The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index.
The perivascular niche regulates breast tumour dormancy
Open accessAbstract
In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumour-promoting factors derived from endothelial tip cells. Our work reveals that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth.
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recent studies are increasingly employing microvascular networks (µVNs)[21, 23, 24], where the permeability, architecture and diameters of vessels are more similar to those found in in vivo microvascular beds (Figure 2A) [21].”
From Microfluidics: A New Tool for Modeling Cancer–Immune Interactions (2016) · cites this paper as [24]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Studies have shown that dormancy can be induced by endothelial derived factors[24], thus demonstrating the need for microfluidic models that recapitulate interactions between ECs and tumor cells, using for example µVNs.”
From Microfluidics: A New Tool for Modeling Cancer–Immune Interactions (2016) · cites this paper as [24]
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
Macrophage Diversity Enhances Tumor Progression and Metastasis
Qian, B., & Pollard, J. W. (2010) · Cell · doi:10.1016/j.cell.2010.03.014 · Cited by 5,338
The distribution of secondary growths in cancer of the breast.
Paget, S. (1889) · The Lancet · doi:10.1016/s0140-6736(00)49915-0 · Cited by 5,277
Dissemination and growth of cancer cells in metastatic sites
Chambers, A. F., Groom, A. C., & MacDonald, I. C. (2002) · Nature reviews. Cancer · doi:10.1038/nrc865 · Cited by 4,018
A perivascular origin for mesenchymal stem cells in multiple human organs
Crisan, M., Yap, S., Casteilla, L., Chen, C.-W., Corselli, M., Park, T. S., Andriolo, G., Sun, B., Zheng, B., Zhang, L., et al. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2008.07.003 · Cited by 3,991
Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET
Peinado, H., Alečković, M., Lavotshkin, S., Matei, I., Costa-Silva, B., Moreno-Bueno, G., Hergueta-Redondo, M., Williams, C., García-Santos, G., Ghajar, C. M., et al. (2012) · Nature Medicine · doi:10.1038/nm.2753 · Cited by 3,715
Self-citationVEGFR1-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
Self-citationRequirement of Vascular Integrin α v β 3 for Angiogenesis
Brooks, P. C., Clark, R. A. F., & Cheresh, D. A. (1994) · Science · doi:10.1126/science.7512751 · Cited by 3,020
Angiogenesis: an organizing principle for drug discovery?
Folkman, J. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2115 · Cited by 2,299
A Perivascular Niche for Brain Tumor Stem Cells
Calabrese, C. R., Poppleton, H., Koçak, M., Hogg, T. L., Fuller, C. E., Hamner, J. B., Oh, E. Y., Gaber, M. W., Finklestein, D., Allen, M., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2006.11.020 · Cited by 2,253
Endothelial and perivascular cells maintain haematopoietic stem cells
Ding, L., Saunders, T. L., Enikolopov, G., & Morrison, S. J. (2012) · Nature · doi:10.1038/nature10783 · Cited by 2,031
Cited by
Sorted by citations
Microenvironmental regulation of tumor progression and metastasis
Quail, D. F., & Joyce, J. A. (2013) · Nature Medicine · doi:10.1038/nm.3394 · Cited by 7,994
Remodelling the extracellular matrix in development and disease
Bonnans, C., Chou, J., & Werb, Z. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3904 · Cited by 4,367
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
“For example, the apparent dormancy-inducing actions of the perivascular niche noted above seem to be reversed during neo-vascularization as sprouting endothelial tip cells secrete TGF-β1 and periostin (POSTN), which can break dormancy and promote tumor cell proliferation (Ghajar et al., 2013).”
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
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
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
Self-citationNeutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice
Albrengues, J., Shields, M. A., Ng, D., Park, C. G., Ambrico, A., Poindexter, M. E., Upadhyay, P., Uyeminami, D. L., Pommier, A., Küttner, V., et al. (2018) · Science · doi:10.1126/science.aao4227 · Cited by 1,476
“In contrast, increased extracellular matrix (ECM) deposition and sprouting angiogenesis have been shown to trigger awakening and metastasis in experimental models (6, 7).”
