Abstract
The NF-κB signaling pathway is a master and commander in ovarian cancer (OC) that promotes chemoresistance, cancer stem cell maintenance, metastasis and immune evasion. Many signaling pathways are dysregulated in OC and can activate NF-κB signaling through canonical or non-canonical pathways which have both overlapping and distinct roles in tumor progression. The activation of canonical NF-κB signaling has been well established for anti-apoptotic and immunomodulatory functions in response to the tumor microenvironment and the non-canonical pathway in cancer stem cell maintenance and tumor re-initiation. NF-κB activity in OC cells helps to create an immune-evasive environment and to attract infiltrating immune cells with tumor-promoting phenotypes, which in turn, drive constitutive NF-κB activation in OC cells to promote cell survival and metastasis. For these reasons, NF-κB is an attractive target in OC, but current strategies are limited and broad inhibition of this major signaling pathway in normal physiological and immunological functions may produce unwanted side effects. There are some promising pre-clinical outcomes from developing research to target and inhibit NF-κB only in the tumor-reinitiating cancer cell population of OC and concurrently activate canonical NF-κB signaling in immune cells to promote anti-tumor immunity.
Highlights
Ovarian cancer (OC) is the most lethal gynecologic malignancy [1]
The inflammatory but immunosuppressive tumor microenvironment contributes to OC progression by the production of cytokines that promote survival signaling in OC cells and suppress the infiltration of anti-tumor immune cells [5]
Another study, focusing on upstream activators of canonical NF-κB signaling in OC, found that high expression of both toll-like receptor 4 (TLR4) and Myeloid differentiation primary response 88 (Myd-88) was associated with a poorer outcome and a more aggressive tumor phenotype and was significantly correlated with the expression of NF-κB pathway proteins IKKβ and matrix metalloprotease 9 (MMP9) [17]
Summary
Ovarian cancer (OC) is the most lethal gynecologic malignancy [1]. The low survival rate of approximately 40% owes to the intra- and inter-tumor heterogeneity, diagnosis at an advanced stage and high rate of recurrence and chemoresistance that classifies this disease [2]. In OC, the expression levels of NF-κB proteins, p65 and p50, are elevated in malignant and borderline serous ovarian tumors [10,11] and the elevated expression of subunits of the NF-κB pathway, such as the activating IκB kinases (IKKs) β and ε, have been associated with worse overall survival in OC [12,13,14,15]. Another study, focusing on upstream activators of canonical NF-κB signaling in OC, found that high expression of both toll-like receptor 4 (TLR4) and Myd-88 was associated with a poorer outcome and a more aggressive tumor phenotype and was significantly correlated with the expression of NF-κB pathway proteins IKKβ and matrix metalloprotease 9 (MMP9) [17]. We examine the role of the NF-κB signaling pathway in OC chemo-resistance and disease recurrence, inflammation and immunosuppression, and the strategies for targeting this pathway clinically in OC
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