RETRACTED ARTICLE: The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase
Open accessAbstract
Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
High expression of LOX in primary tumors is associated with the formation of osteolytic bone lesions in mice.
“high expression of LOX in primary tumors was found to be associated with the formation of osteolytic bone lesions in mice”
From Hypoxic control of metastasis (2016) · cites this paper as [96]
LOX expression is clinically associated with estrogen receptor negative breast cancer metastasis to bone.
“Additionally, LOX expression is clinically associated with estrogen receptor negative (ER−) breast cancer metastasis to bone.”
From Hypoxic control of metastasis (2016) · cites this paper as [96]
Proteomic analysis of the hypoxic secretome in bone tropic MDA-231 human breast cancer cells compared to MDA-231 parental cells identified LOX as one of the most highly up-regulated secreted proteins in bone-tropic cells.
“Proteomic analysis of the hypoxic secretome in bone tropic MDA-231 human breast cancer cells compared to MDA-231 parental cells identified LOX as one of the most highly up-regulated secreted proteins in bone-tropic cells”
From Hypoxic control of metastasis (2016) · cites this paper as [96]
LOX regulates osteoclastogenesis.
“LOX regulates osteoclastogenesis”
From Hypoxic control of metastasis (2016) · cites this paper as [96]
In preclinical models, LOX expression in MDA-231 bone-tropic cells within the primary tumor is both necessary and sufficient to induce osteolytic bone lesions and cortical bone loss in immunocompromised mice even before the arrival of tumor cells.
“In preclinical models, LOX expression in MDA-231 bone-tropic cells within the primary tumor is both necessary and sufficient to induce osteolytic bone lesions and cortical bone loss in immunocompromised mice even before the arrival of tumor cells.”
From Hypoxic control of metastasis (2016) · cites this paper as [96]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Lysyl oxidase is essential for hypoxia-induced metastasis
Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhöfer, N., Kong, C., Le, Q.-T., Chi, J.-T. A., Jeffrey, S. S., & Giaccia, A. J. (2006) · Nature · doi:10.1038/nature04695 · Cited by 1,309 · see citing works
Self-citationRetractedMolecular Mechanisms of Stress-Responsive Changes in Collagen and Elastin Networks in Skin
Aziz, J., Shezali, H., Radzi, Z., Yahya, N. A., Abu Kassim, N. H., Czernuszka, J., & Rahman, M. T. (2016) · Skin Pharmacology and Physiology · doi:10.1159/000447017 · Cited by 7,323 · see citing works
Osteoclast differentiation and activation
Boyle, W. J., Simonet, W. S., & Lacey, D. L. (2003) · Nature · doi:10.1038/nature01658 · Cited by 6,670 · see citing works
A Gene-Expression Signature as a Predictor of Survival in Breast Cancer
van de Vijver, M. J., He, Y. D., Veer, L. V. ‘., Dai, H. A., Hart, A. A. M., Voskuil, D. W., Schreiber, G. J., Peterse, J. L., Roberts, C., Marton, M. J., et al. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa021967 · Cited by 6,411 · see citing works
PARFITT, A. M., Drezner, M. K., Glorieux, F. H., Kanis, J. А., Malluche, H. H., Meunier, P. J., Ott, S. M., & Recker, R. R. (1987) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.5650020617 · Cited by 5,015 · see citing works
VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche
Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., MacDonald, D. D., Jin, D. K., Shido, K., Kerns, S. A., et al. (2005) · Nature · doi:10.1038/nature04186 · Cited by 3,288 · see citing works
Bone Histomorphometry : Standardization of Nomenclature, Symbols, and Units