BackgroundInfluentialExtracellular vesicles in cancer — implications for future improvements in cancer care
Xu, R., Rai, A., Chen, M., Suwakulsiri, W., Greening, D. W., & Simpson, R. J. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0036-9 · Cited by 1,472
Neutrophil diversity and plasticity in tumour progression and therapy
Jaillon, S., Ponzetta, A., Mitri, D. D., Santoni, A., Bonecchi, R., & Mantovani, A. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0281-y · Cited by 1,318
Characteristics and Significance of the Pre-metastatic Niche
Liu, Y., & Cao, X. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.09.011 · Cited by 1,314
“Some important ECM components are fibronectin, MMPs, versican, periostin, and tenascin-C (Ghajar et al., 2013; Kim et al., 2009).”
BackgroundThe lung microenvironment: an important regulator of tumour growth and metastasis
Altorki, N. K., Markowitz, G. J., Gao, D., Port, J. L., Saxena, A., Stiles, B. M., McGraw, T. E., & Mittal, V. (2018) · Nature reviews. Cancer · doi:10.1038/s41568-018-0081-9 · Cited by 1,170
Mechanisms of disseminated cancer cell dormancy: an awakening field
Sosa, M. S., Bragado, P., & Aguirre‐Ghiso, J. A. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3793 · Cited by 1,179
Ganesh, K., & Massagué, J. (2021) · Nature Medicine · doi:10.1038/s41591-020-01195-4 · Cited by 1,105
Metastatic heterogeneity of breast cancer: Molecular mechanism and potential therapeutic targets
Liang, Y., Zhang, H., Song, X., & Yang, Q. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.08.012 · Cited by 1,018
Cox, T. R. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-020-00329-7 · Cited by 998
Cooper, J. M., & Giancotti, F. G. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.01.007 · Cited by 967
“Intriguingly, the signals that induce dormancy and reactivation appear to be physically segregated along blood vessels: even if fully competent for metastatic reactivation, TNBC cells receive either inhibitory (TSP1, which inhibits TGF-β) or stimulatory (TGF-β and TGF-β-induced matrix proteins— such as TNC, fibronecti…”
BackgroundCrossing the endothelial barrier during metastasis
Reymond, N., d'Água, B. B., & Ridley, A. J. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3628 · Cited by 922
TGF-β signaling in health and disease
Massagué, J., & Sheppard, D. (2023) · Cell · doi:10.1016/j.cell.2023.07.036 · Cited by 890
Cancer Stem Cells: Basic Concepts and Therapeutic Implications
Nassar, D., & Blanpain, C. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044438 · Cited by 897
Microenvironmental regulation of therapeutic response in cancer
Klemm, F., & Joyce, J. A. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.11.006 · Cited by 789
In Vitro Tumor Models: Advantages, Disadvantages, Variables, and Selecting the Right Platform
Katt, M. E., Placone, A. L., Wong, A. D., Xu, Z. S., & Searson, P. C. (2016) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2016.00012 · Cited by 754
“Tumor cells embedded within the surrounding ECM on the periphery of self-assembled vessel networks can be both activated or arrested in a dormant state due to interactions with the vessel endothelium (Ghajar et al., 2013).”
