title: Activated nuclear factor-kappa B and cytokine profiles in the esophagus parallel tumor regression following neoadjuvant chemoradiotherapy.
abstract: Esophageal adenocarcinoma is increasing in incidence; it relates to chronic gastroesophageal reflux, it is difficult to cure, and treatment modalities increasingly use chemotherapy and radiation therapy prior to resectional surgery. Nuclear factor-kappa B (NF-kappaB) is a pleiotropic transcription factor that regulates several genes for cytokines and enzymes involved in inflammation and immunity, and we have previously described sequential expression of NF-kappaB from the normal esophagus through Barrett's metaplasia to adenocarcinoma. The aim of this exploratory study was to assess the NF-kappaB status and cytokine profiles pre- and post-chemoradiotherapy for esophageal adenocarcinoma. Fresh biopsy specimens obtained from 20 patients with esophageal adenocarcinoma and normal adjacent squamous epithelium were obtained pre-, during and post-chemoradiotherapy, and NF-kappaB expression was analyzed by electrophoretic mobility shift assay. The cytokine protein content of interleukin-1 beta (IL-1beta) and interleukin-8 (IL-8) of tissue homogenates was measured using the ELISA technique. NF-kappaB was constitutively activated in tumor tissues from esophageal adenocarcinoma but was not detected in adjacent normal esophageal mucosa. Elevated levels of IL-1beta and IL-8 were significantly (P < 0.05) higher in tumor tissues compared to control tissues. Patients with a major or complete pathological response (responders) were associated with absence of activated NF-kappaB from nuclear extracts after treatment. Moreover, IL-1beta and IL-8 levels were significantly (P < 0.05) down-regulated in tumor tissues from patients who demonstrated a complete pathological response. No differences in NF-kappaB, IL-1beta and IL-8 levels were detected pre- and post-treatment in patients who did not have a major or complete pathological response (non-responders). The study suggests that monitoring of molecular and cytokine patterns in patients undergoing this neoadjuvant regimen may help subselect the cohort that derives most benefit from the multimodal approach.
authors.affiliation: Department of Clinical Surgery, Trinity Centre for Health Sciences, St. James's Hospital, Dublin, Ireland. abdellmm@tcd.ie
authors.forename: M M M
authors.initials: MM
authors.lastname: Abdel-Latif
authors.forename: J M
authors.initials: JM
authors.lastname: O'Riordan
authors.forename: N
authors.initials: N
authors.lastname: Ravi
authors.forename: D
authors.initials: D
authors.lastname: Kelleher
authors.forename: J V
authors.initials: JV
authors.lastname: Reynolds
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D015536:Down-Regulation; D004848:Epithelium / Q000473:pathology; D004938:Esophageal Neoplasms / Q000473:pathology / Q000628:therapy*; D016629:Esophagectomy; D004947:Esophagus / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007375:Interleukin-1 / Q000032:analysis*; D016209:Interleukin-8 / Q000032:analysis*; D008297:Male; D016328:NF-kappa B / Q000032:analysis*; D020360:Neoadjuvant Therapy; D011879:Radiotherapy Dosage; D018714:Radiotherapy, Adjuvant; D012074:Remission Induction
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D007375:Interleukin-1; D016209:Interleukin-8; D016328:NF-kappa B; D002945:Cisplatin; D005472:Fluorouracil