Open access peer-reviewed chapter

Vascular Endothelial Growth Factor Expression in the Pathological Angiogenesis in Oral Squamous Cell Carcinoma

Written By

Biagio Rapone and Elisabetta Ferrara

Submitted: October 13th, 2019 Reviewed: December 20th, 2019 Published: January 16th, 2020

DOI: 10.5772/intechopen.90924

From the Edited Volume

Oral Diseases

Edited by Gokul Sridharan, Anil Sukumaran and Alaa Eddin Omar Al Ostwani

Chapter metrics overview

831 Chapter Downloads

View Full Metrics


Tumor angiogenesis and tumor progression to late oral squamous cell carcinoma are closely related. Vascular endothelial growth factor (VEGF), a heparin-binding growth factor with mitogenic activity specific for vascular endothelial cells, regulates key events of the pathological angiogenesis involved in the metabolic functions of malignant tissues. The level of high-affinity tyrosine kinase receptor for VEGF, flt, in tumor endothelial cells in vivo is seen upregulated, supporting the role of VEGF as a potential signaling tumor angiogenesis axis in vivo and sustaining the notion that paracrine mechanisms are responsible for the regulation of tumor angiogenesis. The expression of VEGFs is increased in the processes of oral squamous cell carcinoma (OSCC) progression and proliferation. Vascular endothelial growth factor C (VEGF-C)/VEGF3 expression induced by chemokine CCL4 is connected to lymph node metastasis in OSCC. This chapter was aimed to summarize and analyze the findings on the role of vascular endothelial growth factor in oral squamous cell carcinoma and briefly discuss the potential of vascular endothelial growth factor that targets this pathway as treatment for OSCC.


  • angiogenesis
  • vascular endothelial growth factor
  • oral cancer
  • overexpression
  • VEGF polymorphism

1. Introduction

The angiogenesis process involves approximately twenty factors, such as basic fibroblast growth factor, placenta growth factor (PIGF-1), epidermal growth factor (EP), as platelet-derived GF (PDGF), and the most important angiogenic factor: vascular endothelial growth factor (VEGF). Studies of restricted expression patterns and functional roles have implicated VEGFs in the generation of new blood vessels from pre-existing vasculature complex genetic pathways. VEGF has since been documented as being a potent stimulator of endothelial cells proliferation and migration and to induce the expression of interstitial collagenases. Specifically, VEGFs regulate physiological angiogenesis, including the vessel and the organ development, the lymphogenesis, and the differentiation during embryogenesis, as well the pathogenesis of a multiplicity of disorders. The hypothesis that VEGF action is required for tumor angiogenesis has been first provided by the findings of the vascular development of tumor xenografts in mice. These results were confirmed through in situ hybridization studies, showing a correlation between the degree of defective angiogenesis and VEGF mRNA upregulation. These studies uniformly concur that VEGF expression enhances tumor growth. In this chapter, we provide a brief historical overview of the discovery of VEGF, structural characterization of the other members of VEGF family and their receptor, and to summarize the main features of the role of vascular endothelial growth factor in angiogenesis of oral cancer development.


2. Discovery of VEGF

VEGF was first described in 1983 as a factor secreted by hepatocarcinoma cell lines [1] that increased microvascular permeability to plasma proteins in the skin of guinea-pigs. It was highly purified to homogeneity from pituitary folliculostellate cells and characterized in 1989 [2]. Other authors supported evidence that this protein potently stimulated endothelial cell migration [3, 4, 5]. It was named “vascular permeability factor” or VPF, potent inducers of vascular hyperpermeability (especially venular endothelium) to fibrinogen and other plasma proteins [6], which upon secretion by tumor cells, promotes vascular leakage [7]. More years later, it was demonstrated that VPF has potent mitogenic activity in a diversity of cell types, and also versus endothelial cells [8]. Vascular endothelial growth factors (VEGFs) are predominantly produced by endothelial, hematopoietic, and stromal cells in response to hypoxia and upon stimulation by growth factors such as transforming growth factor β (TGFβ), interleukins, or platelet-derived growth factors (PDGFs). VEGFs specifically interact with one or several receptor tyrosine kinases (RTKs), VEGF receptor −1, −2, and −3 (VEGFR-1, −2, −3), and with distinct coreceptors such as neuropilins or heparan sulfate glycosaminoglycans. VEGF receptors are classified as type V RTKs whose extracellular domains consist of seven immunoglobulin-like (Ig-like) domains [9, 10]. The intracellular domain consists of seven immunoglobulin-like domains (I–VII), a single transmembrane (TM) region, and a tyrosine kinase consensus sequence (TK) interrupted by a cytoplasmatic kinase domain [11, 12].