BackgroundTumor metastasis: moving new biological insights into the clinic
Wan, L., Pantel, K., & Kang, Y. (2013) · Nature Medicine · doi:10.1038/nm.3391 · Cited by 763
Three-dimensional organotypic culture: experimental models of mammalian biology and disease
Shamir, E. R., & Ewald, A. J. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3873 · Cited by 719
Metastatic Stem Cells: Sources, Niches, and Vital Pathways
Óskarsson, T., Batlle, E., & Massagué, J. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.02.002 · Cited by 726
Ono, M., Kosaka, N., Tominaga, N., Yoshioka, Y., Takeshita, F., Takahashi, R., Yoshida, M., Tsuda, H., Tamura, K., & Ochiya, T. (2014) · Science Signaling · doi:10.1126/scisignal.2005231 · Cited by 703
Notch Signaling in the Tumor Microenvironment
Meurette, O., & Mehlen, P. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.07.009 · Cited by 680
Xiao, Y., Cong, M., Li, J., He, D., Wu, Q., Tian, P., Wang, Y., Yang, S., Liang, C., Liang, Y., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2020.12.012 · Cited by 662
The lingering mysteries of metastatic recurrence in breast cancer
Riggio, A. I., Varley, K. E., & Welm, A. L. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-01161-4 · Cited by 656
Coleman, R. E., Croucher, P. I., Padhani, A. R., Clézardin, P., Chow, E., Fallon, M., Guise, T. A., Colangeli, S., Capanna, R., & Costa, L. (2020) · Nature Reviews Disease Primers · doi:10.1038/s41572-020-00216-3 · Cited by 625
Vanharanta, S., & Massagué, J. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.09.007 · Cited by 563
Cancer Stem Cells: The Architects of the Tumor Ecosystem
Prager, B. C., Xie, Q., Bao, S., & Rich, J. N. (2019) · Cell stem cell · doi:10.1016/j.stem.2018.12.009 · Cited by 603
“The nutrient-rich environment in conjunction with signaling via VEGF, MYC, and other molecules elevated in the perivascular region promote CSC proliferation, although one study in breast cancer found that this effect is dependent upon the type of vasculature and the signaling molecules expressed (Ghajar et al., 2013;…”
BackgroundMechanisms Governing Metastatic Dormancy and Reactivation
Giancotti, F. G. (2013) · Cell · doi:10.1016/j.cell.2013.10.029 · Cited by 586
The dormant cancer cell life cycle
Phan, T. G., & Croucher, P. I. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0263-0 · Cited by 588
Tumor Heterogeneity in Breast Cancer
Turashvili, G., & Brogi, E. (2017) · Frontiers in Medicine · doi:10.3389/fmed.2017.00227 · Cited by 571
“Interactions between this non-cancerous microenvironment and tumor cells can contribute to carcinogenesis (154), exemplified by decreased sensitivity of tumor cells to growth inhibitors (155) and suppressed tumor growth by microvasculature (156).”
BackgroundThe biology of circulating tumor cells
Pantel, K., & Speicher, M. R. (2015) · Oncogene · doi:10.1038/onc.2015.192 · Cited by 556
The Extracellular Matrix Modulates the Metastatic Journey
Kai, F., Drain, A. P., & Weaver, V. M. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.03.026 · Cited by 561
“Metastatic tumor cells are frequently found associated with the basement membrane surrounding the vascular niche in distal organs (Ghajar et al., 2013).”
BackgroundUnderstanding the Bone in Cancer Metastasis
Fornetti, J., Welm, A. L., & Stewart, S. A. (2018) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3618 · Cited by 534
“In work done by Ghajar and colleagues,((160)) dormant DTCs were found in the vasculature of the bone, lung and brain, and decreased thrombospondin-1 within the perivascular niche caused vascular sprouting/neogenesis, which drove tumor cell proliferation through TGFb and periostin.”
BackgroundEnabling Technologies for Personalized and Precision Medicine
Ho, D., Quake, S. R., McCabe, E. R. B., Chng, W. J., Chow, E. K., Ding, X., Gelb, B. D., Ginsburg, G. S., Hassenstab, J., Ho, C.-M., et al. (2020) · Trends in Biotechnology · doi:10.1016/j.tibtech.2019.12.021 · Cited by 517
“Imaging dormant breast cancer cells in mice has shown that vascular triggers are responsible for proliferation and growth, revealing new therapeutic targets in the vasculature [67].”
BackgroundGenetically engineered mouse models in oncology research and cancer medicine
Kersten, K., de Visser, K. E., van Miltenburg, M. H., & Jonkers, J. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201606857 · Cited by 502
“In addition, these models revealed that disseminated breast cancer cells reside adjacent to blood vessels, which might provide a niche regulating dormancy of disseminated cancer cells (Ghajar et al , 2013).”
