Wnt/beta-catenin signaling in cancer stemness and malignant behavior.

Stem cells are defined by their intrinsic capacity to self-renew and differentiate. Cancer stem cells retain both these features but have lost homeostatic mechanisms which maintain normal cell numbers. The canonical Wnt/beta-catenin signaling pathway plays a central role in modulating the delicate balance between stemness and differentiation in several adult stem cell niches such as the hair follicles in the skin, the mammary gland, and the intestinal crypt. Accordingly, constitutive Wnt signaling activation, resulting from mutations in genes encoding its downstream components, underlies tumorigenesis in these tissues. In the majority of sporadic colorectal cancer cases, the rate-limiting event is either loss of APC function or oncogenic beta-catenin mutations. However, although the presence of these initiating mutations would predict nuclear beta-catenin accumulation throughout the tumor mass, heterogeneous intracellular distributions of this key Wnt signaling molecule are observed within primary tumors and their metastases. In particular, tumor cells located at the invasive front and those migrating into the adjacent stromal tissues show nuclear beta-catenin staining. Hence, different levels of Wnt signaling activity reflect tumor heterogeneity and are likely to account for distinct cellular activities such as proliferation and epithelial-mesenchymal transitions, which prompt tumor growth and malignant behavior, respectively. Several intrinsic (cell-autonomous and/or autocrine) and extrinsic (paracrine, derived from the tumor microenvironment) factors may explain this heterogeneity of Wnt/beta-catenin signaling activity within the tumor mass.