Stromal-Initiated Changes in the Bone Promote Metastatic Niche Development
Open accessAbstract
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.
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Senescent osteoblasts drive colonization of the bone niche by metastatic breast cancer cells in an IL-6-dependent manner.
“In addition, senescent osteoblasts drive the colonization of the bone niche of metastatic breast cancer cells in an IL-6-dependent manner.198”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [198]
FASST mice show a significant increase in the number of senescent cells within the skin stroma compared with littermate controls, as well as within the mammary gland, lung, and bone.
“We observed a significant increase in the number of senescent cells within the skin stroma of FASST mice compared with littermate controls (Fig. 1a,b) as well as within the mammary gland, lung (data not shown) and bone20, reflecting the mesenchymal nature of the collagen promoter used in our system.”
From Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis (2016) · cites this paper as [20]
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Senescent Stromal Cells in the Tumor Microenvironment: Victims or Accomplices?
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Stromal senescence contributes to age-related increases in cancer
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- Authors
- Luo, X., Fu, Y., Loza, A. J., Murali, B., Leahy, K. M., Ruhland, M. K., Gang, M., Su, X., Zamani, A., Shi, Y., Lavine, K. J., Ornitz, D. M., Weilbaecher, K. N., Long, F., Novack, D. V., Faccio, R., Longmore, G. D., & Stewart, S. A.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Stewart, Sheila A.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-01
- Volume
- 14
- Issue
- 1
- Pages
- 82-92
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4706805
- OpenAlex
- W2201784569
- Cited by
- 141
- References
- 40
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 13 · 2023: 16 · 2022: 8 · 2021: 14 · 2020: 23 · 2019: 12 · 2018: 15 · 2017: 11 · 2016: 4 · 2014: 1
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Washington University in St. Louis
- Foundation for Barnes-Jewish Hospital
- Alvin J. Siteman Cancer Center
- National Institutes of Health (CA143868, AR057235)
- National Cancer Institute (R01CA097250, U54CA143868, R01CA151518, R56CA097250, CA143868, P50CA094056, CA097250, R01CA196205, T32CA113275)
- National Institute of General Medical Sciences (T32GM007200)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR055923, AR052705, P30AR057235, R01AR052705, AR057235)
- National Institute of Biomedical Imaging and Bioengineering (T32EB018266)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD049808, R01HD049808)
- Topics
- Health Sciences › Medicine › Oncology › Bone health and treatments
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- breast cancer bone metastasis, reactive stroma, osteoblast senescence, senescence-associated secretory phenotype, interleukin-6, osteoclastogenesis, bone mineralization, metastatic niche, tumor microenvironment, bone colonization
- MeSH terms
- Animals, Bone Neoplasms, Female, Humans, Mammary Neoplasms, Experimental, Mice, Transgenic, Neoplasm Metastasis, Neoplasm Proteins, Osteoblasts, Interleukin-6, Cellular Senescence, Mice, Tumor Microenvironment
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