3. The VEGF gene and isoforms

The VEGFs term identifies a large and heterogeneous family of secreted polypeptides, named VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and placenta growth factor (PGF), characterized by a highly conserved receptor-binding cystine-knot structure similar to that of the platelet-derived growth factors [1314]. Of those six members, VEGF-A plays a key role in vasculogenesis and angiogenesis [15]. PGF is mainly expressed in placenta, heart and lungs; it is a ligand for VEGFR-2 and it is involved in angiogenesis regulation. VEGF-B binds VEGFR-1 and neuropilin-1, mostly expressed in the extracellular matrix and abundantly expressed in brown fat, in the myocardium and skeletal muscle; it is implicated in high cellular energy metabolism. VEGF-C is produced as a precursor protein [16, 17]. VEGF-C promotes mitogenesis, migration and survival of ECs [18], and regulates the lymphatic vessel growth by binding to VEGF-receptor-3 (VEGFR-3, Flt-4) [19, 20]. VEGF-D, binds and activates VEGFR-2 and VEGFR-3, because is mitogenic for EC, angiogenic, and lymphangiogenic. Its expression was demonstrated mainly in the lung and skin during embryogenesis. VEGF-E expression, binding the VEGFR-2, promotes the release of tissue factors, proliferation, chemotaxis and sprouting of cultured vascular ECs in vitro and angiogenesis in vivo [6, 21]. The major function of VEGF-C consist in regulation VEGF exerts its effect on tissues at several levels; mechanisms range from a plethora of physiological processes which regulate blood vessel growth, such as during pregnancy and in tissue repair to pathological conditions, including chronic inflammation, would healing process, and cancer [6, 22]. It has been proven that VEGF causes a pronounced angiogenic response in a variety of in vivo models, including the chick chorioallantoic membrane [23, 24]. Native VEGF is a basic, heparin-binding, homodimeric glycoprotein of 45,000 daltons. Interestingly, the VEGF gene has been mapped to chromosome 6 at position p21.3 [25] and consists of eight exons and seven introns in the coding sequence, which covers a region of 14 kilobases. Among these, there is evidence that the −634G/C, −1154G/A, and −2578C/A VEGFpolymorphisms have been shown to be associated with increased VEGF production. Alternative splicing of the mRNA from the gene of VEGF, VEGF-B, and PIGF results in the expression of five known human isoforms with differential diffusibility and heparin-binding properties containing 121, 145, 165, 183, 189 and 206 amino acids with different biological properties: VEGF121, VEGF165, VEGF189, and VEGF206 [26]. The VEGF121 is a weakly acidic polypeptide with a 44 amino-acid insertionencoded by exon 7a, that fails to bind to heparin [27]; VEGF189 hasa further insertionof 24 amino acids, highly enriched in basic residuesencoded by exon 6a. VEGF121 and VEGF165 have been detected predominantly in normal tissue, but VEGF121 isoform is both more angiogenic and tumorigenic than being the 165 and 189 isoforms [27, 28]. In particular, the isoform 121 has been shown to predominate in primary human breast carcinomas (Relf M) VEGF189 expression has been shown to be dominant in normal lung [29] and the 183 isoform predominates in heart [30, 31]. Several studies have reported that the expression of VEGF206 occurs mainly in fetal liver.

