CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth

Babic, Alexander M.; Kireeva, Maria L.; Kolesnikova, Tatiana V.; Lau, Lester F.

doi:10.1073/pnas.95.11.6355

Cited by 495Angiogenesis and VEGF in CancerConnective Tissue Growth Factor ResearchCancer Mechanisms and Therapy

CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth

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Babic, Alexander M., Kireeva, Maria L., Kolesnikova, Tatiana V., Lau, Lester F.·1998·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.95.11.6355PMC PMC27701

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Abstract

CYR61 is a secreted, cysteine-rich, heparin-binding protein encoded by a growth factor-inducible immediate–early gene. Acting as an extracellular, matrix-associated signaling molecule, CYR61 promotes the adhesion of endothelial cells through interaction with the integrin α V β 3 and augments growth factor-induced DNA synthesis in the same cell type. In this study, we show that purified CYR61 stimulates directed migration of human microvascular endothelial cells in culture through an α V β 3 -dependent pathway and induces neovascularization in rat corneas. Both the chemotactic and angiogenic activities of CYR61 can be blocked by specific anti-CYR61 antibodies. Whereas most human tumor-derived cell lines tested express CYR61 , the gastric adenocarcinoma cell line RF-1 does not. Expression of the CYR61 cDNA under the regulation of a constitutive promoter in RF-1 cells significantly enhances the tumorigenicity of these cells as measured by growth in immunodeficient mice, resulting in tumors that are larger and more vascularized than those produced by control RF-1 cells. Taken together, these results identify CYR61 as an angiogenic inducer that can promote tumor growth and vascularization; the results also suggest potential roles for CYR61 in physiologic and pathologic neovascularization.

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CCN1 has potent angiogenic activity, first demonstrated in a corneal micropocket implant assay and confirmed in a rabbit ischemic hindlimb model.
“Indeed, CCN1 has potent angiogenic activity, first demonstrated in a corneal micropocket implant assay [83] and subsequently confirmed in a rabbit ischemic hindlimb model [84].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [83]
CCN1 promotes tumor growth and increases tumor vascularization when overexpressed in human gastric adenocarcinoma cells in SCID mice.
“With the discovery of its angiogenic activity, CCN1 was shown to promote tumor growth and increase tumor vascularization when overexpressed in human gastric adenocarcinoma cells in SCID mice [83].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [83]
CCN1 can promote growth of tumors generated by transformed cells, typically in xenografts transplanted into immunodeficient mice.
“These findings demonstrated the ability of CCN1 to promote the growth of tumors generated by transformed cells, typically observed in xenografts transplanted into immunodeficient mice.”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [83]
CCN1 is a powerful angiogenic inducer in vivo.
“First, CCN1 is a powerful angiogenic inducer in vivo [72,83], and angiogenesis is essential for the supply of oxygen and nutrients to nourish the growing tumor [140].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [83]