PARFITT, A. M., Drezner, M. K., Glorieux, F. H., Kanis, J. А., Malluche, H. H., Meunier, P. J., Ott, S. M., & Recker, R. R. (1987) · Journal of Bone and Mineral Research · Cited by 3,258 · see citing works
A multigenic program mediating breast cancer metastasis to bone
Kang, Y., Siegel, P. M., Shu, W., Drobnjak, M., Käkönen, S.-M., Cordon‐Cardo, C., Guise, T. A., & Massagué, J. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00132-6 · Cited by 2,562 · see citing works
Héroux, J., & Gharib, A. M. (2008) · CRC Press eBooks · doi:10.3109/9781420019957-3 · Cited by 2,216 · see citing works
Tumor metastasis: mechanistic insights and clinical challenges
Steeg, P. S. (2006) · Nature Medicine · doi:10.1038/nm1469 · Cited by 2,135 · see citing works
Erler, J. T., Bennewith, K. L., Cox, T. R., Lang, G., Bird, D., Koong, A., Le, Q.-T., & Giaccia, A. J. (2009) · Cancer Cell · doi:10.1016/j.ccr.2008.11.012 · Cited by 1,231 · see citing works
Self-citationThe clinical course of bone metastases from breast cancer
Coleman, R., & Rubens, R. (1987) · British Journal of Cancer · doi:10.1038/bjc.1987.13 · Cited by 1,070 · see citing works
Hiratsuka, S., Watanabe, A., Aburatani, H., & Maru, Y. (2006) · Nature Cell Biology · doi:10.1038/ncb1507 · Cited by 1,016 · see citing works
Subtypes of Breast Cancer Show Preferential Site of Relapse
Smid, M., Wang, Y., Zhang, Y., Sieuwerts, A. M., Yu, J. X., Klijn, J. G. M., Foekens, J. A., & Martens, J. W. M. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5644 · Cited by 817 · see citing works
Garrett, I. R., Boyce, B. F., Oreffo, R. O. C., Bonewald, L. F., Poser, J. W., & Mundy, G. R. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114485 · Cited by 807 · see citing works
Chi, J., Wang, Z., Nuyten, D. S. A., Rodriguez, E. H., Schaner, M. E., Salim, A., Wang, Y., Kristensen, G. B., Helland, Å., Børresen‐Dale, A., et al. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030047 · Cited by 622 · see citing works
The rationale for targeting the LOX family in cancer
Barker, H. E., Cox, T. R., & Erler, J. T. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3319 · Cited by 592 · see citing works
Self-citationLOX-Mediated Collagen Crosslinking Is Responsible for Fibrosis-Enhanced Metastasis
Cox, T. R., Bird, D., Baker, A.-M., Barker, H. E., Ho, M. W.-Y., Lang, G., & Erler, J. T. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-2233 · Cited by 571 · see citing works
Self-citationHypoxic gene expression and metastasis
Le, Q., Denko, N. C., & Giaccia, A. J. (2004) · Cancer and Metastasis Reviews · doi:10.1023/b:canc.0000031768.89246.d7 · Cited by 466 · see citing works
Baker, A.-M., Bird, D., Lang, G., Cox, T. R., & Erler, J. T. (2012) · Oncogene · doi:10.1038/onc.2012.202 · Cited by 332 · see citing works
Self-citationHypoxia, gene expression, and metastasis
Chan, D. A., & Giaccia, A. J. (2007) · Cancer and Metastasis Reviews · doi:10.1007/s10555-007-9063-1 · Cited by 276 · see citing works
Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy
El-Haibi, C. P., Bell, G. W., Zhang, J., Collmann, A. Y., Wood, D. K., Scherber, C. M., Csizmadia, E., Mariani, O., Zhu, C., Campagne, A., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206653109 · Cited by 218 · see citing works
The Role of Lysyl Oxidase in SRC-Dependent Proliferation and Metastasis of Colorectal Cancer
Baker, A., Cox, T. R., Bird, D., Lang, G., Murray, G. I., Sun, X., Southall, S. M., Wilson, J. R., & Erler, J. T. (2011) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djq569 · Cited by 206 · see citing works
Self-citationStimulation of osteoclastic bone resorption by hydrogen peroxide
Bax, B. E., Alam, A. S. M. T., Banerji, B., Bax, C. M. R., Bevis, P. J. R., Stevens, C. R., Moonga, B. S., Blake, D. R., & Zaidi, M. (1992) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(05)80311-0 · Cited by 201 · see citing works