Bragado, P., Estrada, Y., Parikh, F., Krause, S., Capobianco, C., Farina, H. G., Schewe, D. M., & Aguirre-Ghiso, J. A. (2013) · Nature Cell Biology · doi:10.1038/ncb2861 · Cited by 503
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
Role of EMT in Metastasis and Therapy Resistance
Smith, B., & Bhowmick, N. A. (2016) · Journal of Clinical Medicine · doi:10.3390/jcm5020017 · Cited by 483
“Proliferative endothelia have been associated with the proliferations and motility of adjacent breast cancer epithelia [27,62].”
BackgroundBone metastasis: the importance of the neighbourhood
Croucher, P. I., McDonald, M. M., & Martin, T. J. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.44 · Cited by 486
Broad targeting of angiogenesis for cancer prevention and therapy
Wang, Z., Dabrosin, C., Yin, X., Fuster, M. M., Arreola, A., Rathmell, W. K., Generali, D., Nagaraju, G. P., El‐Rayes, B. F., Ribatti, D., et al. (2015) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.01.001 · Cited by 479
Fu, T., Dai, L.-J., Wu, S.-Y., Xiao, Y., Ma, D., Jiang, Y.-Z., & Shao, Z.-M. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01103-4 · Cited by 480
Tumour-associated mesenchymal stem/stromal cells: emerging therapeutic targets
Shi, Y., Du, L., Lin, L., & Wang, Y. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.193 · Cited by 463
Systems Biology of Cancer Metastasis
Suhail, Y., Cain, M. P., Vanaja, K. G., Kurywchak, P. A., Levchenko, A., Kalluri, R., & Gupta, K. (2019) · Cell Systems · doi:10.1016/j.cels.2019.07.003 · Cited by 474
“…state of the dormant cancer cell, such as their epigenetic state, while others provide evidence for elements of the microenvironment, such as the resident quiescent vascular cells, for maintaining adjacent disseminated tumor cells in a dormant, growth arrested state 53,54 ,(Ghajar et al., 2013).”
BackgroundKuczynski, E. A., Vermeulen, P. B., Pezzella, F., Kerbel, R. S., & Reynolds, A. R. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0181-9 · Cited by 457
The role of periostin in tissue remodeling across health and disease
Conway, S. J., Izuhara, K., Kudo, Y., Litvin, J., Markwald, R. R., Ouyang, G., Arron, J. R., Holweg, C. T. J., & Kudō, A. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1494-y · Cited by 423
“Recent findings also suggest that periostin may have a role in sprouting neovascular endothelial tips of disseminated tumor cells, promoting breast cancer cell outgrowth in a tumor-suppressive microenvironment [52].”
Chen, W.-J., Ho, C., Chang, Y., Chen, H., Ling, T., Ling, T., Yuan, S., Yuan, S.-S., Chen, Y.-J. L., Lin, C.-Y., et al. (2014) · Nature Communications · doi:10.1038/ncomms4472 · Cited by 448
Bone metastasis: mechanisms, therapies, and biomarkers
Clézardin, P., Coleman, R., Puppo, M., Ottewell, P. D., Bonnelye, E., Paycha, F., Confavreux, C. B., & Holen, I. (2020) · Physiological Reviews · doi:10.1152/physrev.00012.2019 · Cited by 436
Fluids and their mechanics in tumour transit: shaping metastasis
Follain, G., Herrmann, D., Harlepp, S., Hyenne, V., Osmani, N., Warren, S. C., Timpson, P., & Goetz, J. G. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0221-x · Cited by 424
Single-cell spatial immune landscapes of primary and metastatic brain tumours
Karimi, E., Yu, M. W., Maritan, S. M., Perus, L. J. M., Rezanejad, M., Sorin, M., Dankner, M., Fallah, P., Doré, S., Zuo, D., et al. (2023) · Nature · doi:10.1038/s41586-022-05680-3 · Cited by 401
Chen, M. B., Whisler, J. A., Fröse, J., Yu, C., Shin, Y., & Kamm, R. D. (2017) · Nature Protocols · doi:10.1038/nprot.2017.018 · Cited by 385
“The protocol consists of 5 sequential components: (1) device fabrication and sterilization, (2) injection of endothelial and fibroblast cell-laden fibrin gels, (3) device culture until formation of perfusable μVNs, (4) perfusion of tumor cells, (5) live tracking of tumor cell extravasation and data analysis.”
