TY - JOUR
T1 - Stromal-Initiated Changes in the Bone Promote Metastatic Niche Development
AU - Luo, Xianmin
AU - Fu, Yujie
AU - Loza, Andrew J.
AU - Murali, Bhavna
AU - Leahy, Kathleen M.
AU - Ruhland, Megan K.
AU - Gang, Margery
AU - Su, Xinming
AU - Zamani, Ali
AU - Shi, Yu
AU - Lavine, Kory J.
AU - Ornitz, David M.
AU - Weilbaecher, Katherine N.
AU - Long, Fanxin
AU - Novack, Deborah V.
AU - Faccio, Roberta
AU - Longmore, Gregory D.
AU - Stewart, Sheila A.
N1 - Funding Information:
We thank Ben Dao, Kelly Carbery, Joshua Behlman, and Cynthia Hernandez for assistance in establishing the FASST mouse breeding colonies and Lynne Collins and Julie Prior for assistance in animal imaging. We thank Rosy Luo for assistance with statistical analysis and Mia Wallace for assistance with speed congenics. We thank Raphael Kopan and Barry Sleckman for mouse genetics advice and Michele A. Hurchla, Jingyu Xiang, Jenna Regan, Diana Zamora, Billy McManus, Yulia Ivanova, Rong Zeng, Marcus Watkins, and Roberto Civitelli for advice and assistance. We extend a special thanks to Drs. Robert Weinberg and Daniel Link and members of S.A.S.’s lab for helpful comments. We thank Dr. Elizabeth Jaffee for the kind gift of the NT2.5 cells and Drs. Denton and Benoit de Crombrugghe for the kind gift of the Col-Cre-ER T2 mice. We thank Drs. Denchi and de Lange for the kind gift of the conditional TRF2 mice. Financial support was provided by NIH 5 R01CA151518 (S.A.S.) and American Cancer Society Research Scholar Award (S.A.S.). The work was supported in part by the Alvin J. Siteman Cancer Research Fund at Washington University in St. Louis, MO (S.A.S.) and Siteman Cancer Center/Barnes-Jewish Hospital Foundation (S.A.S.), the Susan G. Komen Breast Cancer Foundation (S.A.S.), Washington University Center for Aging (S.A.S.), Mary Kay Ash Charitable Foundation (S.A.S.), NIH AR052705 (D.V.N.), NIH HD049808 (D.M.O.), NIH CA143868 (G.D.L.), and NIH CA097250 (K.N.W.). A.J.L. was supported by training grants T32EB018266 and T32GM007200. Histologic analysis was supported in part by the Washington University Center for Musculoskeletal Research and the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant AR057235. The Molecular Imaging Center and NIH P50 CA094056 (PIs Samuel Achilefu and David Piwnica-Worms) support animal imaging.
Funding Information:
We thank Ben Dao, Kelly Carbery, Joshua Behlman, and Cynthia Hernandez for assistance in establishing the FASST mouse breeding colonies and Lynne Collins and Julie Prior for assistance in animal imaging. We thank Rosy Luo for assistance with statistical analysis and Mia Wallace for assistance with speed congenics. We thank Raphael Kopan and Barry Sleckman for mouse genetics advice and Michele A. Hurchla, Jingyu Xiang, Jenna Regan, Diana Zamora, Billy McManus, Yulia Ivanova, Rong Zeng, Marcus Watkins, and Roberto Civitelli for advice and assistance. We extend a special thanks to Drs. Robert Weinberg and Daniel Link and members of S.A.S.’s lab for helpful comments. We thank Dr. Elizabeth Jaffee for the kind gift of the NT2.5 cells and Drs. Denton and Benoit de Crombrugghe for the kind gift of the Col-Cre-ERT2 mice. We thank Drs. Denchi and de Lange for the kind gift of the conditional TRF2 mice. Financial support was provided by NIH 5 R01CA151518 (S.A.S.) and American Cancer Society Research Scholar Award (S.A.S.). The work was supported in part by the Alvin J. Siteman Cancer Research Fund at Washington University in St. Louis, MO (S.A.S.) and Siteman Cancer Center/Barnes-Jewish Hospital Foundation (S.A.S.), the Susan G. Komen Breast Cancer Foundation (S.A.S.), Washington University Center for Aging (S.A.S.), Mary Kay Ash Charitable Foundation (S.A.S.), NIH AR052705 (D.V.N.), NIH HD049808 (D.M.O.), NIH CA143868 (G.D.L.), and NIH CA097250 (K.N.W.). A.J.L. was supported by training grants T32EB018266 and T32GM007200. Histologic analysis was supported in part by the Washington University Center for Musculoskeletal Research and the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant AR057235. The Molecular Imaging Center and NIH P50 CA094056 (PIs Samuel Achilefu and David Piwnica-Worms) support animal imaging.
Publisher Copyright:
© 2016 The Authors.
PY - 2016/1/5
Y1 - 2016/1/5
N2 - 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. Luo et al. show that stromal-derived changes are sufficient to increase tumor cell colonization and metastatic growth in the bone. They report that senescent osteoblasts, and, in particular, the senescence-associated secretory phenotype factor IL-6 drives localized osteoclastogenesis and tumor cell growth.
AB - 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. Luo et al. show that stromal-derived changes are sufficient to increase tumor cell colonization and metastatic growth in the bone. They report that senescent osteoblasts, and, in particular, the senescence-associated secretory phenotype factor IL-6 drives localized osteoclastogenesis and tumor cell growth.
UR - http://www.scopus.com/inward/record.url?scp=84952985171&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.12.016
DO - 10.1016/j.celrep.2015.12.016
M3 - Article
C2 - 26725121
AN - SCOPUS:84952985171
SN - 2211-1247
VL - 14
SP - 82
EP - 92
JO - Cell Reports
JF - Cell Reports
IS - 1
ER -