LGR5 is associated with tumor aggressiveness in papillary thyroid cancer
Open accessAbstract
// Gregory Michelotti 1 , Xiaoyin Jiang 2 , Julie Ann Sosa 3 , Anna Mae Diehl 1 , Brittany Bohinc Henderson 4 1 Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina, USA 2 Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA 3 Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA 4 Division of Endocrinology, Diabetes and Metabolism, Wake Forest University, Winston-Salem, North Carolina, USA Correspondence to: Brittany Bohinc Henderson, e-mail: bbhender@wakehealth.edu Keywords: R-spondin, Wnt, β-catenin, metastasis, BRAFV600E Received: May 07, 2015 Accepted: September 14, 2015 Published: September 25, 2015 ABSTRACT PURPOSE: Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a cancer stem cell marker and a down-stream target in Wnt/β-catenin signaling. In human papillary thyroid cancer (PTC), over activation of Wnt/β-catenin has been associated with tumor aggressiveness. PATIENTS AND METHODS: Using established human cell lines (TPC-1, KTC-1, Nthy-ori-3–1), we report LGR5 and R-spondin (RSPO1–3) overexpression in PTC and manipulate LGR5 and Wnt/β-catenin signaling via both pharmacologic and genetic interventions. We test the association of LGR5 tumor expression with markers of PTC aggressiveness using a Discovery Cohort ( n = 26 patients) and a Validation Cohort ( n = 157 patients). Lastly, we explore the association between LGR5 and the BRAFV600E mutation ( n = 33 patients). RESULTS: Our results reveal that LGR5 and its ligand, RSPO, are overexpressed in human PTC, whereby Wnt/β-catenin signaling regulates LGR5 expression and promotes cellular migration. In two separate cohorts of patients, LGR5 and RSPO2 were associated with markers of tumor aggressiveness including: lymph node metastases, vascular invasion, increased tumor size, aggressive histology, advanced AJCC TNM stage, microscopic extra thyroidal extension, capsular invasion, and macroscopic invasion. As a biomarker, LGR5 positivity predicts lymph node metastasis with 95.5% sensitivity (95% CI 88.8%-98.7%) and 61% specificity (95% CI: 48.4%–72.4%) and has a negative predictive value (NPV) of 91.3% (95% CI 79.2%–97.5%) for lymph node metastatic disease. In human PTC, LGR5 is also strongly associated with the BRAFV600E mutation ( p = 0.005). CONCLUSION: We conclude that overexpression of LGR5 is associated with markers of tumor aggressiveness in human PTC. LGR5 may serve as a future potential biomarker for patient risk stratification and loco regional metastases in PTC.
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?
Both KTC-1 and TPC-1 harbor mutations (RET/PTC1 and BRAFV600E, respectively) that upregulate MAPK/ERK signaling associated with promoting tumor migration and metastases.
“Both the cell lines KTC-1 and TPC-1 harbor mutations (RET/PTC1 and BRAFV600E, respectively) that upregulate MAPK/ERK signaling transductions associated with promoting tumor migration and metastases [35].”
From Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells (2017) · cites this paper as [35]
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
Cooper, D. S., Doherty, G. M., Haugen, B. R., Kloos, R. T., Lee, S. L., Mandel, S. J., Mazzaferri, E. L., McIver, B., Pacini, F., Schlumberger, M., et al. (2009) · Thyroid · doi:10.1089/thy.2009.0110 · Cited by 6,707 · see citing works
Identification of stem cells in small intestine and colon by marker gene Lgr5
Barker, N., van Es, J. H., Kuipers, J., Kujala, P., van den Born, M., Cozijnsen, M., Haegebarth, A., Korving, J., Begthel, H., Peters, P. J., et al. (2007) · Nature · doi:10.1038/nature06196 · Cited by 5,687 · see citing works
Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling
de Lau, W., Barker, N., Low, T. Y., Koo, B., Li, V. S. W., Teunissen, H., Kujala, P., Haegebarth, A., Peters, P. J., van de Wetering, M., et al. (2011) · Nature · doi:10.1038/nature10337 · Cited by 1,267 · see citing works
Lgr5 marks cycling, yet long-lived, hair follicle stem cells
Jaks, V., Barker, N., Kasper, M., van Es, J. H., Snippert, H. J., Clevers, H., & Toftgård, R. (2008) · Nature Genetics · doi:10.1038/ng.239 · Cited by 966 · see citing works
Recurrent R-spondin fusions in colon cancer
Seshagiri, S., Stawiski, E. W., Durinck, S., Modrusan, Z., Storm, E. E., Conboy, C. B., Chaudhuri, S., Guan, Y., Janakiraman, V., Jaiswal, B. S., et al. (2012) · Nature · doi:10.1038/nature11282 · Cited by 960 · see citing works
Merlos-Suárez, A., Barriga, F. M., Jung, P., Iglesias, M., Céspedes, M. V., Rossell, D., Sevillano, M., Hernando-Momblona, X., da Silva-Diz, V., Muñoz, P., et al. (2011) · Cell Stem Cell · doi:10.1016/j.stem.2011.02.020 · Cited by 934 · see citing works
Carmon, K. S., Gong, X. W., Lin, Q., Thomas, A., & Liu, Q. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1106083108 · Cited by 857 · see citing works
Lymph Node Metastasis From 259 Papillary Thyroid Microcarcinomas
Wada, N., Duh, Q., Sugino, K., Iwasaki, H., Kameyama, K., Mimura, T., Ito, K., Takami, H. E., & Takanashi, Y. (2003) · Annals of Surgery · doi:10.1097/01.sla.0000055273.58908.19 · Cited by 810 · see citing works
LGR4 and LGR5 are R‐spondin receptors mediating Wnt/β‐catenin and Wnt/PCP signalling
Glinka, A., Dolde, C. E., Kirsch, N., Huang, Y., Kazanskaya, O., Ingelfinger, D., Boutros, M., Cruciat, C., & Niehrs, C. (2011) · EMBO Reports · doi:10.1038/embor.2011.175 · Cited by 565 · see citing works
Grigoryan, T., Wend, P., Klaus‐Bergmann, A., & Birchmeier, W. (2008) · Genes & Development · doi:10.1101/gad.1686208 · Cited by 558 · see citing works
Hsu, S. Y., 工藤, 正., Chen, T., Nakabayashi, K., Bhalla, A., van der Spek, P. J., van Duin, M., & Hsueh, A. J. W. (2000) · Molecular Endocrinology · doi:10.1210/mend.14.8.0510 · Cited by 359 · see citing works
β-Catenin Signaling Controls Metastasis in Braf-Activated Pten-Deficient Melanomas
Damsky, W., Curley, D. P., Santhanakrishnan, M., Rosenbaum, L. E., Platt, J. T., Rothberg, B. E. G., Taketo, M. M., Dankort, D. L., Rimm, D. L., McMahon, M., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.10.030 · Cited by 351 · see citing works
Leucine-Rich Repeat-Containing G-Protein-Coupled Receptors as Markers of Adult Stem Cells
Barker, N., & Clevers, H. C. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.03.002 · Cited by 338 · see citing works
Papillary Thyroid Cancer: Time Course of Recurrences During Postsurgery Surveillance
Durante, C., Montesano, T., Torlontano, M., Attard, M., Monzani, F., Tumino, D., Costante, G., Meringolo, D., Bruno, R., Trulli, F., et al. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3401 · Cited by 310 · see citing works
Monoclonal Antibodies Against Lgr5 Identify Human Colorectal Cancer Stem Cells
Kemper, K., Prasetyanti, P. R., de Lau, W., Rodermond, H. M., Clevers, H. C., & Medema, J. P. (2012) · Stem Cells · doi:10.1002/stem.1233 · Cited by 254 · see citing works
