Recent insights into the role of NF-kappaB in ovarian carcinogenesis.

Alvero AB
Genome medicine · 2010 · doi:10.1186/gm177 · PMID:20804565 · PMC2945013
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Recent research reveals that the NF-κB transcription factor family plays a specific role in the initiation, progression, and maintenance of ovarian cancer.

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This paper reviews and synthesizes evidence on how NF-κB signaling contributes to epithelial ovarian cancer (EOC), integrating findings from clinical correlation studies with mechanistic work in ovarian cancer cell lines, including experiments that activate the pathway (e.g., via TWEAK) or inhibit it (e.g., via NF-κB or IKKβ inhibitors and siRNA). It reports that NF-κB activation correlates with worse tumor differentiation, later FIGO stage, poorer cumulative survival, and shorter median survival, and that pathway modulation alters EOC cell behaviors such as adhesion, migration, invasion, anchorage-independent growth, gene programs related to proliferation and a pro-inflammatory/angiogenic microenvironment; a limitation is that much of the evidence is based on observational correlations and in vitro/investigational models rather than established early-detection or definitive clinical endpoints. The review also describes its own work linking a TLR4–NF-κB axis, paclitaxel-induced NF-κB activation, constitutive cytokine secretion driven by IKKβ, CD44+ ovarian cancer stem cell properties, and NF-κB–related chemoresistance and apoptosis sensitivity. Relevance to endometriosis: the paper cites endometriosis as an inflammatory process linked to ovarian carcinogenesis and, by extension, frames NF-κB as the molecular link between inflammation and cancer that encompasses endometriosis.

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Abstract

The NF-κBs are a family of ubiquitously expressed transcription factors that have been described to be responsible for the establishment of an inflammatory response. Studies in the past decade have also demonstrated this family's role in the initiation and progression of hematological and solid tumors. Recently, research has uncovered a specific role for NF-κBs in the development and maintenance of ovarian cancer.
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Nf Κb

Our group has identified a subpopulation of EOC cells that is responsive to the pathway involving Toll-like receptor 4 (TLR4) and NF-κB [ 17 ]. Treatment with the chemotherapy agent paclitaxel, which is a known TLR4 ligand, induced NF-κB activation, leading to enhanced cell proliferation. NF-κB is constitutively active in these cells, resulting in constitutive secretion of pro-inflammatory cytokines [ 17 ], and this is brought about by constitutive IKKβ activity [ 18 ]. These cells also express the cancer stem cell marker CD44 and are in fact the ovarian cancer stem cells (OCSCs) [ 19 ]. The CD44 + OCSCs are resistant to chemotherapeutic agents, and this resistance is partly regulated by the NF-κB pathway [ 19 ]. In our most recent study [ 20 ], we showed that the NF-κB inhibitor Eriocalyxin B can sensitize these cells to TNFα- and Fas-mediated apoptosis. The CD44+ OCSCs can also serve as tumor vascular progenitors in vitro and in vivo , an effect also regulated by the NF-κB pathway [ 21 ].

Clinical

Epithelial ovarian cancer (EOC) accounts for the majority of ovarian cancer and is the most lethal of all gynecological malignancies. It was expected that 21,550 new cases of EOC would be diagnosed in the US in 2009 and that 14,600 women would die from the disease [ 1 ]. Although ovarian cancer accounts for only 3% of all female cancers, it is the fifth most common cause of cancer deaths in women. Given that EOC usually presents with non-specific symptoms, such as bloating or abdominal discomfort, which can all be mistaken for a more benign condition, and because there is currently no means for early detection, patients with EOC are often diagnosed with late-stage disease (International Federation of Gynecology and Obstetrics (FIGO) stage III or IV). On initial diagnosis, patients undergo complete surgical debulking (resection whose only goal is to make subsequent therapy more effective) followed by combination chemotherapy usually consisting of carboplatin and paclitaxel. Approximately 80% of patients respond to this treatment regimen, which has been the standard for more than 10 years [ 2 ]. However, 60 to 80% of the responders present with recurrent disease between 6 months and 2 years after treatment. Unfortunately, disease recurrence is characterized by chemoresistance, resulting in disease progression and death. As a result, the 5-year survival rate for patients diagnosed with late-stage disease is only 15 to 20% [ 3 ].

Competing

The authors declare that they have no competing interests.

Conclusions

Research in the past 5 years has unraveled the multiple mechanisms that enable NF-κB to support ovarian carcinogenesis, including that this pathway confers some of the properties of OCSCs. These findings highlight the clinical potential for NF-κB inhibitors to prevent recurrence and improve survival in EOC patients. The fact that the main effectors of this pathway significantly correlate with disease activity suggests the feasibility of choosing patients that may benefit from targeting this molecular pathway.

Abbreviations

EOC: epithelial ovarian cancer cells; IKKα: inhibitor of NF-κB kinase α; IKKβ: inhibitor of NF-κB kinase β; IκB: inhibitor of NFκB; IL: interleukin; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; OCSC: ovarian cancer stem cells; shRNA: short hairpin RNA; siRNA: small interfering RNA; TNFα: tumor necrosis factor α.

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