Metastasis-Initiating Cells and Ecosystems
Massagué, J., & Ganesh, K. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0010 · Cited by 372
Metastasis Organotropism: Redefining the Congenial Soil
Gao, Y., Bado, I., Wang, H., Zhang, W., Rosen, J. M., & Zhang, X. H.-F. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.04.012 · Cited by 395
Cancer progression and the invisible phase of metastatic colonization
Klein, C. A. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-00300-6 · Cited by 387
Organoids — Preclinical Models of Human Disease
Li, M., & Belmonte, J. C. I. (2019) · New England Journal of Medicine · doi:10.1056/nejmra1806175 · Cited by 369
Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy
Correia, A. L., Guimaraes, J. C., Auf der Maur, P., De Silva, D., Trefny, M. P., Okamoto, R., Bruno, S., Schmidt, A., Mertz, K., Volkmann, K., et al. (2021) · Nature · doi:10.1038/s41586-021-03614-z · Cited by 339
A framework for the development of effective anti-metastatic agents
Anderson, R. L., Balasas, T., Callaghan, J., Coombes, R. C., EVANS, J., Hall, J. A., Kinrade, S. A., Jones, D., Jones, P. S., Jones, R. J., et al. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0134-8 · Cited by 349
Mechanisms and Barriers in Cancer Nanomedicine: Addressing Challenges, Looking for Solutions
Anchordoquy, T. J., Barenholz, Y., Boraschi, D., Chorny, M., Decuzzi, P., Dobrovolskaia, M. A., Farhangrazi, Z. S., Farrell, D. F., Gabizón, A., Ghandehari, H., et al. (2017) · ACS Nano · doi:10.1021/acsnano.6b08244 · Cited by 340
Distinctive properties of metastasis-initiating cellsPreprint
Celià-Terrassa, T., & Kang, Y. (2016) · Genes & Development · doi:10.1101/gad.277681.116 · Cited by 342
“Endothelial cell sprouting abolishes inhibitory growth signals in dormant tumor cells to allow metastasis of breast cancer cells in different organs (Ghajar et al. 2013).”
BackgroundWeigelt, B., Ghajar, C. M., & Bissell, M. J. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.01.001 · Cited by 347
“These organotypic 3D models recapitulated what was observed in vivo in mice and zebra fish, where the stable trunk of the microvasculature allowed breast cancer cell lines to become dormant but where the vessels were sprouting, the tumor cells ‘woke’ up and grew, revealing that a stable microvasculature induces sustai…”
BackgroundResultInfluentialSelf-citationInsights into new mechanisms and models of cancer stem cell multidrug resistance
Garcia‐Mayea, Y., Mir, C., Masson, F., Paciucci, R., & LLeonart, M. E. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.07.022 · Cited by 332
A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy
Martino, J. S. D., Nobre, A. R., Mondal, C., Taha, I. N., Farias, E., Fertig, E. J., Naba, A., Aguirre‐Ghiso, J. A., & Bravo‐Cordero, J. J. (2021) · Nature Cancer · doi:10.1038/s43018-021-00291-9 · Cited by 337
“The perivascular niche contains ECM molecules that signal to maintain dormancy, including thrombospondin 1 30 .”
Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunitiesPreprint
Rambow, F., Marine, J., & Goding, C. R. (2019) · Genes & Development · doi:10.1101/gad.329771.119 · Cited by 348
“It has been proposed that some melanoma cells may actually reside in the vasculature of the lungs (Ghajar et al. 2013), and be maintained in a dormant state for a prolonged period of time.”
