title: Stromal-Initiated Changes in the Bone Promote Metastatic Niche Development.
abstract: More than 85% of advanced breast cancer patients suffer from metastatic bone lesions, yet the mechanisms that facilitate these metastases remain poorly understood. Recent studies suggest that tumor-derived factors initiate changes within the tumor microenvironment to facilitate metastasis. However, whether stromal-initiated changes are sufficient to drive increased metastasis in the bone remains an open question. Thus, we developed a model to induce reactive senescent osteoblasts and found that they increased breast cancer colonization of the bone. Analysis of senescent osteoblasts revealed that they failed to mineralize bone matrix and increased local osteoclastogenesis, the latter process being driven by the senescence-associated secretory phenotype factor, IL-6. Neutralization of IL-6 was sufficient to limit senescence-induced osteoclastogenesis and tumor cell localization to bone, thereby reducing tumor burden. Together, these data suggest that a reactive stromal compartment can condition the niche, in the absence of tumor-derived signals, to facilitate metastatic tumor growth in the bone.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; ICCE Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Xianmin
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; ICCE Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Fu
authors.affiliation: ICCE Institute, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Loza
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; ICCE Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Bhavna
authors.initials: B
authors.lastname: Murali
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; ICCE Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Leahy
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; ICCE Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Ruhland
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; ICCE Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Margery
authors.initials: M
authors.lastname: Gang
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Xinming
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Zamani
authors.affiliation: Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Kory J
authors.initials: KJ
authors.lastname: Lavine
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Weilbaecher
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Deborah V
authors.initials: DV
authors.lastname: Novack
authors.affiliation: Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Faccio
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; ICCE Institute, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Longmore
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; ICCE Institute, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: sheila.stewart@wustl.edu.
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Stewart
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016922:Cellular Senescence / Q000235:genetics; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: D015850:Interleukin-6; D009363:Neoplasm Proteins; C577686:interleukin-6, mouse