Dissociated invasively growing cancer cells with NF-kappaB/p65 positivity after radiotherapy: a new marker for worse clinical outcome in rectal cancer? Preliminary data

Abstract

Objectives Nuclear factor-kappaB (NF-kappaB), especially p65 subunit, seems to be associated with origin and progression of cancer. The aim of the study was to determine expression of NF-kappaB/p65 in rectal cancer patients before and after radiotherapy as well as to assess the relationship between NF-kappaB/p65 expression, other tumor characteristics, and disease progression. Further aim was to evaluate whether expression of NF-kappaB/p65 in tumor tissue may serve as a predictive marker of patient outcome. Patients and methods Twenty-five patients with rectal cancer undergoing pre-operative radiotherapy were included in the study. Unirradiated rectal cancer specimens were obtained from diagnostic colonoscopy. Irradiated rectal cancer specimens were obtained from surgically removed part of the rectum with the tumor. NF-kappaB/p65 expression was determined by immunohistochemistry. Results Cytoplasmic positivity in cancer cells and nuclear positivity in lymphocytes were detected. In post-radiotherapy specimens single tumor cells or small clones of them deeply infiltrating the wall of the rectum, that were characterized by high NF-kappaB/p65 expression, were found. Patients with presence of these cells in post-radiotherapy specimens have worse clinical outcome in terms of overall survival and disease-free interval. Conclusion While the NF-kappaB/p65 positive staining of the epithelial cells did not have any clinical implications in this study, it may be of clinical significance in the future. Residual invasively growing cancer cells with high NF-kappaB/p65 positivity found in specimens after radiotherapy and surgery may be used to find what patients have a worse outcome. Thus, patients being at risk of cancer progression and requiring more aggressive anti-cancer therapy may be identified.

NF-κB/p65 expression before and after treatment in rectal cancer patients undergoing neoadjuvant (chemo)radiotherapy and surgery: prognostic marker for disease progression and survival

“…Monoclonal antibody used for immunohistochemistry in our study could detect only activated form of NF-κB/p65 protein released from its inhibitory molecule IκB. In our study [22] we discussed cytoplasmic positivity of NF-κB/p65 found in tumor cells in detail.…”

“…The criteria for selection included availability of a preoperative biopsy suitable for immunohistochemical analysis and surgery performed at the above mentioned hospital. The study was performed according to the Institutional Guidelines and approved by the Institutional Ethics Committee as described in our previous study [22].…”

“…Approximately 6 weeks after radiotherapy, the surgery with removal of the affected part of the rectum was performed. Each patient was followed up at regular basis according to standardized protocol as described in our previous study [22]. Development of local disease recurrence and/or metastatic relapse was assessed.…”

“…We showed in our in vitro experiments on colorectal cancer cell lines that activated NF-κB is associated with resistance to irradiation [19], inhibition of NF-κB leads to radiosenzitization [20] and enhances the cytotoxic effect of 5-FU [21]. Moreover, we reported in a clinical study that NF-κB/p65 positivity in single cancer cells displaying dissociated pattern of growth found after radiotherapy in rectal cancer patients may be associated with worse clinical outcome in terms of shortened disease-free interval and overall survival [22].…”

Targeting the inflammatory pathways to enhance chemotherapy of cancer

“…First, NFκB has been related to cell transformation. 21 Second, NFκB is constitutively active in tissues of many cancers [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] (Table 2). Third, activation of inflammatory pathway is mediated through NFκB in response to lifestyle-related factors such as tobacco, stress, dietary agents, obesity, alcohol, infectious agents, irradiation and environmental stimuli, which account for as much as 95% of all cancers.…”