Differentiation Generates Paracrine Cell Pairs That Maintain Basaloid Mouse Mammary Tumors: Proof of Concept
Figure 5
(A) In normal mammary epithelium, the Wnt source that maintains Lrp5+ mammary stem cells is indicated by a red-colored nucleus in a non-epithelial cell type, inferred from [40]. (B) For Wnt1-induced mammary tumors, we have illustrated a paracrine signaling network that depends upon interactive basal and luminal cells. Wnt1 ligand and Lrp5 receptor are necessary and sufficient to maintain tumors (Lindvall et al., 2006). Wnt1, under the control of the MMTV-LTR sequence, is expressed by luminal cells (this cis sequence is only upregulated in luminal cells). Lrp5 protein is typically expressed by basal cells. (C) Cells that comprise the tumor cell community include (Lrp5+) basal cells that can differentiate to luminal cells to provide a ligand-expressing luminal partner. We have shown that some of these luminal cells also express Lrp5. (D) All cells with stem cell activity express Lrp5 and are able to regenerate robust mixtures of basal and luminal cells that support tumor growth by paracrine interactions. Thus, basal cells are predictable stem cells, since they differentiate to Wnt1-expressing luminal cells, whereas luminal cells are novel, Wnt-induced stem cells that express sufficient Lrp5 to enable their survival, but also show fate plasticity, to enable retro-differentiation to basal cells.