VEGF: a marker of angiogenesis with potential as a prognostic cancer biomarker
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Vascular endothelial growth factor (VEGF) is a key contributor in the formation of new blood vessels.
VEGF can induce growth of pre-existing (angiogenesis) or de novo vessels (vasculogenesis), and is therefore key for embryonic development and vessel repair. VEGF is also hijacked by solid tumors to support their neoplastic growth.
The VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor 1 and 2 (PIGF-1 and PIGF-2, respectively)1,2. VEGF-A is the most potent inducer of blood vessel growth known to date, whereas VEGF-E is more specific for localized pathological processes of angiogenesis.
Family members are encoded by multiple exons that can give rise different isoforms after alternative splicing, with consequences on solubility and receptor binding3. For example, VEGF-A exists in seven isoforms, while VEGF-B presents two isoforms.
VEGF family members transduce their signal intercellularly by binding to membrane-bound tyrosine kinase receptors: VEGF-A and B have a preference for VEGFR-1; VEGF-A, C, D and E can bind to VEGFR-2; VEGF-C and D to VEGFR-3 (expressed only in hematopoietic cells). The activation of VEGF receptors is considered one of the most critical events in angiogenesis3.
Contents
- VEGF signaling pathways
- VEGF and the formation of new blood vessels
- VEGF's value as a prognostic cancer biomarker
- Antibodies, recombinant proteins, and assay kits to study VEGF receptors and their ligands
- Antibodies, inhibitors, and assay kits VEGF downstream signaling
- Human angiogenesis antibody arrays
VEGF signaling pathways
VEGF has activity in diverse cell types, such as muscle4 and neuronal cells5, however its main actions are on endothelial cells6. Family members play key roles in orchestrating the formation of new blood vessels, such as induction of gene expression, regulation of vascular permeability, and promotion of cell migration, proliferation and survival.
These are all induced by the binding of VEGF to VEGF-Rs, and the resulting activation of multiple downstream signaling pathways. These include: the Ras/MAPK pathway to regulate cell proliferation and gene expression; the FAK/paxillin pathway involved in the rearrangement of the cytoskeleton; the PI3K/AKT pathway regulating cell survival; the RhoA/ROCK pathway to form of new capillaries; the PLCγ pathway which controls vascular permeability6,7.
VEGF and the formation of new blood vessels
High levels of VEGF are observed during embryo development, where it cooperates with multiple endothelial growth factors to control the formation of new blood vessels1. As a consequence, disruption of VEGF pathways in mice increases embryonic lethality due to circulatory problems8.
Expression of VEGF decreases significantly after birth. However, localized levels can be up-regulated in tissues undergoing wound healing or fracture repair2. Recent studies have emphasized the role VEGF plays in pathological conditions involving the formation of new blood vessels, such as cancer, rheumatoid arthritis and age-related macular degeneration3,9,10.
Once the angiogenic switch is induced to promote the formation of new blood vessels, a complex and highly regulated sequence of events takes place. By activating multiple proteases, this pathway promotes the degradation of the basement membrane surrounding the existing vessel. This is followed by increased proliferation of endothelial cells, the formation of a lumen and a new basement membrane, and the fusion of newly formed vessels2.
VEGF's value as a prognostic cancer biomarker
Immunohistochemistry analysis of VEGF and its family members has been associated with the prognosis of multiple cancer types including; cervical cancer11, oral cancer12, multiple lung cancers13, colorectal cancers14, ovarian cancer15, renal cancer16 and liver cancer17.
VEGF Receptor 1 | VEGF Receptor 2 | ||
Antibody | Rabbit monoclonal (ab1316) | Rabbit monoclonal (ab32152) | Rabbit polyclonal (ab39256) |
Inhibitor | Melittin (ab143517) | ZM306416 hydrochloride (ab144576) | AZD4547 (ab216311) |
Recombinant protein | VEGFA protein (ab9571) | VEGF R1 protein (ab84771) | VEGF R2 protein (ab106310) |
Human ELISA Kit | VEGF ELISA Kit (ab100663) | VEGF R1 ELISA Kit (FLT1) (ab195210) | VEGF R2 ELISA Kit (ab213476) |
Add antibodies, inhibitors and assay kits to your reagents to study VEGF downstream signaling.
RAS/MAPK | FAK/Paxillin | PI3K/AKT | |
Total and phospho antibodies |
| Rabbit mono to FAK (ab40794) | Rabbit mono to AKT1 (ab32505) |
Rabbit mono to ERK1+ERK2 (ab184699) | Rabbit mono to Paxillin (ab32084) | Mouse mono to PI3K (ab86714) | |
Rabbit mono to ERK1 pT202 +ERK2 pT185 (ab201015) | Rabbit mono to Paxillin pY31 (ab32115) | Rabbit mono to AKT pS437 (ab81283) | |
Rabbit mono to PI3K pY607 (ab182651) | |||
Activity and detection kits | Ras GTPase ELISA Kit (ab134640) | Human FAK ELISA Kit (ab187395) | Akt + Akt pS473 ELISA (ab126433) |
Mouse FAK Matched Antibody Pair Kit (ab215072) | Akt Kinase Activity Assay (ab139436) | ||
Pathway inhibition | p38 inhibtor SB202190 (ab120638) | FAK inhibitor 14 (ab144503) | Akt inhibitor Akti-1/2 (ab142088) |
JNK inhibitor (ab120065) | PF-562271 FAK inhibitor (ab141360) | TGX-221 PI3K inhibitor (ab120924) |
Array format (product code) | Angiogenesis factors detected | WB-like detection | Laser scanner detection |
Membrane (ab193655) | 43 | ||
Membrane (ab134000) | 20 | ||
Membrane (ab169808) | 23 | ||
Slide – Quantitative (ab197419) | 10 | ||
Slide A – Quantitative (ab197420) | 30 | ||
Slide B – Quantitative (ab197421) | 30 | ||
Slide – Quantitative (ab197418) | 60 |
References
- 1. Gilbert, SF (2000) Developmental biology (6th Edition). Sunderland (MA): Sinauer Associates.
