The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index.
Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival
Open accessAbstract
Metastasis underlies the majority of cancer-related deaths. Thus, furthering our understanding of the molecular mechanisms that enable tumor cell dissemination is a vital health issue. Epithelial-to-mesenchymal transitions (EMTs) endow carcinoma cells with enhanced migratory and survival attributes that facilitate malignant progression. Characterization of EMT effectors is likely to yield new insights into metastasis and novel avenues for treatment. We show that the presence of the receptor tyrosine kinase Axl in primary breast cancers independently predicts strongly reduced overall patient survival, and that matched patient metastatic lesions show enhanced Axl expression. We demonstrate that Axl is strongly induced by EMT in immortalized mammary epithelial cells that establishes an autocrine signaling loop with its ligand, Gas6. Epiallelic RNA interference analysis in metastatic breast cancer cells delineated a distinct threshold of Axl expression for mesenchymal-like in vitro cell invasiveness and formation of tumors in foreign and tissue-engineered microenvironments in vivo. Importantly, in two different optical imaging-based experimental breast cancer models, Axl knockdown completely prevented the spread of highly metastatic breast carcinoma cells from the mammary gland to lymph nodes and several major organs and increased overall survival. These findings suggest that Axl represents a downstream effector of the tumor cell EMT that is required for breast cancer metastasis. Thus, the detection and targeted treatment of Axl-expressing tumors represents an important new therapeutic strategy for breast cancer.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
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
“A growing body of literature supports an essential role for AXL in promoting metastasis within many tumor types, including breast (81), ovarian (82), and lung (83).”
From Hypoxic control of metastasis (2016) · cites this paper as [81]
Citations
Cites
The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells
Mani, S. A., Guo, W., Liao, M.-J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., Brooks, M. W., Reinhard, F., Zhang, C. C., Shipitsin, M. V., et al. (2008) · Cell · doi:10.1016/j.cell.2008.03.027 · Cited by 8,839
Epithelial–mesenchymal transitions in tumour progression
Thiery, J. P. (2002) · Nature reviews. Cancer · doi:10.1038/nrc822 · Cited by 6,767
Involvement of chemokine receptors in breast cancer metastasis
Müller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M. E., McClanahan, T., Murphy, E., Yuan, W., Wagner, S. N., et al. (2001) · Nature · doi:10.1038/35065016 · Cited by 5,340
Complex networks orchestrate epithelial–mesenchymal transitions
Thiery, J. P., & Sleeman, J. P. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1835 · Cited by 3,947
Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis
Yang, J., Mani, S. A., Donaher, J. L., Ramaswamy, S., Itzykson, R., Côme, C., Savagner, P., Gitelman, I., Richardson, A. L., & Weinberg, R. A. (2004) · Cell · doi:10.1016/j.cell.2004.06.006 · Cited by 3,917
Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits
Polyak, K., & Weinberg, R. A. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2620 · Cited by 3,302
A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes
Neve, R. M., Chin, K., Fridlyand, J., Yeh, J., Baehner, F. L., Fevr, T., Clark, L., Bayani, N., Coppé, J., Tong, F. K., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.10.008 · Cited by 3,224
Snail, Zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype?
Peinado, H., Olmeda, D., & Cano, A. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2131 · Cited by 3,121
PETERSEN, O. W., Rønnov‐Jessen, L., Howlett, A. R., & Bissell, M. J. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.19.9064 · Cited by 1,096
Cancer Metastasis Is Accelerated through Immunosuppression during Snail-Induced EMT of Cancer Cells
Kudo‐Saito, C., Shirako, H., Takeuchi, T., & Kawakami, Y. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.01.023 · Cited by 872
Engineering tumors with 3D scaffolds
Fischbach, C., Chen, R., Matsumoto, T., Schmelzle, T., Brugge, J. S., Polverini, P. J., & Mooney, D. J. (2007) · Nature Methods · doi:10.1038/nmeth1085 · Cited by 834
Stabilization of Snail by NF-κB Is Required for Inflammation-Induced Cell Migration and Invasion
Wu, Y., Deng, J., Rychahou, P. G., Qiu, S., Evers, B. M., & Zhou, B. P. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.03.016 · Cited by 814
Linger, R. M. A., Keating, A. K., Earp, H. S., & Graham, D. K. (2008) · Advances in cancer research · doi:10.1016/s0065-230x(08)00002-x · Cited by 750
Epithelial-Mesenchymal Transition
Klymkowsky, M. W., & Savagner, P. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.080545 · Cited by 578
Imagable 4T1 model for the study of late stage breast cancer
Tao, K. X., Fang, M., Alroy, J., & Sahagian, G. G. (2008) · BMC Cancer · doi:10.1186/1471-2407-8-228 · Cited by 525
Bone marrow cells in the ‘pre-metastatic niche’: within bone and beyond
Kaplan, R. N., Psaila, B., & Lyden, D. C. (2006) · Cancer and Metastasis Reviews · doi:10.1007/s10555-006-9036-9 · Cited by 344
