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The NF-κB Pathway and Cancer Stem Cells
Amanda L. Rinkenbaugh 1,2 and Albert S. Baldwin 2,*
Academic Editor: Ruaidhri Carmody Received: 10 February 2016; Accepted: 31 March 2016; Published: 6 April 2016
Abstract: The NF-κB transcription factor pathway is a crucial regulator of inflammation and immune responses. Additionally, aberrant NF-κB signaling has been identified in many types of cancer. Downstream of key oncogenic pathways, such as RAS, BCR-ABL, and Her2, NF-κB regulates transcription of target genes that promote cell survival and proliferation, inhibit apoptosis, and mediate invasion and metastasis. The cancer stem cell model posits that a subset of tumor cells (cancer stem cells) drive tumor initiation, exhibit resistance to treatment, and promote recurrence and metastasis. This review examines the evidence for a role for NF-κB signaling in cancer stem cell biology.
….Cancer Stem Cells Given the connections between the NF-κB pathway and the earliest events in oncogenesis, it follows that NF-κB signaling would be important in the tumor initiating cells. The cancer stem cell (CSC) model has been proposed to describe the cells which are responsible for tumor initiation. This phenomenon was first described in acute myeloid leukemia (AML), where cells from patients were transplanted into NOD/SCID mice and monitored for engraftment. Results from that study demonstrated that the CD34+ CD38 Ì population of cells caused disease more frequently and at lower cell numbers than CD34 Ì cells [75]. Subsequent to these findings, CSCs have been described in many solid tumors including those of the brain, prostate, breast, colon, and pancreas [76-81]. In addition to being responsible for primary tumor formation, CSCs are also generally thought to drive metastasis and exhibit increased resistance to radiation and chemotherapy. Due to their stem-like characteristics, these cells are also capable of differentiation into multiple lineages, which accounts for some of the heterogeneity seen in tumors [82]. While CSCs are frequently depicted at the top of a hierarchically arranged tumor, there is evidence that plasticity allows for the conversion of bulk tumor cells into CSCs [83].
……..NF-κB was shown to be activated in cancer-associated fibroblasts promoting the expression of inflammatory cytokines, although the role of this response in promoting tumorigenesis is controversial [70-72].
…..NF-κB signaling also has ties to mediating resistance to radiation and chemotherapy, so there could be utility in combining NF-κB inhibition with traditional cancer therapies. Early work found that expression of IκBα-SR sensitized cancer cells to ionizing radiation, daunorubicin, and CPT-11 (a topoisomerase inhibitor) [171-173]. More recently, use of NF-κB inhibitors in combination with temozolomide, adriamycin, or radiation has shown increased apoptosis in glioblastoma cells [174-176]. Doxorubicin-resistant glioblastoma stem cells upregulated expression of MDR1 through a PI3K-NF-κB pathway [177]. In another study, KRas-NF-κB signaling mediated resistance to EGFR inhibitors in CSCs [178]. Upregulation of IRAK1 drives NF-κB activation and cytokine production, leading to CSC enrichment and paclitaxel resistance in breast cancer [179]. Taken together, these results suggest that not only could NF-κB inhibition be an effective treatment against CSCs, but it could also restore sensitivity to other therapeutic options.
5. Conclusions
The NF-κB pathway is integrated into many critical aspects of tumor biology. Its function in inflammation and immune responses often sets the stage for tumor development. Expression of several potent oncoproteins, including mutant RAS and BCR-ABL, leads to NF-κB activation early in tumorigenesis. Here, we have detailed crucial roles and contributions of NF-κB in cancer stem cells, which are driving tumor initiation, recurrence, and metastasis. NF-κB regulation of critical target genes””prominently including IAPs, cytokines, and EMT transcription factors””drive CSC phenotypes. In addition to direct NF-κB effects, there is also cooperation between other crucial CSC-associated
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pathways, such as STAT3, Notch, and TGF-β. Future work will need to determine if therapeutic targeting of the NF-κB pathway impacts tumor growth at the level of the cancer stem cells.