The canonical NF-κB pathway regulates transcription of a wide range of genes involved in various processes including inflammation and proliferation, suggesting that it might provide a link between the systemic inflammatory response (SIR), local inflammatory response (LIR) and tumor signalling, the present study was to examine the relationship between SIR, tumor NF-κB pathway, tumor microenvironment including LIR and cancer specific survival in patients with colorectal cancer
Immunohistochemistry of inhibitory kappa β kinase (IKK)-β, p65 (Rel A) and phosphorylated p65 (p-p65) was performed using colorectal cancer tissue microarray of 151 patients and the weight histoscore method was employed to assess protein expression. The relationship between these proteins, BRAF status, tumor stroma percentage, local inflammation, systemic inflammation, and cancer-specific survival were examined. In addition, western blotting was performed to assess expression of key members of the canonical NF-κB pathway following stimulation with either TNFα or IL-1 in BRAF wildtype (T84) and BRAF V600E mutated cells (HT-29).
Expression of neither p65 nor p-p65, at any cellular location, was associated with clinical outcome measures. However a significant association between cancer specific survival and cytoplasmic IKKβ (p = 0.015), was observed and 10 year survival stratified from 78% to 59%. In addition, when patients were stratified by BRAF status the association with cancer specific survival and cytoplasmic IKKβ was upheld in those patients with wild type BRAF (p = 0.014) but negated in those with mutated BRAF (p = 0.287). Cytoplasmic IKKβ was significantly associated with venous invasion (p = 0.024), immunoscore (p = 0.023), Klintrup-Makinen grade (p = 0.050) and Glasgow microenvironment score. Total cell IKKβ expression was also associated with cancer specific survival, (p = 0.015) and 10 year survival was stratified from 73% to 53%. Total cell IKKβ was significantly associated with TNM (p = 0.004), tumor differentiation (p = 0.001), venous invasion (p = 0.011), necrosis (p = 0.003) and tumor stoma percentage (p = 0.048). In vitro, the canonical NF-κB pathway was induced in colon cancer cell lines T84 and HT-29 by exposure to either TNFα or IL-1 (p-p65 levels increased at 15 min), IKKβ expression remained constant.
In colorectal cancer patients, cytoplasmic and total cell IKKβ expression is associated with cancer specific survival and this was related to tumor microenviroment and LIR but not the SIR. Interactions between stromal and NF-κB pathway may be an important method by which disease progression occurs.
Citation Format: Jean A. Quinn, Lindsay Bennett, Antonia Roseweir, James H. Park, Paul G. Horgan, Donald C. McMillan, Joanne Edwards. The relationship between members of the canonical NF-κB pathway, components of the microenvironment and survival in patients with colorectal cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B125.
- ©2016 American Association for Cancer Research.