Cancer stem cells, pluripotency, and cellular heterogeneity: a WNTer perspective

Cancer stem cells (CSCs) are thought to represent the "beating heart" of malignant growth as they continuously fuel tumors through their ability to self-renew and differentiate. Moreover, they are also believed to underlie malignant behavior, local invasion, and metastasis in distal organ sites upon reversible epithelial-to-mesenchymal transitions (EMTs). Nevertheless, the CSC concept has been the object of controversy, mainly due to the absence of robust operational definitions and to the lack of consistency in the use of the often incorrect nomenclature employed to refer to these cells. Notwithstanding the controversies, it is now generally accepted that primary cancers are organized in hierarchical fashion with neoplastic stem-like cells able to give rise to new CSCs and to more committed malignant cells. Notably, these hierarchical structures are not unidirectional, but are rather characterized by a more dynamic equilibrium where stem-like and more committed cancer cells transit from one meta-state to the other partly because of cues from the microenvironment (niche), but also because of intrinsic and yet incompletely understood characteristics in the activation/silencing of specific signal transduction pathways. Here, we will focus on the Wnt/β-catenin signaling pathway as one of the major regulator of stemness in homeostasis and cancer, and on germ cell tumors as the type of malignancy that most closely mimics normal embryonic development and as such serve as a unique model to study the role of stem cells in neoplasia.