Login Register Cart 0
Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

The Lymphangiogenic Factor CCBE1 Promotes Angiogenesis and Tumor Growth in Colorectal Cancer

Author(s): Wenjun Ding, Wenfang Tang* and Jiajun Zhi*

Volume 22, Issue 9, 2022

Published on: 14 January, 2022

Page: [819 - 825] Pages: 7

DOI: 10.2174/1566524021666211124092804

Price: $65

Abstract

Background: Collagen and calcium-binding EGF domain-1 (CCBE1) is essential for the development of the lymphatic vasculature and colorectal cancer (CRC) lymphangiogenesis as it enhances the proteolytic process of vascular endothelial growth factor C (VEGFC) activating VEGFR3. The fully processed mature VEGFC could also activate VEGFR2, the important endothelial-specific receptor tyrosine kinase, involved in blood vascular development and tumor angiogenesis. However, the role of CCBE1 in cancer angiogenesis remains undefined.

Methods: In this paper, we find that the protein expression of CCBE1 is higher in the primary CRC tissue with distant metastasis and positively correlated with blood vessel density.

Results: The mRNA expression of CCBE1 is closely positively correlated with the vascular endothelial marker CD31 and VEGFR2 in CRC from TCGA datasets. The supernatant of the colorectal cancer cell line HCT116 with CCBE1 overexpression significantly promotes the tube formation ability of the human umbilical vein endothelial cells (HUVECs) in vitro and enhances angiogenesis and tumor growth in vivo. Knockdown of CCBE1 decreases the angiogenic ability of CRC.

Conclusion: Our results demonstrate the angiogenic role of CCBE1 in CRC.

Keywords: Angiogenesis, CCBE1, colorectal cancer, VEGFC, VEGFR2, tumor growth.

« Previous Next »
[1]
De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer 2017; 17(8): 457-74.
[http://dx.doi.org/10.1038/nrc.2017.51] [PMID: 28706266]
[2]
La Porta S, Roth L, Singhal M, et al. Endothelial Tie1-mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis. J Clin Invest 2018; 128(2): 834-45.
[http://dx.doi.org/10.1172/JCI94674] [PMID: 29355844]
[3]
Varney ML, Singh S, Backora M, Chen Z, Singh RK. Lymphangiogenesis and anti-tumor immune responses. Curr Mol Med 2009; 9(6): 694-701.
[http://dx.doi.org/10.2174/156652409788970733] [PMID: 19689296]
[4]
Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 2006; 7(5): 359-71.
[http://dx.doi.org/10.1038/nrm1911] [PMID: 16633338]
[5]
Zheng W, Aspelund A, Alitalo K. Lymphangiogenic factors, mechanisms, and applications. J Clin Invest 2014; 124(3): 878-87.
[http://dx.doi.org/10.1172/JCI71603] [PMID: 24590272]
[6]
Zhao Y, Adjei AA. Targeting angiogenesis in cancer therapy: Moving beyond vascular endothelial growth factor. Oncologist 2015; 20(6): 660-73.
[http://dx.doi.org/10.1634/theoncologist.2014-0465] [PMID: 26001391]
[7]
Alders M, Hogan BM, Gjini E, et al. Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet 2009; 41(12): 1272-4.
[http://dx.doi.org/10.1038/ng.484] [PMID: 19935664]
[8]
Hogan BM, Bos FL, Bussmann J, et al. Ccbe1 is required for embryonic lymphangiogenesis and venous sprouting. Nat Genet 2009; 41(4): 396-8.
[http://dx.doi.org/10.1038/ng.321] [PMID: 19287381]
[9]
Jeltsch M, Jha SK, Tvorogov D, et al. CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation. Circulation 2014; 129(19): 1962-71.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002779] [PMID: 24552833]
[10]
Joukov V, Pajusola K, Kaipainen A, et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 1996; 15(2): 290-8.
[http://dx.doi.org/10.1002/j.1460-2075.1996.tb00359.x] [PMID: 8617204]
[11]
Joukov V, Sorsa T, Kumar V, et al. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J 1997; 16(13): 3898-911.
[http://dx.doi.org/10.1093/emboj/16.13.3898] [PMID: 9233800]
[12]
Song J, Chen W, Cui X, et al. CCBE1 promotes tumor lymphangiogenesis and is negatively regulated by TGFβ signaling in colorectal cancer. Theranostics 2020; 10(5): 2327-41.
[http://dx.doi.org/10.7150/thno.39740] [PMID: 32089745]
[13]
Le Guen L, Karpanen T, Schulte D, et al. Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis. Development 2014; 141(6): 1239-49.
[http://dx.doi.org/10.1242/dev.100495] [PMID: 24523457]
[14]
Parab S, Quick RE, Matsuoka RL. Endothelial cell-type-specific molecular requirements for angiogenesis drive fenestrated vessel development in the brain. eLife 2021; 10: 10.
[http://dx.doi.org/10.7554/eLife.64295] [PMID: 33459592]
[15]
Bonet F, Pereira PNG, Bover O, Marques S, Inácio JM, Belo JA. CCBE1 is required for coronary vessel development and proper coronary artery stem formation in the mouse heart. Dev Dyn 2018; 247(10): 1135-45.
[http://dx.doi.org/10.1002/dvdy.24670] [PMID: 30204931]
[16]
Silva MM, Gomes-Alves P, Rosa S, et al. Full-length human CCBE1 production and purification: Leveraging bioprocess development for high quality glycosylation attributes and functionality. J Biotechnol 2018; 285: 6-14.
[http://dx.doi.org/10.1016/j.jbiotec.2018.08.015] [PMID: 30165116]
[17]
Tian GA, Zhu CC, Zhang XX, et al. CCBE1 promotes GIST development through enhancing angiogenesis and mediating resistance to imatinib. Sci Rep 2016; 6: 31071.
[http://dx.doi.org/10.1038/srep31071] [PMID: 27506146]

Rights & Permissions Print Cite
Article Metrics
20
1
© 2025 Bentham Science Publishers | Privacy Policy