BackgroundMetastasis prevention by targeting the dormant niche
Ghajar, C. M. (2015) · Nature reviews. Cancer · doi:10.1038/nrc3910 · Cited by 325
Self-citationEndothelial Notch1 Activity Facilitates Metastasis
Wieland, E., Rodríguez‐Vita, J., Liebler, S. S., Mogler, C., Moll, I., Herberich, S. E., Espinet, E., Herpel, E., Menuchin, A., Chang-Claude, J. C., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.01.007 · Cited by 321
Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1
Zhuang, X., Zhang, H., Li, X., Li, X., Cong, M., Peng, F., Yu, J., Zhang, X., Yang, Q., & Hu, G. (2017) · Nature Cell Biology · doi:10.1038/ncb3613 · Cited by 309
Mouse models of metastasis: progress and prospects
Gómez-Cuadrado, L., Tracey, N., Ma, R., Qian, B., & Brunton, V. G. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.030403 · Cited by 314
“…but using a spontaneousmodel of breast cancer metastasis, DTCswere found to reside on the microvasculature of different organs and subsequent in vitro experiments demonstrated that distinct endothelial niches can induce dormancy through the secretion of thrombospondin-1 (Ghajar et al., 2013).”
BackgroundTGF-β in developmental and fibrogenic EMTs
Lee, J. H., & Massagué, J. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.09.004 · Cited by 291
“TGF-β induces the entry of disseminated carcinoma cells into a non-proliferative dormant state [134].”
BackgroundEr, E. E., Valiente, M., Ganesh, K., Zou, Y., Agrawal, S., Hu, J., Griscom, B., Rosenblum, M., Boire, A., Brogi, E., et al. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0138-8 · Cited by 292
Breast Tumor Heterogeneity: Source of Fitness, Hurdle for Therapy
Koren, S., & Bentires‐Alj, M. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.10.031 · Cited by 289
“Similarly, the tumor microvasculature influences disseminated tumor cells, as demonstrated by the promotion of tumor growth by sprouting of neovasculature; in contrast, a stable microvasculature induces tumor cell quiescence and is, thus, tumor suppressive (Ghajar et al., 2013).”
BackgroundVascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α
Wang, Q., He, Z., Huang, M., Liu, T., Wang, Y., Xu, H., Duan, H., Ma, P., Zhang, L., Zamvil, S. S., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03050-0 · Cited by 291
Selection and adaptation during metastatic cancer progression
Klein, C. A. (2013) · Nature · doi:10.1038/nature12628 · Cited by 275
Metastasis Dormancy in Estrogen Receptor–Positive Breast Cancer
Zhang, X. H.-F., Giuliano, M., Trivedi, M. V., Schiff, R., & Osborne, C. K. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-0838 · Cited by 266
“Ghajar and colleagues showed that endothelial cells secrete thrombospondin 1 to suppress cancer cell proliferation, and this suppression is lost in sprouting neovasculature, which leads to outgrowth (40).”
Johnson, R. W., Finger, E. C., Olcina, M. M., Vilalta, M., Aguilera, T. A., Miao, Y. R., Merkel, A. R., Johnson, J., Sterling, J. A. R., Wu, J. Y., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3408 · Cited by 266
“mechanisms enabling tumor cells to emerge from dormancy are poorly understood, but there is increasing evidence that tumor-stromal interactions, and the osteoblast 2, 3 , perivascular 4 and perisinusoidal 5 niche are critical mediators of tumor cell dormancy and bone colonization.”