3.1 Biological effects of VEGF expression

The VEGF and the “fibroblastic growth factor” (bFGF) demonstrate a powerful synergism in the promotion of angiogenesis in vitro, as shown by models using microvascular endothelial cells invading the three-dimensional collagengel system [32, 33]. Also, VEGF exerts its effect by coordinating of angiopoietins, another class of angiogenic factors. Specifically, VEGF is involved in the early sequences of events leading to the vessel development, whereas angiopoietin 1 (Ang1), an agonist ligand for the endothelial-specific Tie2 receptor, binds and activates Tie2 to promote vessel maturation, vascular stability and leakiness [34]; Ang2 acts as a Tie2 agonist in lymphatic endothelial cells generating an important vascular signaling pathway involved in angiogenesis, vascular stability and quiescence. VEGF achieves its functions of endothelial cell differentiation and proliferation by binding a family of tyrosine kinases receptors (VEGFRs), known as Flt-1 receptor (VEGF receptor-1) and VEGF receptor-2 (VEGF-2 or KDR/Flk-1). VEGFR-1 binds VEGF, VEGF-B and PlGF with high affinity and induces weak mitogenic signals in ECs. [23, 35] VEGFR-1 expression is up-regulated by hypoxia via (transcription hypoxia inducible factor) HIF-dependent mechanism [36, 37]. In the lung, VEGFR-1 provokes secretion of Matrix Metalloproteinase 9 (MMP9) at the vascular bed, thus empowering metastasis. Also, it has been discovered the role of VEGFR-1 in releasing tissue specific factors in a perivascular specific pattern at the level of vascular endothelium [38]. VEGFR-2, the major mediator of endothelial cell mitogenesis, proliferation and survival [39, 40] binds VEGF, VEGF-C, VEGF-D, VEGF-E and PlGF [22, 39]. VEGFR-2 expression is down-regulated in the adult blood vascular ECs, and is again up-regulated in the endothelium of angiogenic process. VEGF, VEGF-C and VEGF-D are bound VEGFR-3 and are involved in regulation of lymphangiogenesis, the growth of new lymphatic vessels [41, 42, 43, 44, 45]. The expression of VEGFR-3 (or Flt-4) is relevant in lymphatic vessels [44] and in hematopoietic cells of monocytic lineage [6, 42], and is also expressed in a subset of capillary endothelia [19]. Studies on animal models showed that VEGF-C/VEGFR-3 axis plays a crucial role in cancer metastasis by inducing lymphangiogenesis [46, 47, 48], but further investigations would be necessary. Furthermore, it has been documented the link between mutations in VEGFR-3 with hereditary lymphedema, an autosomal dominant disorder of the lymphatic system that can lead to lymphangiosarcomas [13, 49]. Neuropilins-1 and -2 are more important in immunology and neuronal development, but they are also involved in angiogenesis [19, 44]. Neuropilins, bind especially class 3 semaphorins but the Neuropilin-1 also binds VEGF, VEGF-B and PlGF, while Neuropilin-2 binds VEGF, VEGF-C and PlGF [50]. When is coexpressed in cells together with VEGFR-2, Neuropilin-1 enhances the binding of VEGF165 to VEGFR-2 and augments tumor angiogenesis in vivo [51, 52]. Nrp-2 is expressed also on lymphatic ECs, and mutated Nrp-2 forms induce abnormalities in the formation of small lymphatic vessels and lymphatic capillaries in mice [53]. In addition, some isoforms bind to known as non-tyrosine kinase receptors, known as neuropilins (NRPs) (neuropilin-1 and neuropilin-2 (22–44)). Neuropilins-1 and -2 are also involved in immunology and neuronal development [50, 54]. Neuropilins bind, especially class 3 semaphorins but the Neuropilin-1 also binds VEGF, VEGF-B and PlGF, while Neuropilin-2 binds VEGF, VEGF-C and PlGF [50]. Neuropilin-1 is capable to improve the binding of VEGF165 to VEGFR-2 and increase tumor angiogenesis in vivo [51, 53]. Nrp-2 is expressed also on lymphatic ECs, and it has been shown in vivo that mutated Nrp-2 form alters the formation of small lymphatic vessels and lymphatic capillaries in mice [54]. The binding results in stimulation of cell-signaling pathways that act to increase cell nucleus division, and contributing to angiogenesis through extracellular matrix dissolution, and endothelial cell movement.


