The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index.
TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling
Open accessAbstract
In patients, non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (such as lung) present growing metastasis. This suggested that the BM might be a metastasis 'restrictive soil' by encoding dormancy-inducing cues in DTCs. Here we show in a head and neck squamous cell carcinoma (HNSCC) model that strong and specific transforming growth factor-β2 (TGF-β2) signalling in the BM activates the MAPK p38α/β, inducing an (ERK/p38)(low) signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of cyclin-dependent kinase 4 (CDK4) and dormancy of malignant DTCs. TGF-β2-induced dormancy required TGF-β receptor-I (TGF-β-RI), TGF-β-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis 'permissive soil' with low TGF-β2 levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-β-RI or p38α/β activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a 'seed and soil' mechanism where TGF-β2 and TGF-β-RIII signalling through p38α/β regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis.
Overview
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
Verification
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?
In the citing paper
“TGF-β2 was reported to contribute to metastatic tumor dormancy333–335”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [334]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
1 retracted
Bao, B., Wang, Z. P., Ali, S. S., Kong, D., Banerjee, S., Ahmad, A., Li, Y., Azmi, A. S., Miele, L., & Sarkar, F. H. (2011) · Journal of Cellular Biochemistry · doi:10.1002/jcb.23150 · Cited by 206
RetractedThe pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited
Fidler, I. J. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1098 · Cited by 4,686
In vitro propagation and transcriptional profiling of human mammary stem/progenitor cellsPreprint
Dontu, G., Abdallah, W. M., Foley, J. M., Jackson, K. W., Clarke, M. F., Kawamura, M., & Wicha, M. S. (2003) · Genes & Development · doi:10.1101/gad.1061803 · Cited by 2,413
Models, mechanisms and clinical evidence for cancer dormancy
Aguirre‐Ghiso, J. A. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2256 · Cited by 1,756
Self-citationCytostatic and apoptotic actions of TGF-β in homeostasis and cancer
Siegel, P. M., & Massagué, J. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1208 · Cited by 1,626
Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells
Ito, K., Hirao, A., Arai, F., Takubo, K., Matsuoka, S., Miyamoto, K., Ohmura, M., Naka, K., Hosokawa, K., Ikeda, Y., et al. (2006) · Nature Medicine · doi:10.1038/nm1388 · Cited by 1,362
Aslakson, C. J., & Miller, F. R. (1992) · PubMed · Cited by 1,234
Systemic Spread Is an Early Step in Breast Cancer
Hüsemann, Y., Geigl, J. B., Schubert, F., Musiani, P., Meyer, M., Burghart, E., Forni, G., Eils, R., Fehm, T. N., Riethmüller, G., et al. (2008) · Cancer Cell · doi:10.1016/j.ccr.2007.12.003 · Cited by 1,220
The perivascular niche regulates breast tumour dormancy
Ghajar, C. M., Peinado, H., Mori, H., Matei, I. R., Evason, K. J., Brazier, H., Almeida, D., Koller, A., Hajjar, K. A., Stainier, D. Y. R., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2767 · Cited by 1,148
TGFβ Primes Breast Tumors for Lung Metastasis Seeding through Angiopoietin-like 4
Padua, D. M., Zhang, X. H.-F., Wang, Q., Nadal, C., Gerald, W. L., Gomis, R. R., & Massagué, J. (2008) · Cell · doi:10.1016/j.cell.2008.01.046 · Cited by 982
