title: Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment.
abstract: Intratumoral hypoxia induces the recruitment of stromal cells, such as macrophages and mesenchymal stem cells (MSCs), which stimulate invasion and metastasis by breast cancer cells (BCCs). Production of macrophage colony-stimulating factor 1 (CSF1) by BCCs is required for macrophage recruitment, but the mechanisms underlying CSF1 expression have not been delineated. Triple-negative breast cancers have increased expression of genes regulated by hypoxia-inducible factors (HIFs). In this study, we delineate two feed-forward signaling loops between human MDA-MB-231 triple-negative BCCs and human MSCs that drive stromal cell recruitment to primary breast tumors. The first loop, in which BCCs secrete chemokine (C-X-C motif) ligand 16 (CXCL16) that binds to C-X-C chemokine receptor type 6 (CXCR6) on MSCs and MSCs secrete chemokine CXCL10 that binds to receptor CXCR3 on BCCs, drives recruitment of MSCs. The second loop, in which MSCs secrete chemokine (C-C motif) ligand 5 that binds to C-C chemokine receptor type 5 on BCCs and BCCs secrete cytokine CSF1 that binds to the CSF1 receptor on MSCs, drives recruitment of tumor-associated macrophages and myeloid-derived suppressor cells. These two signaling loops operate independent of each other, but both are dependent on the transcriptional activity of HIFs, with hypoxia serving as a pathophysiological signal that synergizes with chemokine signals from MSCs to trigger CSF1 gene transcription in triple-negative BCCs.
authors.affiliation: Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, and.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Chaturvedi
authors.affiliation: Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, and.
authors.forename: Daniele M
authors.initials: DM
authors.lastname: Gilkes
authors.affiliation: Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, and.
authors.forename: Naoharu
authors.initials: N
authors.lastname: Takano
authors.affiliation: Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, andDepartments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205 gsemenza@jhmi.edu.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D045744:Cell Line, Tumor; D002465:Cell Movement; D054357:Chemokine CXCL10 / Q000378:metabolism; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D019713:Receptors, CCR5 / Q000378:metabolism; D051116:Receptors, Scavenger / Q000378:metabolism; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*
chemical_list: C584933:CCR5 protein, human; C114753:CXCL10 protein, human; C423727:CXCL16 protein, human; D054357:Chemokine CXCL10; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D051793:Hypoxia-Inducible Factor 1; D019713:Receptors, CCR5; D051116:Receptors, Scavenger
keywords: HIF-1; lung metastasis; lymph node metastasis; mammary fat pad; orthotopic implantation