Oesophageal cancer is a virulent malignancy that has a high fatality rate once it progresses beyond disease Stage I. The presence of lymph node metastasis and vascular invasion as well as distant organ involvement leads to a poor clinical outcome . The optimal management of oesophageal cancer is complicated because both global and institutional standard therapies vary and patients often need specific individual management strategies. There are data to support multimodal approaches for this disease. Surgery is considered the mainstay of treatment for patients, especially those with locoregionally confined oesophageal cancer. However, the 5-year survival rate is generally 20–50%, mainly due to the high rate of recurrence, even after curative surgery [1, 2]. In Japan, preoperative chemotherapy has been proven to be associated with a better clinical outcome than postoperative chemotherapy (randomised trial of the Japan Esophageal Oncology Group, JCOG9907) . Moreover, preoperative chemoradiotherapy (CRT) has been accepted as a first-line therapy in the Unites States . Since 1996, we have advocated a trimodal therapy, a combination of radical surgery with preoperative CRT, and have reported increased resectability, reduced incidence of both local recurrence and distant metastasis, and better clinical outcome for CRT responders . However, the benefit of preoperative CRT over chemotherapy alone has not yet been established in Japan, and remains controversial in Europe. 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 therapy-resistant cancer cells. Therefore, it is clearly imperative to develop biomarkers for predicting recurrence and to implement efficient treatments for preventing recurrence after surgery.
Therapy-resistant cancer cells are thought to be the founder population that causes patient relapse and subsequent metastasis. A recent ‘cancer stem cell’ concept has suggested the existence of a small subpopulation of tumour cells harbouring stem cell-like unique properties of self-renewal, asymmetric division, and pluripotency. It is thought that these ‘more aggressive’ cancer progenitor cells, refractory to conventional therapy, survive the treatment to later regenerate a tumour with increased resistance to therapy . To date, putative cancer stem cells have been identified in various cancer types including breast , lung , colon [11, 12], and pancreatic cancer . To treat the patients who harbour these cancer stem cells, chemo(radio)therapy and/or molecular-targeted therapy, which has power to kill these cells, is essential.
B-cell-specific Moloney murine leukaemia virus integration site 1 (Bmi1) was first identified by retroviral insertional mutagenesis when assessing collaborating oncogenes in Eμ-myc transgenic mice [14, 15]. Bmi1 is a transcriptional repressor that belongs to the polycomb group (PcG) family of proteins involved in axial patterning, haematopoiesis, regulation of proliferation, and senescence . It has been shown to play a role in sustaining self-renewing cell activity by repressing the INK4A locus encoding p16
, which are capable of inducing growth arrest, cellular senescence and apoptosis [17–19]. PcG proteins are known to modify the chromatin structure around their binding sites by marking the chromatin of their target genes through methylation at lysine 27 of histone H3; these sites include the promoters of many developmental regulator genes, leading to gene repression . Recent studies have documented increased BMI1 expression in a variety of human cancers, such as non-small cell lung cancers , medulloblastomas , prostate carcinomas , colorectal cancers , breast carcinomas , and oesophageal squamous cell carcinomas (ESCCs) . Furthermore, BMI1, as well as Gli-1 of the hedgehog (Hh) pathway, has been shown to be a key regulator of self-renewal in both normal and tumourigenic human mammary stem cells . In our recent study, we have shown the clinical significance of Hh signal activation to predict very earlier relapse and poorer prognosis in patients with ESCC after CRT . Hence, aberrant BMI1 expression might also be involved in the characteristics of the ‘more aggressive’ cancer cell population after CRT, because BMI1 is thought to be a downstream target in the Hh pathway in medulloblastoma .
No data are currently available on the role of BMI1, a candidate downstream target of the Hh pathway, in oesophageal cancer progression after CRT. In this study, therefore, 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.