4. Role of VEGF in oral squamous cell carcinoma

4.1 The role of VEGF in invasion

Angiogenesis, the formation of new blood vessels, is not only a normal physiological process, but it is closely linked to both tumor growth and metastasis, providing the principal pathway through tumor cells exit the primary tumor site and enter the circulation. A multiplicity of molecular determinants is involved in these different mechanisms of vascular growth, and VEGFs play a significant role in pathological angiogenesis. In particular, the role of VEGF-A in tumor angiogenesis are clarified by several studies [23, 55], but the results concerning VEGF-expression in normal and dysplastic oral epithelium, as well as about the potential role of VEGF in oral squamous cell carcinoma progression shown contradictions. VEGF-A overexpression has been reported in most types of cancer, including oral squamous cell carcinoma, and it is thought to be a prognostic factor for survival. Some studies revealed no altered VEGF expression in the normal and mildly dysplastic oral epithelium, or the expression was significantly lower than neoplastic epithelium [16, 17, 18]. A considerable upregulation of VEGF expression during the transition from normal oral epithelium through dysplasia to OSCC, but no correlation was found between VEGF expression and the grade of dysplasia. Many researchers demonstrated an upregulation of VEGF expression in cancerous tissues in comparison to the normal oral mucosa. These results suggest that VEGF could be implicated in tumor progression by expanding the vascularity during the process of transition from the normal oral mucosa to invasive carcinoma [18, 51, 52, 53, 54, 55, 56]. Immunohistochemical study of VEGF expression in oral squamous cell carcinomas clarify the relationship between vascular endothelial growth factor (VEGF) expression and clinicopathological factors in oral squamous cell carcinoma (OSCC), showing that serum VEGF levels were significantly higher in oral cancer patients as compared to normal controls that further showed an increasing trend with clinical stage and lymph node involvement, suggesting that VEGF level may be a reliable biomarker and may be a potential target for development of chemotherapeutic strategies for patients with oral carcinoma.

4.2 The role of VEGF in metastasis

Lymphangiogenesis plays a vital role in tumor growth and systemic dissemination of different carcinomas [2]. Although vascular endothelial growth factor C (VEGF-C) is well known to be associated with lymph node metastasis in patients with OSCC, inducing the production of urokinase by cancer and playing a crucial role in the extracellular matrix remodeling and tumor cell invasion, the specific mechanisms of lymphangiogenesis in OSCC are largely unknown. Further, it has been implicated in inducing the growth of both blood and lymphatic vessels and in regulation of proliferation, differentiation and migration of lymphatic endothelial cells in many physiological and pathological conditions [19, 20]. Overexpression of VEGF-C has been detected in various malignancies and is frequently associated with lymphatic invasion, nodal and distant metastasis and consequently poor survival [23, 33]. VEGF-C signaling is involved in the progression of several malignancies that put forward VEGF-C as a potential target for the development of new anticancer therapies to prevent local invasion and metastatic spread of disease. The progression of several malignancies involves VEGF-C signaling. The immunohistochemical analysis and real-time quantitative RT-PCR studies showed a significant correlation between the levels of VEGF-C mRNA expression in a human OSCC cell line, through the phosphoinositide 3-kinase-Akt pathway. The angiogenic action of this growth factor is achievable by binding to two receptor tyrosine kinases (RTK), VEGFR-1 (Flt-1) and VEGFR-2 (KDR, Flk-1) [17, 22]. VEGFR-2 is the major mediator of the mitogenic, angiogenic and permeability-enhancing effects of VEGF-A, while the role of VEGFR-1 in the regulation of angiogenesis is controversial. It is implicated in a paracrine release of growth factors, but the central role of this receptor is to prevent the interaction of VEGF with VEGFR-2. Also, it may promote angiogenesis by recruitment in tumor vasculature of monocytes and other bone marrow-derived cells [48, 52, 57]. Moreover, VEGFR-1 is involved in the induction of matrix metalloproteinases [49] that retrovirus-mediated expression of a dominant negative VEGFR-2, because of inhibition of signal transduction through wild-type VEGFR-2, suppression of the growth of glioblastoma multiforme and other tumor cell lines in vivo. Correlation of VEGF expression with clinical stage of OSCC is controversial. Clinicopathologic findings suggest that evaluation of VEGF expression is of prognostic value in patients with OSCC. VEGF expression was found to increase significantly with advancing stage of the tumor. Elevated expression of VEGF was associated with aggressive phenotype and advanced stage of the tumor [58], as well as demonstrated by Yu Hong Li et al. which found a higher VEGF expression in stage 3 and 4 tumors as compared to stage 1 and 2 [59]. An explanation could be attributed to the correlation with the intensity of VEGF expression and the degree of differentiation or invasiveness of carcinoma. The results support the findings of previous resultson the average density of immunohistochemistry (IHC), indicating that in normal oral squamous cells, VEGF expression was detected only in the vascular endothelial cells in the mesenchymal tissues [60, 61]. According to these results, to Kim’s study on the up-regulation of vascular endothelial growth factor (VEGF) expression in oral squamous cell carcinoma, immunohistochemical staining with VEGF, found a very little expression of VEGF in normal oral squamous cell tissues and a significant positive relationship between VEGF expression and the degree of differentiation or invasiveness of carcinoma [62]. In addition, histopathological findings showed that the VEGF had higher expressionlevels in less-differentiated invasive oral squamous cell carcinoma, while it was expressed at slightly higher levels in well-differentiated and less-invasive intraepithelial carcinoma tissues or highly differentiated oral squamous cell carcinoma than in normal cells [62]. In contrast, Shang and Li found that VEGF expression was significantly higher in patients in patients with stage 1 and 2 tumors as compared to when there were a stage 3 and 4 tumors [63].

