title: Wnt1 expression induces short-range and long-range cell recruitments that modify mammary tumor development and are not induced by a cell-autonomous beta-catenin effector.
abstract: Xenograft model studies have shown that tumor-associated, or genetically modified, activated stromal cells can promote tumor cell growth. Here, we examined mammary tumors arising in response to two different transgene-mediated Wnt signaling effectors: Wnt1 (a ligand with cell-nonautonomous effects) and DeltaNbeta-catenin (a constitutively active form of the intracellular effector). Although the route of tumor development has been shown to be similar for these two models, histologic analysis shows that Wnt1-induced tumors are associated with tracts of activated stroma, whereas most DeltaNbeta-catenin-induced tumors are solid adenocarcinomas. Furthermore, quantification of the "reactive stroma index" indicates that abundant activated stroma correlates with accelerated tumor progression. Wnt1-expressing mammary epithelial cells induce Wnt-specific target gene expression in local stromal cells (Wnt1-induced secreted protein 1/CCN4) but also induce long-range effects. Thus, mice with rapid tumor progression have 2-fold more circulating endothelial progenitor cells in peripheral blood than control or DeltaNbeta-catenin transgenic mice. Using tagged bone marrow (BM) transplants, we show that BM-derived cells are massively recruited to infiltrate the stroma of Wnt1-induced tumors where they differentiate into multiple cell types. Thus, localized ectopic expression of the proto-oncogene Wnt1 in mammary glands induces systemic responses, and we propose that this response modifies the tumorigenic outcome.
authors.affiliation: McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Kim
authors.forename: Rod J
authors.initials: RJ
authors.lastname: Clark
authors.forename: Erik A
authors.initials: EA
authors.lastname: Ranheim
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Alexander
mesh_terms: D000818:Animals; D018450:Disease Progression; D005260:Female; D008264:Macrophages / Q000473:pathology; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology; D051155:Wnt1 Protein / Q000096:biosynthesis* / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D051176:beta Catenin