The bone microenvironment invigorates metastatic seeds for further dissemination
Zhang, W., Bado, I., Hu, J., Wan, Y., Wu, L., Wang, H., Gao, Y., Jeong, H.-H., Xu, Z., Hao, X., et al. (2021) · Cell · doi:10.1016/j.cell.2021.03.011 · Cited by 261
Invasion and metastasis in cancer: molecular insights and therapeutic targets
Li, Y., Liu, F., Cai, Q., Deng, L., Ouyang, Q., Zhang, X. H.-F., & Zheng, J. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02148-4 · Cited by 288
Stock, K., Estrada, M. F., Vidic, S., Gjerde, K., Rudisch, A., Santo, V. E., Barbier, M., Blom, S., Arundkar, S. C., Selvam, I., et al. (2016) · Scientific Reports · doi:10.1038/srep28951 · Cited by 253
Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy
Carlson, P., Dasgupta, A., Grzelak, C. A., Kim, J., Barrett, A. S., Coleman, I. M., Shor, R. E., Goddard, E. T., Dai, J., Schweitzer, E. M., et al. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0267-0 · Cited by 248
Self-citationThe Multifaceted Role of Perivascular Macrophages in Tumors
Lewis, C. E., Harney, A. S., & Pollard, J. W. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.05.017 · Cited by 253
Esposito, M., Mondal, N., Greco, T. M., Wei, Y., Spadazzi, C., Lin, S.-C., Zheng, H., Cheung, C., Magnani, J. L., Lin, S.-H., et al. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0309-2 · Cited by 250
STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma
Hu, J. Y., Rivera, F. J. S., Wang, Z., Johnson, G. N., Ho, Y.-J., Ganesh, K., Umeda, S., Gan, S., Mujal, A. M., Delconte, R. B., et al. (2023) · Nature · doi:10.1038/s41586-023-05880-5 · Cited by 256
Gao, H., Chakraborty, G., Zhang, Z., Akalay, I., Gadiya, M. M., Gao, Y., Sinha, S., Hu, J. M., Jiang, C., Akram, M. M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.06.009 · Cited by 247
“…can be physically segregated along the abluminal surface of blood vessels, as mature endothelial cells produce thrombospondin, which induces dormancy, whereas angiogenic endothelial cells produce periostin, tenascin C, versican and TGF-, which promote metastatic outgrowth (Ghajar et al., 2013).”
Targeting cancer stem cells to suppress acquired chemotherapy resistance
Vidal, S. J., Rodríguez-Bravo, V., Galsky, M. D., Cordon‐Cardo, C., & Domenech, J. M. D. (2013) · Oncogene · doi:10.1038/onc.2013.411 · Cited by 244
Interstitial fluid flow in cancer: implications for disease progression and treatment
Munson, J. M., & Shieh, A. C. (2014) · Cancer Management and Research · doi:10.2147/cmar.s65444 · Cited by 247
Targeting Breast Cancer Metastasis
Jin, X., & Mu, P. (2015) · Breast Cancer Basic and Clinical Research · doi:10.4137/bcbcr.s25460 · Cited by 248
Inducing Angiogenesis, a Key Step in Cancer Vascularization, and Treatment Approaches
Saman, H. T., Raza, S. S., Shahab Uddin, M. S., & Rasul, K. I. (2020) · Cancers · doi:10.3390/cancers12051172 · Cited by 258
“Interestingly, bone marrow appears to be an important site for vessel co-option in both primary and secondary bone malignancies which, in turn, might explain the development of tumour dormancy in bones and the higher rate of chemoresistance [55,56].”
BackgroundThe current paradigm and challenges ahead for the dormancy of disseminated tumor cells
Risson, E., Nobre, A. R., Maguer‐Satta, V., & Aguirre‐Ghiso, J. A. (2020) · Nature Cancer · doi:10.1038/s43018-020-0088-5 · Cited by 244
Human bone perivascular niche-on-a-chip for studying metastatic colonization
Marturano-Kruik, A., Nava, M. M., Yeager, K. J., Chramiec, A. G., Hao, L. Y., Robinson, S. T., Guo, E. X., Raimondi, M. T., & Vunjak‐Novakovic, G. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1714282115 · Cited by 228
“For example, endothelial cells (ECs) mixed with stromal cells in a 3D hydrogel provided insights on how vascular sprouts mediate breast cancer growth (6).”
BackgroundResultMechanisms of Cancer Cell Dormancy—Another Hallmark of Cancer?
Yeh, A. C., & Ramaswamy, S. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-1370 · Cited by 232
“In a recent study using engineered microvascular niches derived from primary human umbilical endothelial cells, the authors examined the behavior of disseminated tumor cells and demonstrated that microvasculature niches that tend to promote cellular quiescence express increased thrombospondin-1, a glycoprotein known t…”
BackgroundMicrofluidics: A New Tool for Modeling Cancer–Immune Interactions
Boussommier-Calleja, A., Li, R., Chen, M. B., Wong, S. C., & Kamm, R. D. (2016) · Trends in Cancer · doi:10.1016/j.trecan.2015.12.003 · Cited by 224
“Recent studies are increasingly employing microvascular networks (μVNs)[21, 23, 24], where the permeability, architecture and diameters of vessels are more similar to those found in in vivo microvascular beds (Figure 2A) [21].”