Betaglycan presents ligand to the TGFβ signaling receptor
López‐Casillas, F., Wrana, J. L., & Massagué, J. (1993) · Cell · doi:10.1016/0092-8674(93)90368-z · Cited by 892
The transforming growth factor-β system, a complex pattern of cross-reactive ligands and receptors
Cheifetz, S., Weatherbee, J. A., Tsang, M., Anderson, J. K., Mole, J. E., Lucas, R., & Massagué, J. (1987) · Cell · doi:10.1016/0092-8674(87)90192-9 · Cited by 701
Chromatin-modifying enzymes as modulators of reprogramming
Önder, T. T., Kara, N., Cherry, A. B. C., Sinha, A. U., Zhu, N., Bernt, K. M., Cahan, P., Mancarci, B. O., Unternaehrer, J., Gupta, P. B., et al. (2012) · Nature · doi:10.1038/nature10953 · Cited by 650
Antibodies to plasminogen activator inhibit human tumor metastasis
Ossowski, L., & Reich, E. (1983) · Cell · doi:10.1016/0092-8674(83)90093-4 · Cited by 634
The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner
Sorrentino, A., Thakur, N., Grimsby, S., Marcusson, A., von Bülow, V., Schuster, N., Zhang, S., Heldin, C., & Landström, M. (2008) · Nature Cell Biology · doi:10.1038/ncb1780 · Cited by 553
Kim, J., Yu, W., Kovalski, K., & Ossowski, L. (1998) · Cell · doi:10.1016/s0092-8674(00)81478-6 · Cited by 468
ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK)
Aguirre‐Ghiso, J. A., Estrada, Y. D., Liu, D., & Ossowski, L. (2004) · Urologic Oncology Seminars and Original Investigations · doi:10.1016/j.urolonc.2003.12.012 · Cited by 465
Self-citationAguirre‐Ghiso, J. A., Liu, D., Mignatti, A., Kovalski, K., & Ossowski, L. (2001) · Molecular Biology of the Cell · doi:10.1091/mbc.12.4.863 · Cited by 447
Self-citationThe BMP Inhibitor Coco Reactivates Breast Cancer Cells at Lung Metastatic Sites
Gao, H., Chakraborty, G., Lee-Lim, A. P., Mo, Q., Decker, M., Vonica, A., Shen, R., Brogi, E., Brivanlou, A. H., & Giancotti, F. G. (2012) · Cell · doi:10.1016/j.cell.2012.06.035 · Cited by 440
Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone
Kobayashi, A., Okuda, H., Xing, F., Pandey, P. R., Watabe, M., Hirota, S., Pai, S. K., Liu, W., Fukuda, K., Chambers, C., et al. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20110840 · Cited by 440
Incidence and Sites of Distant Metastases from Head and Neck Cancer
Ferlito, A., Shaha, A. R., Silver, C. E., Rinaldo, A., & Mondin, V. (2001) · ORL · doi:10.1159/000055740 · Cited by 386
Requirement of Type III TGF-β Receptor for Endocardial Cell Transformation in the Heart
Brown, C. B., Boyer, A. S., Runyan, R. B., & Barnett, J. V. (1999) · Science · doi:10.1126/science.283.5410.2080 · Cited by 383
ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK).
Aguirre‐Ghiso, J. A., Estrada, Y. D., Liu, D., & Ossowski, L. (2003) · PubMed · Cited by 350
Self-citationCheifetz, S., Hernandez, H., Laiho, M., ten Dijke, P., Iwata, K. K., & Massagué, J. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)30535-5 · Cited by 348
Ranganathan, A. C., Zhang, L., Adam, A. P., & Aguirre‐Ghiso, J. A. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3092 · Cited by 336
Self-citationTGF-β as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation
Yamazaki, S., Iwama, A., Takayanagi, S., Eto, K., Ema, H., & Nakauchi, H. (2008) · Blood · doi:10.1182/blood-2008-04-146480 · Cited by 327
The “seed and soil” hypothesis revisited
Fidler, I. J., & Poste, G. H. (2008) · The Lancet Oncology · doi:10.1016/s1470-2045(08)70201-8 · Cited by 319
