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Wnt1 Expression Induces Short-Range and Long-Range Cell Recruitments That Modify Mammary Tumor Development and Are Not Induced by a Cell-Autonomous β-Catenin Effector

¹ McArdle Laboratory for Cancer Research and ² Clinical Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin

Requests for reprints: Caroline M. Alexander, University of Wisconsin, 1400 University Avenue, Madison, WI 53706. Phone: 608-265-5182; Fax: 608-262-2824; E-mail: alexander{at}oncology.wisc.edu.

Key Words: Stroma • Wnt • Mammary tumor • Bone marrow–derived cells • Endothelial progenitor cells

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 Nβ-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 Nβ-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 Nβ-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. [Cancer Res 2008;68(24):10145–53]