BackgroundCao, Z., Ding, B., Guo, P., Lee, S. B., Butler, J. M., Casey, S. C., Simons, M., Tam, W., Felsher, D. W., Shido, K., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.005 · Cited by 227
“Vascular endothelial cells (ECs) are a specialized component of the tumor microenvironment that can orchestrate tumor growth and invasion (Beck et al., 2011; Bergers and Hanahan, 2008; Butler et al., 2010a; Calabrese et al., 2007; Carmeliet and Jain, 2011; Charles et al., 2010; Ghajar et al., 2013; Lu et al., 2013; We…”
Circulating and disseminated tumor cells: harbingers or initiators of metastasis?
Dasgupta, A., Lim, A. R., & Ghajar, C. M. (2017) · Molecular Oncology · doi:10.1002/1878-0261.12022 · Cited by 225
“But one component common to every PVN is microvascular endothelium, and in the case of breast cancer, growth-arrested DTCs are intimately associated with brain, lung, and bone marrow vasculature (Ghajar et al., 2013).”
BackgroundInfluentialSelf-citationParadoxical effects of chemotherapy on tumor relapse and metastasis promotion
D’Alterio, C., Scala, S., Sozzi, G., Roz, L., & Bertolini, G. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.08.019 · Cited by 231
Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment
Tsai, H.-F., Trubelja, A., Shen, A. Q., & Bao, G. (2017) · Journal of The Royal Society Interface · doi:10.1098/rsif.2017.0137 · Cited by 214
Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer
Takai, K., Le, A., Weaver, V. M., & Werb, Z. (2016) · Oncotarget · doi:10.18632/oncotarget.12658 · Cited by 207
“TGF-β promotes breast cancer cell outgrowth from dormancy in metastatic sites, and our PDX models implicate TGF-β signaling activation in metastasisinitiating cells [20, 66], suggesting that combination therapy of doxorubicin and PFD may have additional inhibitory effects on metastasis-initiating cells.”
BackgroundSlow growth determines nonheritable antibiotic resistance in Salmonella enterica
Pontes, M. H., & Groisman, E. A. (2019) · Science Signaling · doi:10.1126/scisignal.aax3938 · Cited by 216
Metadata
- Authors
- 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., Chen, E. I., Lyden, D., & Bissell, M. J.
- Affiliations
- Lawrence Berkeley National Laboratory (US)
- Weill Cornell Medicine (US)
- University of California, San Francisco (US)
- Stony Brook University (US)
- Champalimaud Foundation (PT)
- Corresponding author
- Ghajar, Cyrus M.
- Bissell, Mina J.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2013-06-02
- Volume
- 15
- Issue
- 7
- Pages
- 807-817
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC3826912
- OpenAlex
- W2155542819
- Cited by
- 1,148
- References
- 65
- Citations by year
- 2026: 62 · 2025: 68 · 2024: 70 · 2023: 86 · 2022: 89 · 2021: 122 · 2020: 125 · 2019: 97 · 2018: 98 · 2017: 69 · 2016: 89 · 2015: 64 · 2014: 78 · 2013: 29
- FWCI
- 46.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL042493, R01HL054737, R01HL090895, HL54737)
- National Cancer Institute (U54CA126552, U54CA143836, U01CA169538, R37CA064786)
- National Center for Research Resources (1 S10 RR023680-1, S10RR023680)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- breast cancer, tumor dormancy, disseminated tumor cells, perivascular niche, endothelial cells, thrombospondin-1, TGF-β1, periostin, organotypic culture, micrometastases, microcirculation
- MeSH terms
- Animals, Brain Neoplasms, Breast Neoplasms, Endothelium, Vascular, Female, Fluorescent Antibody Technique, Humans, Lung Neoplasms, Neovascularization, Pathologic, Tumor Cells, Cultured, Zebrafish, Cell Adhesion Molecules, Transforming Growth Factor beta, Neoplasm, Residual, Bone Marrow Neoplasms, Thrombospondin 1, Pericytes, Mice, Stem Cell Niche, 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