Shiozawa, Y., Pedersen, E. A., Patel, L. R., Ziegler, A. M., Havens, A. M., Jung, Y., Wang, J., Zalucha, S., Loberg, R. D., Pienta, K. J., et al. (2010) · Neoplasia · doi:10.1593/neo.91384 · Cited by 317
Review: Biological relevance of disseminated tumor cells in cancer patients
Riethdorf, S., Wikman, H., & Pantel, K. (2008) · International Journal of Cancer · doi:10.1002/ijc.23825 · Cited by 310
Zijlstra, A., Lewis, J. D., Degryse, B., Stuhlmann, H., & Quigley, J. P. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.01.031 · Cited by 250
The type III TGF-β receptor suppresses breast cancer progression
Dong, M., How, T., Kirkbride, K. C., Gordon, K. J., Lee, J. D., Hempel, N., Kelly, P., Moeller, B. J., Marks, J. R., & Blobe, G. C. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29293 · Cited by 248
SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors
Montagner, M., Enzo, E., Forcato, M., Zanconato, F., Parenti, A. R., Rampazzo, E., Basso, G., Leo, G., Rosato, A., Bicciato, S., et al. (2012) · Nature · doi:10.1038/nature11207 · Cited by 247
Toolan, H. W. (1954) · PubMed · Cited by 231
Dormancy Signatures and Metastasis in Estrogen Receptor Positive and Negative Breast Cancer
Kim, R. S., Avivar‐Valderas, A., Estrada, Y. D., Bragado, P., Sosa, M. S., Aguirre‐Ghiso, J. A., & Segall, J. E. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035569 · Cited by 212
Self-citationZijlstra, A., Mellor, R. L., Panzarella, G., Aimes, R. T., Hooper, J. D., Marchenko, N. D., & Quigley, J. P. (2002) · PubMed · Cited by 207
Framework models of tumor dormancy from patient-derived observations
Klein, C. A. (2010) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2010.10.011 · Cited by 207
Turley, R. S., Finger, E. C., Hempel, N., How, T., Fields, T. A., & Blobe, G. C. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3117 · Cited by 181
Ossowski, L. (1988) · Cell · doi:10.1016/s0092-8674(88)80025-4 · Cited by 181
Adam, A. P., George, A. D., Schewe, D. M., Bragado, P., Iglesias, B. V., Ranganathan, A. C., Kourtidis, A., Conklin, D. S., & Aguirre‐Ghiso, J. A. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3820 · Cited by 177
Self-citationAguirre‐Ghiso, J. A., Ossowski, L., & Rosenbaum, S. K. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0113 · Cited by 173
Self-citationExperimental model for quantitative study of metastasis.
Ossowski, L., & Reich, E. (1980) · PubMed · Cited by 156
The role of tumor microenvironment in prostate cancer bone metastasis
Morrissey, C. M., & Vessella, R. L. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21214 · Cited by 112
Metastasis Awakening: Targeting dormant cancer
Aguirre‐Ghiso, J. A., Bragado, P., & Sosa, M. S. (2013) · Nature Medicine · doi:10.1038/nm.3120 · Cited by 97
Self-citationSun, C. K.-W., Chua, M., He, J., & Samuel, K. S. (2011) · Neoplasia · doi:10.1593/neo.11664 · Cited by 92
Deryugina, E. I., Zijlstra, A., Partridge, J. J., Kupriyanova, T. A., Madsen, M. A., Papagiannakopoulos, T. Y., & Quigley, J. P. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-2228 · Cited by 91
Mechanisms of breast cancer bone metastasis
Zhang, Y., Ma, B., & Fan, Q. (2009) · Cancer Letters · doi:10.1016/j.canlet.2009.11.003 · Cited by 91
TGFBR3 loss and consequences in prostate cancer
Sharifi, N., Hurt, E. M., Kawasaki, B. T., & Farrar, W. L. (2006) · The Prostate · doi:10.1002/pros.20526 · Cited by 62
Minimal Residual Disease in Head and Neck Cancer
Gath, H. J., & Brakenhoff, R. H. (1999) · Cancer and Metastasis Reviews · doi:10.1023/a:1006268621730 · Cited by 62