- 2. Adair, TH and Montani JP (2010) Angiogenesis. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.
- 3. Sullivan LA and Brekken RA (2010) The VEGF family in cancer and antibody-based strategies for their inhibition. MAbs. 2010 Mar-Apr; 2(2): 165–175.
- 4. Bryan B, Walshe T, Mitchell D, Havumaki J, Saint-Geniez M, Maharaj A, Maldonado A and D'Amore P (2008) Coordinated Vascular Endothelial Growth Factor Expression and Signaling During Skeletal Myogenic Differentiation. Mol Biol Cell. 2008 March; 19(3): 994–1006.
- 5. Jin K, Mao XO, Greenberg DA. Vascular endothelial growth factor stimulates neurite outgrowth from cerebral cortical neurons via Rho kinase signaling. J Neurobiol. 2006 Feb 15;66(3):236-42.
- 6. Lee S, Chen T, Barber C, Jordan M, Murdock J, Desai S, Ferrara N, Nagy A, Roos K and Iruela-Arispe M (2007) Autocrine VEGF signaling is required for vascular homeostasis. Cell. 2007 August 24; 130(4): 691–703.
- 7. Zachary I. VEGF signalling: integration and multi-tasking in endothelial cell biology. Biochem Soc Trans. 2003 Dec;31(Pt 6):1171-7.
- 8. Ji Y, Lu X, Zhong Q, Liu P, An Y, Zhang Y, Zhang S, Jia R, Tesfamariam IG, Kahsay AG, Zhang L, Zhu W, Zheng Y (2013). Transcriptional profiling of mouse uterus at pre-implantation stage under VEGF repression. PLoS One. 8(2):e57287.
- 9. Szekanecz Z, Besenyei T, Paragh G, Koch AE (2009) Angiogenesis in rheumatoid arthritis. Autoimmunity. 42(7):563-73.
- 10. Foxton RH, Finkelstein A, Vijay S, Dahlmann-Noor A, Khaw PT, Morgan JE, Shima DT, Ng YS (2013) VEGF-A is necessary and sufficient for retinal neuroprotection in models of experimental glaucoma. Am J Pathol. 2013 Apr;182(4):1379-90.
- 11. Rahmani A H, Babiker A Y, Alsahli M A, Almatroodi S A and Husain N E O S (2018) Prognostic Significance of Vascular Endothelial Growth Factor (VEGF) and Her-2 Protein in the Genesis of Cervical Carcinoma. Maced J Med Sci. 2018 Feb 15; 6(2); 263-268
- 12. Lee L T, Wong Y K, Chan M Y, Chang K W, Chen S C, Chang C T & Wang J (2018) The correlation between HIF-1 alpha and VEGF in oral squamous cell carcinomas: Expression patterns and quantitative immunohistochemical analysis. Journal of the Chinese Medical Association. 2015 Apr; 81 (4): 370- 375
- 13. Usuda K, Iwai S, Funasaki A, Sekimura A, Motono N, Ueda Y, Shimazaki M and Uramoto H (2018) Expression and Prognostic Impact of VEGF, CD31 and αSMA in Resected Primary Lung Cancers. Anticancer research. 2018 July; 38(7): 4057 – 4063
- 14. Mohamed S Y, Mohamed H L, Ibrahim H M, Elshaimaa M M and Salah M (2017) Role of VEGF, CD105 and CD31 in the Prognosis of Colorectal Cancer Cases. Journal of Gastrointestinal Reseearch. 2019 March; 50 (1): 23-34
- 15. Guo B Q and Lu W Q (2018) The prognostic significance of high/positive expression of tissue VEGF in ovarian cancer. Oncotarget. 2018 July 17; 9(55): 30552-30560
- 16. Osman W M and Youssef N S (2015) Combined use of COX-1 and VEGF immunohistochemistry refines the histopathologic prognosis of renal cell carcinoma. Int J Clin Exp Pathol. 2015; 8(7): 8165-8177
- 17. Cao G, Li X, Qin C and Li J (2015) Prognostic Value of VEGF in Hepatocellular Carcinoma Patients Treated with Sorafenib: A Meta-Analysis. Med Sci Monit. 2015 Oct 18; 21: 3144-3151
- 18. Peña, A., Lathia, C., Shan, M., Escudier, B., and Bukowski, R. M. (2010) Biomarkers Predicting Outcome in Patients with Advanced Renal Cell Carcinoma: Results from Sorafenib Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial. Clinical Cancer Research; 16(19):4853-63