Abstract
BackgroundThe polycomb group (PcG) family BMI1, acting downstream of the hedgehog (Hh) pathway, plays an essential role in the self-renewal of haematopoietic, neural, and intestinal stem cells, and is dysregulated in many types of cancer. Our recent report has demonstrated that Hh signalling activation can predict very earlier relapse of oesophageal cancers. As data were not available on the clinical role of BMI1 expression in oesophageal cancers after chemoradiotherapy (CRT), we analysed whether it could be also used to predict disease progression and prognosis in oesophageal cancer patients undergoing trimodality therapy of preoperative CRT and oesophagectomy.MethodsExpressions of BMI1 and p16INK4A, a downstream target of PcG, were analysed in 78 patients with histologically confirmed oesophageal squamous cell carcinoma (ESCC) after preoperative CRT by immunohistochemical staining. The association of BMI1 and p16INK4A expression with clinicopathologic characteristics was analysed by χ2-test. Survival analysis was carried out by the log-rank test using Kaplan-Meier method.ResultsAmong 78 ESCC patients, 24 patients (30.8%) showed BMI1 positivity, mainly localised in the nuclei of tumour cells. Patients harbouring BMI1-positive tumour cells showed significantly poorer prognoses than those without such cells or residual tumours (mean disease-free survival (DFS) time 16.8 vs 71.2 months; 3-yr DFS 13.3% vs 49.9%, P=0.002; mean OS time 21.8 vs 76.6 months; 3-yr OS 16.2% vs 54.9%, P=0.0005). There was no significant correlation between p16INK4A expression and BMI1 expression.ConclusionsOur study shows that BMI1 expression is a predictor of early relapse and poor prognosis in ESCC after CRT. These findings suggest that BMI1 signal activation might be involved in promoting cancer regrowth and progression after CRT, and might be indicative of emergence of ‘more aggressive’ cancer progenitor cells.
Highlights
The polycomb group (PcG) family BMI1, acting downstream of the hedgehog (Hh) pathway, plays an essential role in the self-renewal of haematopoietic, neural, and intestinal stem cells, and is dysregulated in many types of cancer
We retrospectively investigated the expression of BMI1 protein in human oesophageal cancer tissues and evaluated the clinical implications of aberrant BMI1 activation for these patients who underwent preoperative CRT and oesophagectomy
On the basis of the tumour-node-metastasis (TNM) system of the International Union Against Cancer (UICC), stage II tumours were seen in 30 patients (38.5%), stage III tumours were seen in 32 patients (41.0%), and stage IV tumours were seen in 16 patients (20.5%)
Summary
The polycomb group (PcG) family BMI1, acting downstream of the hedgehog (Hh) pathway, plays an essential role in the self-renewal of haematopoietic, neural, and intestinal stem cells, and is dysregulated in many types of cancer. Some clinical trials in the West have shown that this preoperative strategy benefits only the 25% of patients who show a pathological complete response (CR; no cancer cells in the resected specimen), whereas the remaining 75% present with CRT-resistant and highly aggressive cancers with lymph node and distant metastases [6,7]. High mortality from this disease after surgery is due to the limited number of current therapies, and refractoriness of the disease due to the emergence of therapyresistant cancer cells. It is clearly imperative to develop biomarkers for predicting recurrence and to implement efficient treatments for preventing recurrence after surgery
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