4.3 The role of VEGF in prognosis

Interestingly, some studies have focused on the potential prognostic importance of VEGFpolymorphisms in head and neck cancers [14, 20, 21]. Results showed the association between −1154GG VEGFgenotype, located in the promoter region of the gene, and higher VEGF production [12]. A study conducted by Ku et al., reported an association of −460C/T polymorphism and VEGF overexpression in oral cancer, showing a higher risk for oral cancer in the patients with a high −460TC ratio [66, 67]. Further investigations showed an association between +960C/T VEGFpolymorphism and oral cancer [23], indicating that the low production of VEGF by the T allele is correlated with increased risk of oral cancer, and vascular invasion in oral squamous cell carcinoma. In contrast, Vairaktaris et al. [56], did not demonstrate an influence of gene polymorphism on the oral cancer in the logistic regression models. However, the genotype VEGF−460CT was associated with early stage tumors. Nasr et al. analyzed the polymorphism VEGF−2578C/A and suggested that carriers of VEGF−2578C allele may play a role in susceptibility to nasopharyngeal carcinoma [64, 65]. The risk for laryngeal squamous cell carcinoma seems to be linked with the increase of the −1154G/G genotype of the VEGFgene, in the −1154G/A polymorphism of the VEGF[27]. Moreover, the polymorphism −1154G/A VEGFhas been shown to be associated with differential expression of VEGF in vitro. However, some of the data are contradictory.

4.4 Vascular endothelial growth factor and advances in developing novel therapeutic strategies for oral squamous cell carcinoma

There is a great need for therapies to prevent and/or slow the progression of OSCC. Recent studies focused on potential of drugs that target VEGF or its receptors-signaling system because their angiogenesis-promoting activity at the level of endothelial cells. Therefore, modulation of these factors to inhibit tumor angiogenesis, currently, is a major focus in developing OSCC therapies. The development of angiogenesis inhibitors as anticancer agents have been developed with data showing promising efficacy at reducing OSCC in in vitro models [1314]. Recent studies found that administration of angiogenesis inhibitors agents in association with chemotherapy and radiotherapy can improve the efficacy of these treatments. For example, Teicher et al. observed that coadministration of the TNR-470, angiogenesis inhibitor agent, induces a substantial cyclophosphamide-induced tumor cell-killing. Jain’s study confirmed these findings suggesting that it was a consequent normalization of the tumor vasculature, as a result of endothelial cell death. Different therapeutic strategies to induce the inhibition of VEGF or its receptor signaling system are being emerging for treatment of OSCC, as VEGFR-1 ribozymes, VEGF toxin conjugates, and soluble VEGF receptors.


