(1,2). Although the stem cell niche varies in nature and location between different organs, in general terms it provides a unique signaling environment to maintain tissue homeostasis, inhibit stem cell loss, and control cell differentiation (1, 3, 4). The mammalian small intestine (SI) and colon represent unique models to study tissue stem cells and their niches because of their stereotypic and compact architecture combined with their exceedingly fast self-renewing kinetics (5, 6). In both SI and colon crypts, cycling stem cells are marked by leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) (7). Murine SI stem cells divide approximately every 24 h to fill a proliferative transit-amplifying compartment that occupies the remainder of the crypts. Cells exiting crypts arrest their cell cycle, differentiate, and move up the flanks of the villi. One of the differentiated cell types derived from the SI stem cell, the Paneth cell, is located at crypt bottoms and is in direct contact with Lgr5 stem cells. It produces factors that promote stem cell maintenance, including epidermal growth factor (EGF) and the related TGF-α, the Notch ligands Dll-1 and Dll-4, and Wnt3 (8-10). Whereas Paneth cells are dispensable for in vivo crypt function (as niche factors are also secreted from nonepithelial cells), Paneth cells are indispensable for the growth of epithelial miniguts in culture (9,11,12

Highlights d The majority of disseminating cells of colorectal cancer are Lgr5 À d Lgr5 À cancer cells are the main seeds of colorectal cancer metastatic lesions d Long-term metastatic growth from Lgr5 À cells requires appearance of Lgr5 + cells d Lgr5 À metastases have the intrinsic capacity to re-establish the cellular hierarchy