Cancer cell angiogenic capability is regulated by 3D culture and integrin engagement
Fischbach, C., Kong, H. J., Hsiong, S. X., Evangelista, M. B., Yuen, W. W., & Mooney, D. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808932106 · Cited by 315
Mahadevan, D., Cooke, L. S., Riley, C., Swart, R. E., Simons, B. W., Croce, K. D., Wisner, L., Iorio, M. V., Shakalya, K., Garewal, H. S., et al. (2007) · Oncogene · doi:10.1038/sj.onc.1210173 · Cited by 285
Hutterer, M., Knyazev, P. G., Abate, A., Reschke, M., Maier, H., Stefanova, N., Knyazeva, T., Barbieri, V., Reindl, M., Muigg, A., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-0862 · Cited by 281
Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases
Hafizi, S., & Dahlbäck, B. (2006) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2006.04.004 · Cited by 266
Kenny, H. A., Krausz, T., Yamada, S. D., & Lengyel, E. (2007) · International Journal of Cancer · doi:10.1002/ijc.22874 · Cited by 243
Vajkoczy, P., Knyazev, P. G., Kunkel, A., Capelle, H., Behrndt, S., von Tengg‐Kobligk, H., Kiessling, F. M., Eichelsbacher, U., Essig, M., Read, T., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510923103 · Cited by 239
AXL Is a Potential Target for Therapeutic Intervention in Breast Cancer Progression
Zhang, Y., Knyazev, P. G., Cheburkin, Y. V., Sharma, K., Knyazev, Y. P., Őrfi, L., Szabadkai, I., Daub, H., Kéri, G., & Ullrich, A. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-2661 · Cited by 217
Phosphoproteomic analysis of Her2/neu signaling and inhibition
Bose, R., Molina, H., Patterson, A., Bitok, J. K., Periaswamy, B., Bader, J. S., Pandey, A., & Cole, P. A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0603948103 · Cited by 215
Koorstra, J.-B. M., Karikari, C. A., Feldmann, G., Bisht, S., Rojas, P. L., Offerhaus, G. J. A., Alvarez, H., & Maitra, A. (2009) · Cancer Biology & Therapy · doi:10.4161/cbt.8.7.7923 · Cited by 208
Multiple Roles for the Receptor Tyrosine Kinase Axl in Tumor Formation
Holland, S. J., Powell, M. J., Franci, C., Chan, E. W., Friera, A. M., Atchison, R. E., McLaughlin, J. R., Swift, S. E., Pali, E. S., Yam, G. C., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0993 · Cited by 204
Self-citationMechanisms of malignant progression
Weinberg, R. A. (2008) · Carcinogenesis · doi:10.1093/carcin/bgn104 · Cited by 167
The Evolving Portrait of Cancer MetastasisPreprint
Gupta, P. B., Mani, S. A., YANG, J., Hartwell, K. A., & Weinberg, R. A. (2005) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2005.70.033 · Cited by 92
Wang, H., Kåresen, R., Hervik, A., & Thoresen, S. (2001) · Cancer Causes & Control · doi:10.1023/a:1008999403069 · Cited by 72
Cited by
Sorted by citations
Scenic: single-cell regulatory network inference and clustering.
Aibar, S., González-Blas, C. B., Moerman, T., Huynh-Thu, V. A., Imrichova, H., Hulselmans, G., Rambow, F., Marine, J.-C., Geurts, P., Aerts, J., et al. (2017) · Nature Methods · doi:10.1038/nmeth.4463 · Cited by 6,520
Nieto, M. A., Huang, R. Y.-J., Jackson, R. A., & Thiery, J. P. (2016) · Cell · doi:10.1016/j.cell.2016.06.028 · Cited by 4,492
Visualization and analysis of gene expression in tissue sections by spatial transcriptomics
Ståhl, P. L., Salmén, F., Vickovic, S., Lundmark, A., Navarro, J. F., Magnusson, J., Giacomello, S., Asp, M., Westholm, J. O., Huss, M., et al. (2016) · Science · doi:10.1126/science.aaf2403 · Cited by 3,834
EMT, CSCs, and drug resistance: the mechanistic link and clinical implications
Shibue, T., & Weinberg, R. A. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.44 · Cited by 2,539
Rankin, E. B., & Giaccia, A. J. (2016) · Science · doi:10.1126/science.aaf4405 · Cited by 1,340
Metadata
- Authors
- Gjerdrum, C., Tiron, C., Høiby, T., Stefansson, I., Haugen, H., Sandal, T., Collett, K., Li, S., McCormack, E., Gjertsen, B. T., Micklem, D. R., Akslen, L. A., Glackin, C., & Lorens, J. B.
- Affiliations
- Department of Biomedicine
- The Gade Institute, Pathology Section
- Beckman Research Institute (US)
- Haukeland University Hospital (NO)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-12-28
- Volume
- 107
- Issue
- 3
- Pages
- 1124-1129
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2824310
- OpenAlex
- W2003445065
- Cited by
- 594
- References
- 29
- Citations by year
- 2026: 14 · 2025: 30 · 2024: 21 · 2023: 44 · 2022: 34 · 2021: 37 · 2020: 55 · 2019: 39 · 2018: 37 · 2017: 45 · 2016: 52 · 2015: 42 · 2014: 40 · 2013: 29 · 2012: 27
- FWCI
- 12.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Helse Vest
- Universitetet i Bergen
- Norges Forskningsråd
- National Institutes of Health
- National Cancer Institute (R21CA107245, CA107245)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- AXL, epithelial-mesenchymal transition, breast cancer metastasis, Gas6, autocrine signaling, patient survival, tumor invasion, lymph node metastasis, therapeutic target, mammary epithelial cells
- MeSH terms
- Axl Receptor Tyrosine Kinase, Animals, Breast Neoplasms, Epithelial Cells, Female, Humans, Mesoderm, Neoplasm Invasiveness, Neoplasm Metastasis, Prognosis, Proto-Oncogene Proteins, Oncogene Proteins, Survival Analysis, Mice, SCID, Mice, Inbred NOD, Receptor Protein-Tyrosine Kinases, Tissue Engineering, RNA Interference, 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