5. Conclusions

Angiogenesis is essentialfor the growth and metastasis of solid tumors, including oral squamous cell carcinoma. The main factor responsible for angiogenesis is VEGFand its receptors. Specifically, VEGF-A is known to be a keyangiogenic factor, and its overexpression has been reported in most types of cancer, including oral squamous cell carcinoma, and it is thought to be a prognostic factor for survival. It was pointed out that VEGF as an attractive candidate for therapeutic intervention, but more studies are needed to clarify the real potential of angiogenesis inhibitors agents in OSCC, to determine optimal timing for VEGF, and to search for drug candidates.


Conflict of interest

The authors declare no conflict of interest.


  1. 1. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219(4587):983-985
  2. 2. Hamilton WJ, Boyd JD, Mossman HW. Human Embryology. Baltimore: William & Wilkins; 1962
  3. 3. Gilbert SF. Developmental Biology. Sunderland, MA: Sinauer; 1988
  4. 4. Folkman J, Klagsbrun M. Angiogenic factors. Science. 1987;235:442-447
  5. 5. Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochemical and Biophysical Research Communications. 1989;161(2):851-858
  6. 6. Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell. 1996;87:1161-1169
  7. 7. Thurston G, Daly C. The complex role of angiopoietin-2 in the angiopoietin-tie signaling pathway. Cold Spring Harbor Perspectives in Medicine. 2012;2:a006550
  8. 8. Favard C, Moukadiri H, Dorey C, Praloran V, Plouët J. Purification and biological properties of vasculotropin, a new angiogenic cytokine. Biology of the Cell. 1991;73(1):1-6
  9. 9. Criscuolo GR, Merrill MJ, Oldfield EH. Further characterization of malignant glioma-derived vascular permeability factor. Journal of Neurosurgery. 1988;69(2):254-262
  10. 10. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989;246(4935):1309-1312
  11. 11. Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. Journal of Cell Science. 2001;114(Pt 5):853-865
  12. 12. Bates DO, Cui TG, Doughty JM, Winkler M, Sugiono M, Shields JD, et al. VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma. Cancer Research. 2002;62:4123-4131. The discovery of a novel inhibitory VEGF-A165 variant resulting from analternative exon 8
  13. 13. Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. Journal of Cell Science. 2001;114:853-865. A review of the splice variants of VEGF-A and their functions
  14. 14. Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G. Neuropilin-2 and neuropilin-1 are receptors for the 165-amino acid form of vascular endothelial growth factor (VEGF) and of placenta growth factor-2, but only neuropilin-2 functions as a receptor for the 145-amino acid form of VEGF. The Journal of Biological Chemistry. 2000;275:18040-18045. This study shows that the VEGF-A145 isoform selectively recognizes NRP2. DOI: 10.1074/jbc.M909259199
  15. 15. Ferrara N, Gerber HP, Lecouter J. The biology of VEGF and its receptors. Nature Medicine. 2003;9(6):669-676
  16. 16. Fong GH, Zhang L, Bryce DM, Peng J. Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development. 1999;126(13):3015-3025
  17. 17. Leung DW, Cachianes G, Kuang W-J, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306-1309
  18. 18. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, et al. Vascular permeability factor, an endothelial cell mitogen related to platelet derived growth factor. Science. 1989;246:1309-1312
  19. 19. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarwicz D, Fiddes JC, et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. The Journal of Biological Chemistry. 1991;266:11947-11954
  20. 20. Turley H, Scott PAE, Watts VM, Bicknell B, Harris AL, Gatter KG. Expression of VEGF in routinely fixed material using a new monoclonal antibody VG1. The Journal of Pathology. 1998;186:313-318
  21. 21. Zhang H, Craft P, Scott PAE, Ziche M, Weich HA, Harris AL, et al. Enhancement of tumor growth and vascular density by transfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells. Journal of the National Cancer Institute. 1995;87:213-219
