Vascular endothelial growth factor-C and its receptor-3 signaling in tumorigenesis

doi:10.1007/s13205-023-03719-4

Review

. 2023 Oct;13(10):326.

doi: 10.1007/s13205-023-03719-4. Epub 2023 Sep 1.

Vascular endothelial growth factor-C and its receptor-3 signaling in tumorigenesis

Selvaraj Vimalraj¹, Krishnasamy Naidu Gopal Hariprabu², Mostafizur Rahaman³, Periyasami Govindasami³, Karthikeyan Perumal⁴, Saravanan Sekaran⁵, Dhanraj Ganapathy⁵

Affiliations

¹ Department of Applied Mechanics and Biomedical Engineering, Indian Institute of Technology, Madras, Chennai, India.
² Centre for Biotechnology, Anna University, Chennai, India.
³ Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh, 11451 Saudi Arabia.
⁴ Department of Chemistry and Biochemistry, The Ohio State University, 151 W. Woodruff Ave, Columbus, OH 43210 USA.
⁵ Department of Prosthodontics, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamil Nadu 600 077 India.

PMID: 37663750
PMCID: PMC10474002
DOI: 10.1007/s13205-023-03719-4

Review

Vascular endothelial growth factor-C and its receptor-3 signaling in tumorigenesis

Selvaraj Vimalraj et al. 3 Biotech. 2023 Oct.

. 2023 Oct;13(10):326.

doi: 10.1007/s13205-023-03719-4. Epub 2023 Sep 1.

Authors

Selvaraj Vimalraj¹, Krishnasamy Naidu Gopal Hariprabu², Mostafizur Rahaman³, Periyasami Govindasami³, Karthikeyan Perumal⁴, Saravanan Sekaran⁵, Dhanraj Ganapathy⁵

Affiliations

¹ Department of Applied Mechanics and Biomedical Engineering, Indian Institute of Technology, Madras, Chennai, India.
² Centre for Biotechnology, Anna University, Chennai, India.
³ Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh, 11451 Saudi Arabia.
⁴ Department of Chemistry and Biochemistry, The Ohio State University, 151 W. Woodruff Ave, Columbus, OH 43210 USA.
⁵ Department of Prosthodontics, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamil Nadu 600 077 India.

PMID: 37663750
PMCID: PMC10474002
DOI: 10.1007/s13205-023-03719-4

Abstract

The cancer-promoting ligand vascular endothelial growth factor-C (VEGF-C) activates VEGF receptor-3 (VEGFR-3). The VEGF-C/VEGFR-3 axis is expressed by a range of human tumor cells in addition to lymphatic endothelial cells. Activating the VEGF-C/VEGFR-3 signaling enhances metastasis by promoting lymphangiogenesis and angiogenesis inside and around tumors. Stimulation of VEGF-C/VEGFR-3 signaling promotes tumor metastasis in tumors, such as ovarian, renal, pancreatic, prostate, lung, skin, gastric, colorectal, cervical, leukemia, mesothelioma, Kaposi sarcoma, and endometrial carcinoma. We discuss and update the role of VEGF-C/VEGFR-3 signaling in tumor development and the research is still needed to completely comprehend this multifunctional receptor.

Keywords: Angiogenesis; Lymphangiogenesis; Tumor; VEGF-C; VEGFR-3.

© King Abdulaziz City for Science and Technology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

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Conflict of interest statement

Conflict of interestThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

**Fig. 1**
VEGFR3 signaling. A Ligand binding to VEGFR3 and activation of downstream signaling pathways. B Endothelial and endothelial-derived cell lines are subject to the regulation of several biological processes by heterodimerization of VEGFR3 and VEGFR2 and activation by VEGFA or VEGFC. VEGFR3 homodimers associate with neuropilin 2 (NRP2), and the activation of both VEGFR3 and NRP2 by their respective ligands, VEGFA and VEGF, respectively, regulates VEGFR3 activity. During the process of angiogenesis and haematopoiesis, VEGFR3 is able to serve as a receptor for VEGFC ligand binding when it is combined with VEGFR2 in the form of a heterodimer. In addition to this, it has been demonstrated that NRP2 is a coreceptor for both VEGFR2 and VEGFR3, and it is capable of acting in response to VEGFA/C

