title: Cancer Stem Cells Regulate Cancer-Associated Fibroblasts via Activation of Hedgehog Signaling in Mammary Gland Tumors.
abstract: Many tumors display intracellular heterogeneity with subsets of cancer stem cells (CSC) that sustain tumor growth, recurrence, and therapy resistance. Cancer-associated fibroblasts (CAF) have been shown to support and regulate CSC function. Here, we investigate the interactions between CSCs and CAFs in mammary gland tumors driven by combined activation of Wnt/β-catenin and Hgf/Met signaling in mouse mammary epithelial cells. In this setting, CSCs secrete the Hedgehog ligand SHH, which regulate CAFs via paracrine activation of Hedgehog signaling. CAFs subsequently secrete factors that promote expansion and self-renewal of CSCs.In vivotreatment of tumors with the Hedgehog inhibitor vismodegib reduce CAF and CSC expansion, resulting in an overall delay of tumor formation. Our results identify a novel intracellular signaling module that synergistically regulates CAFs and CSCs. Targeting CAFs with Hedgehog inhibitors may offer a novel therapeutic strategy against breast cancer.Cancer Res; 77(8); 2134-47. ©2017 AACR.
authors.affiliation: Cancer Research Program, Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Society, Berlin, Germany.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Valenti
authors.affiliation: Cancer Research Program, Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Society, Berlin, Germany.
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Quinn
authors.affiliation: Cancer Research Program, Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Society, Berlin, Germany.
authors.forename: Guus J J E
authors.initials: GJJE
authors.lastname: Heynen
authors.affiliation: Cancer Research Program, Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Society, Berlin, Germany.
authors.forename: Linxiang
authors.initials: L
authors.lastname: Lan
authors.affiliation: Cancer Research Program, Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Society, Berlin, Germany.
authors.forename: Jane D
authors.initials: JD
authors.lastname: Holland
authors.affiliation: Cancer Research Program, Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Society, Berlin, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Vogel
authors.affiliation: Experimental Pharmacology & Oncology (EPO), Berlin, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Wulf-Goldenberg
authors.affiliation: Cancer Research Program, Max Delbrueck Center for Molecular Medicine (MDC) in the Helmholtz Society, Berlin, Germany. wbirch@mdc-berlin.de.
authors.forename: Walter
authors.initials: W
authors.lastname: Birchmeier
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000813:Anilides; C495267:CTNNB1 protein, mouse; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; D051153:Wnt Proteins; D051176:beta Catenin; D019859:Proto-Oncogene Proteins c-met