as modulate signal transduction pathways [170] that may have a key role in cancer stem cell survival. Bone morphogenetic proteins (BMPs) and Wnt signaling act synergistically in decisions about stem cell fate by restricting their activation, self-renewal and maintenance of their multipotency as shown during neurogenesis on neural crest stem cells [172].

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