title: Myeloid WNT7b mediates the angiogenic switch and metastasis in breast cancer.
abstract: Oncogenic targets acting in both tumor cells and tumor stromal cells may offer special therapeutic appeal. Interrogation of the Oncomine database revealed that 52 of 53 human breast carcinomas showed substantial upregulation of WNT family ligand WNT7B. Immunolabeling of human mammary carcinoma showed that WNT7B immunoreactivity was associated with both tumor cells and with tumor-associated macrophages. In the MMTV-PymT mouse model of mammary carcinoma, we found tumor progression relied upon WNT7B produced by myeloid cells in the microenvironment. Wnt7b deletion in myeloid cells reduced the mass and volume of tumors due to a failure in the angiogenic switch. In the tumor overall, there was no change in expression of Wnt/β-catenin pathway target genes, but in vascular endothelial cells (VEC), expression of these genes was reduced, suggesting that VECs respond to Wnt/β-catenin signaling. Mechanistic investigations revealed that failure of the angiogenic switch could be attributed to reduced Vegfa mRNA and protein expression in VECs, a source of VEGFA mRNA in the tumor that was limiting in the absence of myeloid WNT7B. We also noted a dramatic reduction in lung metastasis associated with decreased macrophage-mediated tumor cell invasion. Together, these results illustrated the critical role of myeloid WNT7B in tumor progression, acting at the levels of angiogenesis, invasion, and metastasis. We suggest that therapeutic suppression of WNT7B signaling might be advantageous due to targeting multiple aspects of tumor progression.
authors.affiliation: Authors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UKAuthors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UK.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Yeo
authors.affiliation: Authors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UK.
authors.forename: Luca
authors.initials: L
authors.lastname: Cassetta
authors.affiliation: Authors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UK.
authors.forename: Bin-Zhi
authors.initials: BZ
authors.lastname: Qian
authors.affiliation: Authors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Lewkowich
authors.affiliation: Authors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UK.
authors.forename: Jiu-feng
authors.initials: JF
authors.lastname: Li
authors.affiliation: Authors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UKAuthors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Stefater
authors.affiliation: Authors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UKAuthors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UK.
authors.forename: April N
authors.initials: AN
authors.lastname: Smith
authors.affiliation: Authors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UK.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Wiechmann
authors.affiliation: Authors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UK.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Authors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UK Richard.Lang@cchmc.org jeffrey.pollard@einstein.yu.edu jeff.pollard@ed.ac.uk.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pollard
authors.affiliation: Authors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UKAuthors' Affiliations: The Visual Systems Group, Divisions of Pediatric Ophthalmology and Developmental Biology; Division of Immunobiology, Cincinnati Children's Hospital Medical Center; Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio; Departments of Developmental and Molecular Biology, Surgery, Pathology, and MRC Centre for Reproductive Health, University of Edinburgh, UK Richard.Lang@cchmc.org jeffrey.pollard@einstein.yu.edu jeff.pollard@ed.ac.uk.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; C490675:WNT7B protein, human; D051153:Wnt Proteins; C095937:Wnt7b protein, mouse; D051176:beta Catenin