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Vascular Endothelial Growth Factor (VEGF)-induced Up-regulation of CCN1 in Osteoblasts Mediates Proangiogenic Activities in Endothelial Cells and Promotes Fracture Healing
Athanasopoulos, A. N., Schneider, D., Keiper, T., Alt, V., Pendurthi, U. R., Liegibel, U. M., Sommer, U., Nawroth, P. P., Kasperk, C., & Chavakis, T. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705200200 · Cited by 99 · see citing works
Involvement of Cyr61 in growth, migration, and metastasis of prostate cancer cells
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Cyr61, a deregulated gene in endometriosis
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Regulation of Cyr61 gene expression by mechanical stretch through multiple signaling pathways
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Endothelial YAP/TAZ Signaling in Angiogenesis and Tumor Vasculature
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Oncolytic HSV-1 Infection of Tumors Induces Angiogenesis and Upregulates CYR61
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RETRACTED ARTICLE: Cyr61 suppresses the growth of non-small-cell lung cancer cells via the β-catenin–c-myc–p53 pathway
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Retracted
Induced Endometriosis in the Baboon (Papio anubis) Increases the Expression of the Proangiogenic Factor CYR61 (CCN1) in Eutopic and Ectopic Endometria1
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Identification of a Novel Integrin αMβ2 Binding Site in CCN1 (CYR61), a Matricellular Protein Expressed in Healing Wounds and Atherosclerotic Lesions
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Self-citation
Decreased expression of the angiogenic regulators CYR61 (CCN1) and NOV (CCN3) in human placenta is associatedwith pre-eclampsia
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Targeted Mutagenesis of the Angiogenic Protein CCN1 (CYR61)
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Self-citation
Coxsackievirus B3 Infection Induces cyr61 Activation via JNK To Mediate Cell Death
Kim, S.-M., Park, J.-H., Chung, S.-K., Kim, J.-Y., Hwang, H.-Y., Chung, K.-C., Jo, I., Park, S.-I., & Nam, J.-H. (2004) · Journal of Virology · doi:10.1128/jvi.78.24.13479-13488.2004 · Cited by 70 · see citing works
Identification of differentially expressed genes induced by transient ischemic stroke
Schwarz, D. A., Barry, G., Mackay, K. B., Manu, F., Naeve, G. S., Vana, A. M., Verge, G., Conlon, P. J., Foster, A. C., & Maki, R. A. (2002) · Molecular Brain Research · doi:10.1016/s0169-328x(02)00135-3 · Cited by 65 · see citing works
Matrix Protein CCN1 Is Critical for Prostate Carcinoma Cell Proliferation and TRAIL-Induced Apoptosis
Franzen, C. A., Chen, C.-C., Todorović, V., Juric, V., Monzon, R. I., & Lau, L. F. (2009) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-09-0017 · Cited by 66 · see citing works
Self-citation
Promoter Function of the Angiogenic Inducer Cyr61Gene in Transgenic Mice: Tissue Specificity, Inducibility During Wound Healing, and Role of the Serum Response Element
Latinkic, B. V. (2001) · Endocrinology · doi:10.1210/en.142.6.2549 · Cited by 61 · see citing works
CCN1 Knockdown Suppresses Neointimal Hyperplasia in a Rat Artery Balloon Injury Model
Matsumae, H., Yoshida, Y., Ono, K., Togi, K., Inoue, K., Furukawa, Y., Nakashima, Y., Kojima, Y., Nobuyoshi, M., Kita, T., et al. (2008) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.108.162362 · Cited by 59 · see citing works
Stimulation of Angiogenesis by Cyr61 Gene: A New Therapeutic Candidate
Fataccioli, V., Abergel, V., Wingertsmann, L., Neuville, P., Spitz, E., Adnot, S., Calenda, V., & Teiger, E. (2002) · Human Gene Therapy · doi:10.1089/10430340260185094 · Cited by 58 · see citing works
Cysteine-Rich 61 (CCN1) Enhances Chemotactic Migration, Transendothelial Cell Migration, and Intravasation by Concomitantly Up-Regulating Chemokine Receptor 1 and 2
Lin, B.-R., Chang, C.-C., Chen, L.-R., Wu, M.-H., Wang, M.-Y., Kuo, I.-H., Chu, C.-Y., Chang, K.-J., Lee, P.-H., Chen, W.-J., et al. (2007) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-06-0289 · Cited by 51 · see citing works
Regulation of the Matricellular Proteins CYR61 (CCN1) and NOV (CCN3) by Hypoxia-Inducible Factor-1α and Transforming-Growth Factor-β3 in the Human Trophoblast
Wolf, N., Yang, W., Dunk, C. E., Gashaw, I., Lye, S. J., Ring, T., Schmidt, M., Winterhager, E., & Gellhaus, A. (2010) · Endocrinology · doi:10.1210/en.2009-1195 · Cited by 52 · see citing works
Stretch-inducible Expression of the Angiogenic Factor CCN1 in Vascular Smooth Muscle Cells Is Mediated by Egr-1
Grote, K., Bavendiek, U., Grothusen, C., Flach, I., Hilfiker-Kleiner, D., Drexler, H., & Schieffer, B. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406532200 · Cited by 52 · see citing works
Cyr61/CCN1 is a tumor suppressor in human hepatocellular carcinoma and involved in DNA damage response
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Cyr61 Protects against Hyperoxia-Induced Cell Death via Akt Pathway in Pulmonary Epithelial Cells
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Self-citation
Cyr61 Mediates Hepatocyte Growth Factor–Dependent Tumor Cell Growth, Migration, and Akt Activation
Goodwin, C. R., Lal, B., Zhou, X., Ho, S., Xia, S., Taeger, A., Murray, J., & Laterra, J. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3570 · Cited by 48 · see citing works
CCN1 promotes the differentiation of endothelial progenitor cells and reendothelialization in the early phase after vascular injury
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Substance P-Mediated Expression of the Pro-Angiogenic Factor CCN1 Modulates the Course of Colitis
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Pathological functions of hypoxia in endometriosis
Hsiao, K.-Y. (2015) · Frontiers in Bioscience · doi:10.2741/e736 · Cited by 61 · see citing works
Genomic and phenotypic analysis reveals a key role for CCN1 (CYR61) in BAG3—modulated adhesion and invasion
Kassis, J. N., Virador, V. M., Guancial, E. A., Kimm, D., Ho, A. S., Mishra, M., Chuang, E. Y., Cook, J., Gius, D., & Kohn, E. C. (2009) · The Journal of Pathology · doi:10.1002/path.2557 · Cited by 34 · see citing works
Induction and function of CYR61 (CCN1) in prostatic stromal and epithelial cells: CYR61 is required for prostatic cell proliferation
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Authors: Babic, A. M., Kireeva, M. L., Kolesnikova, T. V., & Lau, L. F.
Affiliations: University of Illinois Chicago (US)
Corresponding author: Lau, Lester F.
ORCID: Kireeva, Maria L.
Lau, Lester F.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1998-05-26
Volume: 95
Issue: 11
Pages: 6355-6360
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.95.11.6355
PMC: PMC27701
OpenAlex: W2032912914
Cited by: 495
References: 53
Citations by year: 2026: 4 · 2025: 9 · 2024: 15 · 2023: 11 · 2022: 9 · 2021: 26 · 2020: 11 · 2019: 13 · 2018: 8 · 2017: 11 · 2016: 20 · 2015: 19 · 2014: 22 · 2013: 15 · 2012: 19
FWCI: 6.28
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (R01CA046565, CA-46565)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
Keywords: CYR61, angiogenesis, tumor growth, immediate early genes, heparin-binding protein, integrin αvβ3, endothelial cell migration, endothelial cell adhesion, neovascularization, cornea, tumor vascularization, gastric adenocarcinoma, tumorigenicity, chemotaxis
MeSH terms: Animals, Cell Division, Cell Movement, Chemotaxis, Endothelium, Vascular, Growth Substances, Humans, Mice, Nude, Neoplasms, Experimental, Neovascularization, Pathologic, Tumor Cells, Cultured, Immediate-Early Proteins, Intercellular Signaling Peptides and Proteins, Mice, Rats, Cysteine-Rich Protein 61

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CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth

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