Alonso, D. F., Farias, E., Urtreger, A. J., Ladeda, V., Vidal, M., & Joffé, E. B. D. K. (1996) · Journal of Surgical Oncology · doi:10.1002/(sici)1096-9098(199608)62:4 · Cited by 58
You, H. J., Bruinsma, M. W., How, T., Ostrander, J. H., & Blobe, G. C. (2007) · Carcinogenesis · doi:10.1093/carcin/bgm195 · Cited by 57
Criswell, T. L., Dumont, N., Barnett, J. V., & Arteaga, C. L. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-6777 · Cited by 47
Henckaerts, E., Langer, J., Orenstein, J., & Snoeck, H. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.4.2486 · Cited by 28
The analysis of metastasis in transgenic mouse models
Hüsemann, Y., & Klein, C. A. (2008) · Transgenic Research · doi:10.1007/s11248-008-9225-0 · Cited by 27
Growth of a human carcinoma (HEp3) in nude mice: Rapid and efficient metastasis
Ossowski, L., Russo, H., Gartner, M., & Wilson, E. L. (1987) · Journal of Cellular Physiology · doi:10.1002/jcp.1041330212 · Cited by 26
Ajiboye, S., Sissung, T. M., Sharifi, N., & Figg, W. D. (2010) · British Journal of Urology · doi:10.1111/j.1464-410x.2009.08999.x · Cited by 15
Flagged first, then by citations
Cited by
Sorted by citations
Emerging Biological Principles of Metastasis
Lambert, A. W., Pattabiraman, D. R., & Weinberg, R. A. (2017) · Cell · doi:10.1016/j.cell.2016.11.037 · Cited by 3,191
Batlle, E., & Clevers, H. (2017) · Nature Medicine · doi:10.1038/nm.4409 · Cited by 2,769
Molecular principles of metastasis: a hallmark of cancer revisited
Fares, J., Fares, M. Y., Khachfe, H. H., Salhab, H. A., & Fares, Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0134-x · Cited by 2,536
Metastatic colonization by circulating tumour cells
Massagué, J., & Obenauf, A. C. (2016) · Nature · doi:10.1038/nature17038 · Cited by 2,062
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
Metadata
- Authors
- Bragado, P., Estrada, Y., Parikh, F., Krause, S., Capobianco, C., Farina, H. G., Schewe, D. M., & Aguirre-Ghiso, J. A.
- Affiliations
- Tisch Cancer Institute (US)
- University Hospital Schleswig-Holstein (DE)
- National University of Quilmes (AR)
- Venue
- Nature Cell Biology
- Published
- 2013-10-27
- Volume
- 15
- Issue
- 11
- Pages
- 1351-1361
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4006312
- OpenAlex
- W2163472474
- Cited by
- 503
- References
- 55
- Citations by year
- 2026: 36 · 2025: 30 · 2024: 50 · 2023: 44 · 2022: 44 · 2021: 75 · 2020: 43 · 2019: 35 · 2018: 39 · 2017: 35 · 2016: 31 · 2015: 23 · 2014: 18
- FWCI
- 10.74
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Americanae (AECID Library) (submittedVersion, cc-by-nc-sa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- Funders
- New York State Stem Cell Science
- Consejo Nacional de Investigaciones Científicas y Técnicas
- Deutsche Krebshilfe
- National Cancer Institute (CA109182, U54CA163131, CA163131, R01CA109182)
- National Institute of Environmental Health Sciences (R21ES017146, ES017146)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- disseminated tumor cells, TGF-beta2, p38 MAPK, head and neck squamous cell carcinoma, tumor dormancy, bone marrow microenvironment, lung metastasis, seed and soil hypothesis, Smad1/5, p27, CDK4
- MeSH terms
- Animals, Enzyme Activation, Mice, Nude, Neoplasms, Experimental, Proteoglycans, Signal Transduction, Receptors, Transforming Growth Factor beta, Cell Lineage, p38 Mitogen-Activated Protein Kinases, Mice, Transforming Growth Factor beta2, Tumor Microenvironment
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