Bondareva, A. A., Downey, C. M., Ayres, F. J., Liu, W., Boyd, S. K., Hallgrímsson, B., & Jirik, F. R. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005620 · Cited by 159 · see citing works
Expression of a P2X7 Receptor by a Subpopulation of Human Osteoblasts
Gartland, A., Hipskind, R. A., Gallagher, J. A., & Bowler, W. B. (2001) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2001.16.5.846 · Cited by 134 · see citing works
Self-citationMonteiro, A. C., Leal, A. C., Gonçalves-Silva, T., Mercadante, A. C. T., Kestelman, F., Chaves, S. B., Azevedo, R. B., Monteiro, J. P., & Bonomo, A. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068171 · Cited by 111 · see citing works
Feres‐Filho, E. J., Choi, Y. J., Han, X., et al. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.51.30797 · Cited by 98 · see citing works
Global secretome analysis identifies novel mediators of bone metastasis
Blanco, M. A., LeRoy, G., Khan, Z., Alečković, M., Zee, B. M., Garcia, B. A., & Kang, Y. (2012) · Cell Research · doi:10.1038/cr.2012.89 · Cited by 96 · see citing works
Differential secretome analysis reveals CST6 as a suppressor of breast cancer bone metastasis
Jin, L., Zhang, Y., Li, H., Yao, L., Fu, D., Yao, X., Xu, L. X., Hu, X., & Hu, G. (2012) · Cell Research · doi:10.1038/cr.2012.90 · Cited by 65 · see citing works
Lysyl Oxidase (Lox) Gene Deficiency Affects Osteoblastic Phenotype
Pischon, N., Mäki, J. M., Weißhaupt, P., et al. (2009) · Calcified Tissue International · doi:10.1007/s00223-009-9252-8 · Cited by 63 · see citing works
Reduced Bone Turnover in Mice Lacking the P2Y13 Receptor of ADP
Wang, N., Robaye, B., Agrawal, A., et al. (2011) · Molecular Endocrinology · doi:10.1210/me.2011-1083 · Cited by 57 · see citing works
Self-citationLysyl Oxidase Propeptide Inhibits FGF-2-induced Signaling and Proliferation of Osteoblasts
Vora, S. R., Palamakumbura, A. H., Mitsi, M., Guo, Y., Pischon, N., Nugent, M. A., & Trackman, P. C. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.033597 · Cited by 45 · see citing works
Human Osteoclast Culture and Phenotypic Characterization
Agrawal, A., Gallagher, J. A., & Gartland, A. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-367-7_23 · Cited by 20 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Tumour exosome integrins determine organotropic metastasis
Hoshino, A., Costa-Silva, B., Shen, T.-L., Rodrigues, G., Hashimoto, A., Tesic Mark, M., Molina, H., Kohsaka, S., Di Giannatale, A., Ceder, S., et al. (2015) · Nature · doi:10.1038/nature15756 · Cited by 5,101 · see citing works
The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth
de Visser, K. E., & Joyce, J. A. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.02.016 · Cited by 4,059 · see citing works
Concepts of extracellular matrix remodelling in tumour progression and metastasis
Winkler, J., Abisoye-Ogunniyan, A., Metcalf, K. J., & Werb, Z. (2020) · Nature Communications · doi:10.1038/s41467-020-18794-x · Cited by 2,296 · see citing works
Metastatic colonization by circulating tumour cells
Massagué, J., & Obenauf, A. C. (2016) · Nature · doi:10.1038/nature17038 · Cited by 2,062 · see citing works
Pre-metastatic niches: organ-specific homes for metastases
Peinado, H., Zhang, H., Matei, I. R., Costa-Silva, B., Hoshino, A., Rodrigues, G., Psaila, B., Kaplan, R. N., Bromberg, J. F., Kang, Y., et al. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.6 · Cited by 1,889 · see citing works
Self-citationEndoplasmic reticulum stress signals in the tumour and its microenvironment
Chen, X., & Cubillos-Ruiz, J. R. (2021) · Nature Reviews Cancer · doi:10.1038/s41568-020-00312-2 · Cited by 1,356 · see citing works
