Invasive colon cancer, but not non-invasive adenomas induce a gradient effect of Wnt pathway receptor frizzled 1 (Fz1) e
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RESEARCH
Open Access
Invasive colon cancer, but not non-invasive adenomas induce a gradient effect of Wnt pathway receptor frizzled 1 (Fz1) expression in the tumor microenvironment Kestutis Planutis1, Marina Planutiene1, Anthony V Nguyen2, Mary Pat Moyer3 and Randall F Holcombe1*
Abstract Background: Wnt signaling in the colon cancer tumor microenvironment (TME) may affect cancer biologic properties including invasion and metastatic dissemination. Prior reports have suggested that the expression of select frizzled (Fz) receptors may be altered in cancers and in the TME. Methods: Colon cancer, colonic adenoma and normal colonic mucosal specimens were obtained under institutional review board approval and analyzed for the expression of Fz1 and Fz2 by confocal fluorescent immunohistochemistry and Wnt-specific membrane array. In vitro, the effect of Wnt3a on Fz1 expression was examined in normal-derived NCM460 cells by qRT-PCR and immunohistochemistry. Results: Fz1 was expressed in colon cancer and villous adenomas but not in more benign tubular adenomas. Fz1 expression was seen in normal colonic mucosa in close proximity to colon cancer, but not villous or tubular adenomas. Normal colonic mucosa distant from colon cancer did not express Fz1. Fz2 was expressed ubiquitously in cancer, adenomas and normal colonic mucosa. Fz1 expression was induced by Wnt3a in a normal colon mucosa-derived cell line in vitro. Conclusions: Fz1 is a Wnt responsive gene in colon-derived tissues. Fz1 expression exhibited increased expression in normal mucosa only in close proximity to colon cancer. This field effect was not seen with pre-malignant adenomas and may be due to Wnt/β-catenin signaling within the TME. Fz1 may represent a new TME-directed therapeutic target for patients with colon cancer. Keywords: Wnt signaling, Colon cancer, Tumor microenvironment, Fz receptors, Wnt3a
Background There is increasing recognition that tumor biology is modulated by signals derived from, and received by cells within the tumor microenvironment (TME) [1]. Interactions with non-transformed cells in the TME may facilitate invasion and metastases, or, alternatively, inhibit tumor progression. Enhanced Wnt pathway signaling has been recognized as a hallmark of colon cancer with over 85% of these malignancies harboring mutations within the pathway that lead to constitutive activation [2]. However, the strength of the Wnt * Correspondence: [email protected] 1 Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA Full list of author information is available at the end of the article
signal is modulated by factors within the TME, including Wnt ligands which augment canonical Wnt signaling and soluble inhibitors which suppress it [3,4]. Wnt activity in colon cancer stem cells is modulated by myofibroblast-secreted factors in the TME [5] and other stromal cells may similarly regulate Wnt activity in colon cancer in a paracrine fashion [6]. Interactions of malignant with stromal cells may affect Wnt
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