The Anti-Helminthic Niclosamide Inhibits Wnt/Frizzled1 Signaling
Chen, M., Wang, J., Lü, J., Bond, M. C., Ren, X.-R., Lyerly, H. K., Barak, L. S., & Chen, W. (2009) · Biochemistry · doi:10.1021/bi9009677 · Cited by 213 · see citing works
Yamamoto, Y., Sakamoto, M., Fujii, G., Tsuiji, H., Kenetaka, K., Asaka, M., & Hirohashi, S. (2003) · Hepatology · doi:10.1053/jhep.2003.50029 · Cited by 200 · see citing works
McClanahan, T. K., Koseoglu, S., Smith, K. B., Grein, J., Gustafson, E. A., Black, S., Kirschmeier, P. T., & Samatar, A. A. (2006) · Cancer Biology & Therapy · doi:10.4161/cbt.5.4.2521 · Cited by 181 · see citing works
R-Spondin Potentiates Wnt/β-Catenin Signaling through Orphan Receptors LGR4 and LGR5
Ruffner, H., Sprunger, J., Charlat, O., Leighton-Davies, J. R., Grosshans, B. L., Salathe, A., Zietzling, S., Beck, V., Therier, M., Isken, A., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040976 · Cited by 170 · see citing works
Inhibition of Wnt/β-catenin pathway by niclosamide: A therapeutic target for ovarian cancer
Arend, R. C., Londoño-Joshi, A. I., Samant, R. S., Li, Y., Conner, M., Hidalgo, B., Alvarez, R. D., Landen, C. N., Straughn, J. M., & Buchsbaum, D. J. (2014) · Gynecologic Oncology · doi:10.1016/j.ygyno.2014.04.005 · Cited by 161 · see citing works
Tanese, K., Fukuma, M., Yamada, T., Mori, T., Yoshikawa, T., Watanabe, W., Ishiko, A., Amagai, M., Nishikawa, T., & Sakamoto, M. (2008) · American Journal Of Pathology · doi:10.2353/ajpath.2008.071091 · Cited by 144 · see citing works
Wnt/β-catenin Signaling in Normal and Cancer Stem Cells
Valkenburg, K. C., Graveel, C. R., Diegel, C. R., Zhong, Z. A., & Williams, B. O. (2011) · Cancers · doi:10.3390/cancers3022050 · Cited by 141 · see citing works
Walker, F., Zhang, H., Odorizzi, A., & Burgess, A. W. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022733 · Cited by 131 · see citing works
RSPO2–LGR5 signaling has tumour-suppressive activity in colorectal cancer
Wu, C., Qiu, S., Lu, L., Zou, J., Li, W., Wang, O., Zhao, H., Wang, H., Tang, J., Chen, L., et al. (2014) · Nature Communications · doi:10.1038/ncomms4149 · Cited by 122 · see citing works
Sakorafas, G. H., Sampanis, D., & Safioleas, M. C. (2009) · Surgical Oncology · doi:10.1016/j.suronc.2009.04.002 · Cited by 107 · see citing works
Structure of Stem Cell Growth Factor R-spondin 1 in Complex with the Ectodomain of Its Receptor LGR5
Peng, W. C., de Lau, W., Forneris, F., Granneman, J. C. M., Huch, M., Clevers, H. C., & Gros, P. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.06.009 · Cited by 100 · see citing works
Lin, R.-Y. (2011) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.127 · Cited by 86 · see citing works
Becker, L. S., Huang, Q. M., & Mashimo, H. L. (2009) · Diseases of the Esophagus · doi:10.1111/j.1442-2050.2009.00979.x · Cited by 84 · see citing works
Chen, Q., Cao, H.-Z., & Zheng, P. (2014) · Oncotarget · doi:10.18632/oncotarget.2377 · Cited by 73 · see citing works
Kharusi, M. A., Smartt, H. J. M., Greenhough, A., Collard, T. J., Emery, E. D., Williams, A. C., & Paraskeva, C. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt020 · Cited by 69 · see citing works
Cassinelli, G., Favini, E., Degl’Innocenti, D., Salvi, A., Petro, G. D., Pierotti, M. A., Zunino, F., Borrello, M. G., & Lanzi, C. (2009) · Neoplasia · doi:10.1593/neo.08916 · Cited by 60 · see citing works
Thyroid stem cells: lessons from normal development and thyroid cancer
Thomas, D., Friedman, S. L., & Lin, R.-Y. (2008) · Endocrine Related Cancer · doi:10.1677/erc-07-0210 · Cited by 54 · see citing works
Liu, Z., Kakudo, K., Bai, Y., et al. (2011) · Journal of Clinical Pathology · doi:10.1136/jcp.2010.083956 · Cited by 51 · see citing works
Identification of a Wnt/β-Catenin Signaling Pathway in Human Thyroid Cells
Helmbrecht, K., Kispert, A., von Wasielewski, R., & Brabant, G. E. (2001) · Endocrinology · doi:10.1210/endo.142.12.8554 · Cited by 45 · see citing works
