title: Carbonic anhydrase IX promotes myeloid-derived suppressor cell mobilization and establishment of a metastatic niche by stimulating G-CSF production.
abstract: The mobilization of bone marrow-derived cells (BMDC) to distant tissues before the arrival of disseminated tumor cells has been shown preclinically to facilitate metastasis through the establishment of metastatic niches. Primary tumor hypoxia has been demonstrated to play a pivotal role in the production of chemokines and cytokines responsible for the mobilization of these BMDCs, especially in breast cancer. Carbonic anhydrase IX (CAIX, CA9) expression is highly upregulated in hypoxic breast cancer cells through the action of hypoxia-inducible factor-1 (HIF1). Preclinical evidence has demonstrated that CAIX is required for breast tumor growth and metastasis; however, the mechanism by which CAIX exerts its prometastatic function is not well understood. Here, we show that CAIX is indispensable for the production of granulocyte colony-stimulating factor (G-CSF) by hypoxic breast cancer cells and tumors in an orthotopic model. Furthermore, we demonstrate that tumor-expressed CAIX is required for the G-CSF-driven mobilization of granulocytic myeloid-derived suppressor cells (MDSC) to the breast cancer lung metastatic niche. We also determined that CAIX expression is required for the activation of NF-κB in hypoxic breast cancer cells and constitutive activation of the NF-κB pathway in CAIX-depleted cells restored G-CSF secretion. Together, these findings identify a novel hypoxia-induced CAIX-NF-κB-G-CSF cellular signaling axis culminating in the mobilization of granulocytic MDSCs to the breast cancer lung metastatic niche.
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Shawn C
authors.initials: SC
authors.lastname: Chafe
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Yuanmei
authors.initials: Y
authors.lastname: Lou
authors.affiliation: Tumour Microenvironment Laboratory, QIMR Berghofer, Herston, Queensland, Australia.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Sceneay
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Marylou
authors.initials: M
authors.lastname: Vallejo
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Melisa J
authors.initials: MJ
authors.lastname: Hamilton
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: McDonald
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Bennewith
authors.affiliation: Tumour Microenvironment Laboratory, QIMR Berghofer, Herston, Queensland, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Möller
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada. sdedhar@bccrc.ca.
authors.forename: Shoukat
authors.initials: S
authors.lastname: Dedhar
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000032:analysis; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000502:physiology*; D015687:Cell Hypoxia; D002465:Cell Movement; D054357:Chemokine CXCL10 / Q000502:physiology; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000473:pathology*
chemical_list: D039481:CD11b Antigen; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D016328:NF-kappa B; D016179:Granulocyte Colony-Stimulating Factor; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C492796:Car9 protein, mouse