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References

1. Achen MG, Jeltsch M, Kukk E, Mäkinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4) Proc Natl Acad Sci USA. 1998;95(2):548–553. doi: 10.1073/pnas.95.2.548. - DOI - PMC - PubMed
1. Alishekevitz D, Gingis-Velitski S, Kaidar-Person O, Gutter-Kapon L, Scherer SD, Raviv Z, Merquiol E, et al. Thalidomide suppresses breast cancer tumor growth by inhibiting tumor-associated macrophage accumulation in breast tumor-bearing mice. Clin Genitourin Cancer. 2014;15(4):105302. doi: 10.1016/j.clgc.2015.12.014. - DOI
1. Alishekevitz D, Gingis-Velitski S, Kaidar-Person O, Gutter-Kapon L, Scherer SD, Raviv Z, Merquiol E, Ben-Nun Y, Miller V, Rachman-Tzemah C, Timaner M, Mumblat Y, Ilan N, Loven D, Hershkovitz D, Satchi-Fainaro R, Blum G, Sleeman JP, Vlodavsky I, Shaked Y. Macrophage-induced lymphangiogenesis and metastasis following paclitaxel chemotherapy is regulated by VEGFR3. Cell Rep. 2016;17(5):1344–1356. doi: 10.1016/j.celrep.2016.09.083. - DOI - PMC - PubMed
1. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell. 2019;176(6):1248–1264. doi: 10.1016/j.cell.2019.01.021. - DOI - PMC - PubMed
1. Arinaga M, Noguchi T, Takeno S, Chujo M, Miura T, Uchida Y. Clinical significance of vascular endothelial growth factor c and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma. Cancer. 2003;97(2):457–464. doi: 10.1002/cncr.11073. - DOI - PubMed

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[1] Achen MG, Jeltsch M, Kukk E, Mäkinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4) Proc Natl Acad Sci USA. 1998;95(2):548–553. doi: 10.1073/pnas.95.2.548. - DOI - PMC - PubMed

[2] Achen MG, Jeltsch M, Kukk E, Mäkinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4) Proc Natl Acad Sci USA. 1998;95(2):548–553. doi: 10.1073/pnas.95.2.548. - DOI - PMC - PubMed

[3] Alishekevitz D, Gingis-Velitski S, Kaidar-Person O, Gutter-Kapon L, Scherer SD, Raviv Z, Merquiol E, et al. Thalidomide suppresses breast cancer tumor growth by inhibiting tumor-associated macrophage accumulation in breast tumor-bearing mice. Clin Genitourin Cancer. 2014;15(4):105302. doi: 10.1016/j.clgc.2015.12.014. - DOI

[4] Alishekevitz D, Gingis-Velitski S, Kaidar-Person O, Gutter-Kapon L, Scherer SD, Raviv Z, Merquiol E, et al. Thalidomide suppresses breast cancer tumor growth by inhibiting tumor-associated macrophage accumulation in breast tumor-bearing mice. Clin Genitourin Cancer. 2014;15(4):105302. doi: 10.1016/j.clgc.2015.12.014. - DOI

[5] Alishekevitz D, Gingis-Velitski S, Kaidar-Person O, Gutter-Kapon L, Scherer SD, Raviv Z, Merquiol E, Ben-Nun Y, Miller V, Rachman-Tzemah C, Timaner M, Mumblat Y, Ilan N, Loven D, Hershkovitz D, Satchi-Fainaro R, Blum G, Sleeman JP, Vlodavsky I, Shaked Y. Macrophage-induced lymphangiogenesis and metastasis following paclitaxel chemotherapy is regulated by VEGFR3. Cell Rep. 2016;17(5):1344–1356. doi: 10.1016/j.celrep.2016.09.083. - DOI - PMC - PubMed

[6] Alishekevitz D, Gingis-Velitski S, Kaidar-Person O, Gutter-Kapon L, Scherer SD, Raviv Z, Merquiol E, Ben-Nun Y, Miller V, Rachman-Tzemah C, Timaner M, Mumblat Y, Ilan N, Loven D, Hershkovitz D, Satchi-Fainaro R, Blum G, Sleeman JP, Vlodavsky I, Shaked Y. Macrophage-induced lymphangiogenesis and metastasis following paclitaxel chemotherapy is regulated by VEGFR3. Cell Rep. 2016;17(5):1344–1356. doi: 10.1016/j.celrep.2016.09.083. - DOI - PMC - PubMed

[7] Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell. 2019;176(6):1248–1264. doi: 10.1016/j.cell.2019.01.021. - DOI - PMC - PubMed

[8] Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell. 2019;176(6):1248–1264. doi: 10.1016/j.cell.2019.01.021. - DOI - PMC - PubMed

[9] Arinaga M, Noguchi T, Takeno S, Chujo M, Miura T, Uchida Y. Clinical significance of vascular endothelial growth factor c and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma. Cancer. 2003;97(2):457–464. doi: 10.1002/cncr.11073. - DOI - PubMed

[10] Arinaga M, Noguchi T, Takeno S, Chujo M, Miura T, Uchida Y. Clinical significance of vascular endothelial growth factor c and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma. Cancer. 2003;97(2):457–464. doi: 10.1002/cncr.11073. - DOI - PubMed

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Vascular endothelial growth factor-C and its receptor-3 signaling in tumorigenesis

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Vascular endothelial growth factor-C and its receptor-3 signaling in tumorigenesis

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