Notch1 signaling is activated in cells expressing embryonic stem cell proteins in human primary nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC), which arises from the mucosal epithelium of the nasopharynx, is one of the most poorly understood and commonly misdiagnosed diseases.1 Although rare in most parts of the world, it is one of the most common cancers found in southern China and Southeast Asia, where an annual incidence of more than 20 cases per 100,000 is reported.1-3 Because NPC occurs in an anatomic site that is poorly accessible to surgeons, high-dose radiotherapy with or without concurrent chemotherapy is the primary treatment.4,5 The 5-year survival rate of about 34 to 52% has not changed significantly over the decades, despite intensive efforts to develop effective therapy.4,5 Numerous studies have linked NPC to infection of the Epstein-Barr virus.6 The molecular mechanisms underlying the carcinogenesis of NPC, however, remain unresolved. Studies have shown that a small subpopulation of cells present in leukemic humans exhibit marked heterogeneity with respect to extensive proliferation and a self-renewal capacity that is not found in the majority of tumour cells.7,8 After transplantation into mice with severe combined immune deficiency (SCID), these cells can form tumours that phenotypically resemble the patient's original tumour.7,8 These cells are necessary and sufficient to sustain leukemia and are therefore tumorigenic. This notion has subsequently been verified in several solid tumours, including cancers of the breast,9 brain,10 prostate,11 ovary,12 colon,13 and pancreas.14 These cells have been termed cancer stem cells (CSCs) because they possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. A recent study showed that side population (SP) cells, a subpopulation of human NPC cell line CNE-2, display stem cell characteristics in vitro and are able to form tumours in vivo.15 However, whether CSCs are present in human primary NPC remains unclear. The findings of CSCs are very important not only for our understanding of the biologic behaviours of cancer cells but also for opening new strategies to treating cancers. Growing evidence has shown that CSCs may contribute to some individuals' resistance to cancer therapy. A plausible explanation is that CSCs have not been completely destroyed. Thus, therapeutic strategies that specifically target CSCs should destroy tumours more effectively than current treatments while reducing the risk of relapse and metastasis. Consistent with this notion, a recent study shows that SP cells have a strong tumorigenic ability and are more resistant to chemotherapy and radiotherapy, which may result in NPC recurrence.15 If this hypothesis holds true, CSCs could be the most promising target for new therapies. In addition, despite the huge growth in the CSC field, the biological behaviours of CSCs remain largely unexplored. Notch signaling defines a fundamental pathway controlling cell fate acquisition during embryonic development.16 New evidence shows that Notch signaling has been found in many solid tumours, plays diverse roles in different malignancies, and affects differentiation, proliferation, survival, cell-cycle progression, angiogenesis, and possibly self-renewal.17,18 Recent studies show that Notch signaling promotes medulloblastoma “stem cell” survival19 and is involved in tumour initiation in pancreatic cancer.20 However, the roles of Notch1 signaling in NPC are less well understood. In the present study, 32 patients with NPC, including (1) a well-differentiated keratinizing type, (2) a moderately differentiated nonkeratinizing type, and (3) an undiffer-entiated type according to the World Health Organization (WHO) classification, were examined by immunocyto-chemistry.21 We found that embryonic stem (ES) cell markers SOX2 and OCT4 were expressed in a small subpopulation of cells for all three subtypes of NPC. Double immunostaining shows that the ES-immuno-reactive cells coexpressed proliferative markers, suggesting that NPC in humans may contain cancer stem–like cells. In addition, we also found that the Notch1-activated form and Hes1, a downstream target of Notch1 signaling, were predominantly expressed in SOX2- and OCT4-positive cells, indicating the activation of Notch1 signaling in these cells. Our findings suggest that Notch1 signaling–mediated cancer stem–like cells might have a role in the tumorigenesis and progression of NPC in humans.