Steeg, P. S. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.25 · Cited by 1,363 · see citing works
Rankin, E. B., & Giaccia, A. J. (2016) · Science · doi:10.1126/science.aaf4405 · Cited by 1,340 · see citing works
The extracellular matrix in tumor progression and metastasis
Eble, J. A., & Niland, S. (2019) · Clinical & Experimental Metastasis · doi:10.1007/s10585-019-09966-1 · Cited by 613 · see citing works
The extracellular matrix in breast cancer
Insua-Rodríguez, J., & Oskarsson, T. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.12.017 · Cited by 470 · see citing works
Medicine in the early twenty-first century: paradigm and anticipation - EPMA position paper 2016
Golubnitschaja, O., Baban, B., Boniolo, G., Wang, W., Bubnov, R., Kapalla, M., Krapfenbauer, K., Mozaffari, M. S., & Costigliola, V. (2016) · EPMA Journal · doi:10.1186/s13167-016-0072-4 · Cited by 396 · see citing works
Islam, M. A., Xu, Y., Tao, W., Ubellacker, J. M., Lim, M., Aum, D., Lee, G. Y., Zhou, K., Zope, H., Yu, M., et al. (2018) · Nature Biomedical Engineering · doi:10.1038/s41551-018-0284-0 · Cited by 339 · see citing works
3D Bioprinting of Breast Cancer Models for Drug Resistance Study
Wang, Y., Shi, W., Kuss, M., Mirza, S., Qi, D., Krasnoslobodtsev, A., Zeng, J., Band, H., Band, V., & Duan, B. (2018) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.8b01277 · Cited by 157 · see citing works
Emerging roles and therapeutic value of exosomes in cancer metastasis
Wu, M., Wang, G., Hu, W., Yao, Y., & Yu, X.-F. (2019) · Molecular Cancer · doi:10.1186/s12943-019-0964-8 · Cited by 140 · see citing works
Enzymatic and non-enzymatic functions of the lysyl oxidase family in bone
Trackman, P. C. (2016) · Matrix Biology · doi:10.1016/j.matbio.2016.01.001 · Cited by 86 · see citing works
Blache, U., Horton, E. R., Xia, T., Schoof, E. M., Blicher, L. H., Schönenberger, A., Snedeker, J. G., Martin, I., Erler, J. T., & Ehrbar, M. (2019) · Life Science Alliance · doi:10.26508/lsa.201900304 · Cited by 49 · see citing works
Self-citation
- Authors
- Cox, T. R., Rumney, R. M. H., Schoof, E. M., Perryman, L., Høye, A. M., Agrawal, A., Bird, D., Latif, N. A., Forrest, H., Evans, H. R., Huggins, I. D., Lang, G., Linding, R., Gartland, A., & Erler, J. T.
- Affiliations
- University of Copenhagen (DK)
- University of Sheffield (GB)
- Technical University of Denmark (DK)
- Institute of Cancer Research (GB)
- Corresponding author
- Gartland, Alison
- Erler, Janine T.
- ORCID
- Venue
- Nature
- Published
- 2015-05-27
- Volume
- 522
- Issue
- 7554
- Pages
- 106-110
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4961239
- OpenAlex
- W1593145356
- Cited by
- 482
- References
- 34
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 15 · 2023: 27 · 2022: 38 · 2021: 54 · 2020: 64 · 2019: 62 · 2018: 57 · 2017: 59 · 2016: 61 · 2015: 29
- FWCI
- 29.99
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2023-04-17)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Cancer Research UK (A11355, C107/A10433)
- Novo Nordisk Fonden (NNF12OC1015992)
- Topics
- Health Sciences › Medicine › Oncology › Bone health and treatments
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- lysyl oxidase, breast cancer bone metastasis, hypoxia, osteoclastogenesis, NFATc1, bone homeostasis, circulating tumor cells, estrogen receptor-negative breast cancer, metastasis biomarkers
- MeSH terms
- Animals, Bone Neoplasms, Breast Neoplasms, Cell Movement, Female, Humans, Protein-Lysine 6-Oxidase, Neoplastic Cells, Circulating, Neoplasm Metastasis, Osteoblasts, Osteoclasts, Receptors, Estrogen, Cell Hypoxia, Cell Line, Tumor, NFATC Transcription Factors, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
