NANOG expression in human development and cancerogenesis

Abstract

NANOG is an important stem cell transcription factor involved in human development and cancerogenesis. Its expression is complex and regulated on different levels. Moreover, NANOG protein might regulate hundreds of target genes at the same time. NANOG is crucial for preimplantation development phase and progressively decreases during embryonic stem cells differentiation, thus regulating embryonic and fetal development. Postnatally, NANOG is undetectable or expressed in very low amounts in the majority of human tissues. NANOG re-expression can be detected during cancerogenesis, already in precancerous lesions, with increasing levels of NANOG in high grade dysplasia. NANOG is believed to enable cancer cells to obtain stem-cell like properties, which are believed to be the source of expanding growth, tumor maintenance, metastasis formation, and tumor relapse. High NANOG expression in cancer is frequently associated with advanced stage, poor differentiation, worse overall survival, and resistance to treatment, and is therefore a promising prognostic and predictive marker. We summarize the current knowledge on the role of NANOG in cancerogenesis and development, including our own experience. We provide a critical overview of NANOG as a prognostic and diagnostic factor, including problems regarding its regulation and detection.

Impact statement: NANOG has emerged as a key stem cell transcription factor in normal development and cancerogenesis. It is generally regarded as a good prognostic and predictive factor in various human cancers. It is less known that it is expressed already at precancerous stages in various organs, suggesting that finally an ideal candidate diagnostic marker has been discovered, enabling to distinguish between true dysplasia and reactive atypia. NANOG regulation is complex, and new insights into our understanding of its regulation might provide important information for future development in a broad field of two entirely different processes, i.e. normal development and cancerogenesis, showing how a physiologic mechanism can be used and abused, transforming itself into a key mechanism of disease development and progression.

Keywords: Nanog; cancer; cancerogenesis; development; precancerosis; stem cells.

Figure 1.

Regulation of NANOG expression in carcinoma. Dashed arrows show predicted regulatory functions. (A color version of this figure is available in the online journal.)

Figure 2.

Fetal ovary, 36 weeks of gestation (a). Immunohistochemistry for NANOG shows positive reaction in oocytes (b). (A color version of this figure is available in the online journal.)

Figure 3.

Dysplasia of the oral mucosa – transition of the normal squamous epithelium to dysplastic epithelium (a). Dysplastic squamous epithelium stains immunohistochemically for NANOG, there is no staining in the normal epithelium (b). (A color version of this figure is available in the online journal.)

Figure 4.

Tubular adenoma of the colon (a). Focally positive immunohistochemical reaction for NANOG in dysplastic glands of adenoma (b). (A color version of this figure is available in the online journal.)

Figure 5.

Adenocarcinoma of the colon – neoplastic glands show marked cellular atypia and focal necrosis (a). Immunohistochemical reaction for NANOG is positive in the majority of tumor cells (b). (A color version of this figure is available in the online journal.)

Figure 6.

Mixed germ cell tumor of the testis, consisting of embryonal carcinoma and choriocarcinoma (a). Immunohistochemical reaction for NANOG is positive in embryonal carcinoma and negative in choriocarcinoma (b). (A color version of this figure is available in the online journal.)