Over-expression of LGR5 correlates with poor survival of colon cancer in mice as well as in patients
Liu, Z., Dai, W., Jiang, L., et al. (2013) · Neoplasma · doi:10.4149/neo_2014_016 · Cited by 43 · see citing works
Russo, M., Malandrino, P., Nicolosi, M. L., et al. (2014) · Thyroid · doi:10.1089/thy.2013.0675 · Cited by 37 · see citing works
Cho, S. W., Lee, E. J., Kim, H.-H., Kim, S. H., Ahn, H. Y., Kim, Y. A., Yi, K. H., Park, D. J., Shin, C. S., Ahn, S., et al. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.12.007 · Cited by 36 · see citing works
Increased expression of Lgr5 is associated with chemotherapy resistance in human gastric cancer
Xi, H., Cui, J., Shen, W., et al. (2014) · Oncology Reports · doi:10.3892/or.2014.3207 · Cited by 36 · see citing works
Rot, S., Taubert, H. W., Bache, M., et al. (2011) · BMC Cancer · doi:10.1186/1471-2407-11-429 · Cited by 24 · see citing works
Controversies in the Management of Papillary Thyroid Cancer Revisited
Guerrero, M. A., & Clark, O. H. (2011) · ISRN Oncology · doi:10.5402/2011/303128 · Cited by 23 · see citing works
Gao, F.-J., Chen, J., Wu, H., et al. (2014) · PubMed · Cited by 18 · see citing works
Knockdown of LGR5 Suppresses the Proliferation of Glioma Cells in Vitro and in Vivo
Parry, P. V., & Engh, J. A. (2014) · Neurosurgery · doi:10.1227/01.neu.0000442976.61335.f6 · Cited by 10 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- [18]de Lau W Barker N Low TY Koo BK Li VS Teunissen H Kujala P Haegebarth A Peters PJ van de Wetering M Stange DE van Es JE Guardavaccaro D LGR5 homologues associate with Wnt receptors and mediate R-spondin signaling Nature 2011 476 293 7 21727895
- [23]Yamamoto Y Sakamoto M Fujii G Tsuiji H Kenetaka K Asaka M Hirohashi S Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with beta-catenin mutations Hepatology (Baltimore, Md) 2003 37 528 533 12601349
- [45]Guidelines for Management of Thyroid Tumor The Japanese Society of Thyroid Surgery - The Japanese Society of Endocrine Surgeons Kanehara Press Tokyo, Japan 2010
Cited by
Sorted by citations
Chen, H., Luo, D., Zhang, L., Lin, X., Luo, Q., Yi, H., Wang, J., Yan, X., Li, B., Chen, Y., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.17398 · Cited by 29 · see citing works
- Authors
- Michelotti, G., Jiang, X., Sosa, J. A., Diehl, A. M., & Henderson, B. B.
- Affiliations
- Duke Medical Center (US)
- Wake Forest University (US)
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2015-09-25
- Volume
- 6
- Issue
- 33
- Pages
- 34549-34560
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC4741472
- OpenAlex
- W2210149345
- Cited by
- 31
- References
- 42
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 8 · 2017: 8 · 2016: 1 · 2015: 2
- FWCI
- 5.51
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- American Thyroid Association
- National Institutes of Health (5rc2aa019399-02, AA010154)
- National Institute on Alcohol Abuse and Alcoholism (RC2-AA019399, R01AA010154)
- National Institute of Diabetes and Digestive and Kidney Diseases (UO1DK061713, U01DK061713, R01DK053792)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Keywords
- Lgr5, papillary thyroid carcinoma, R-spondin, RSPO2, Wnt/β-catenin signaling, tumor aggressiveness, lymph node metastasis, BRAF V600E mutation, cancer stem cells, cell migration, prognostic factors, vascular invasion, extrathyroidal extension, capsular invasion
- MeSH terms
- Thyroid Cancer, Papillary, R-Spondins, Adult, Carcinoma, Carcinoma, Papillary, Female, Humans, Immunohistochemistry, Lymphatic Metastasis, Male, Middle Aged, Mutation, Sensitivity and Specificity, Thyroid Neoplasms, Biomarkers, Tumor, Thrombospondins, Receptors, G-Protein-Coupled, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Cell Proliferation, beta Catenin, Gene Knockdown Techniques, Wnt Signaling Pathway, Real-Time Polymerase Chain Reaction
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