  22. 22. Park JE, Keller GA, Ferrara N. The vascular endothelial growth factor (VEGF) isoforms: Differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Molecular Biology of the Cell. 1993;4:1317-1326
  23. 23. Meyer M, Clauss M, Lepple-Wienhues A, Waltenberger J, Augustin HG, Ziche M, et al. A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. The EMBO Journal. 1999;18(2):363-374
  24. 24. Gille H, Kowalky J, LI B, Lecouter J, Moffat B, Zioncheck TF, et al. Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. The Journal of Biological Chemistry. 2001;276(5):3222-3230
  25. 25. Wise LM, Veikkola T, Mercer AA, Savory LJ, Fleming SB, Caesar C, et al. Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1. Proceedings of the National Academy of Sciences of the United States of America. 1999;96(6):3071-3076
  26. 26. Partanet TA, Alitalo K, Miettinen M. Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors. Cancer. 1999;86(11):2406-2412
  27. 27. Cross MJ, Claesson-Welsh L. FGF and VEGF function in angiogenesis: Signalling pathways, biological responses and therapeutic inhibition. Trends in Pharmacological Sciences. 2001;22(4):201-207
  28. 28. Matsumoto T, Claesson-Welsh L. VEGF receptor signal transduction. Science's STKE. 2001;2001(112):re21
  29. 29. Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell. 2002;1(3):219-227
  30. 30. Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proceedings of the National Academy of Sciences of the United States of America. USA. 1996;93:14765-14770
  31. 31. Carmeliet P, Ng Y-S, Nuyens D, Theilmeier G, Brusselmans K, Cornelissen I, et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nature Medicine. 1999;5:495-502
  32. 32. Cheung N, Wong MP, Yuen ST, Leung SY, Chung LP. Tissue-specific expression pattern of vascular endothelial growth factor isoforms in the malignant transformation of lung and colon. Human Pathology. 1998;29:911-914
  33. 33. Coltrini D, Gualandris A, Nelli EE. Growth advantage and vascularisation induced by basic fibrolblast growth factor overexpression in endometrial HEC-1-B cells: An export -dependent mechanism of action. Cancer Research. 1995;55:4729-4738
  34. 34. Gitay-Goren H, Cohen T, Tessler S, Soker S, Gengrinovitch S, Rockwell P, et al. Selective binding of VEGF121 to one of the three vascular endothelial growth factor receptors of vascular endothelial cells. The Journal of Biological Chemistry. 1996;271:5519-5523
  35. 35. Relf M, LeJeune S, Scott PAE, Fox S, Smith K, Leek R, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, transforming growth factor β-1, platelet-derived endothelial cell growth factor, placenta growth factor and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Research. 1997;57:963-969
  36. 36. Plate K. From angiogenesis to lymphangiogenesis. Nature Medicine. 2001;7(2):151-152
  37. 37. Shibuya M, Claesson-Welsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Experimental Cell Research. 2006;312(5):549-560
  38. 38. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nature Medicine. 2001;7(2):192-198
  39. 39. Taipale J, Makinen T, Arighi E, Kukk E, Karkkainen M, Alitalo K. Vascular endothelial growth factor receptor-3. Current Topics in Microbiology and Immunology. 1999;237:85-96
  40. 40. Partanen TA, Arola J, Saaristo A, Jussila L, Ora A, Miettinen M, et al. VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR-3, in fenestrated blood vessels in human tissues. The FASEB Journal. 2000;14(13):2087-2096
  41. 41. Klagsbrun M, Folkman J. Angiogenesis. In: Sporn MB, Roberts AB, editors. Peptide Growth Factors and their Receptors. New York: Springer-Verlag; 1991. pp. 549-586
  42. 42. Soker S, Takashima S, Miao HQ , Neufeld G, Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell. 1998;92(6):735-745
  43. 43. Yuan L, Moyon D, Pardanaud L, Bréant C, Karkkainen MJ, Alitalo K, et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development. 2002;129(20):4797-4806
  44. 44. Safran M, Kaelin WG. HIF hydroxylation and the mammalian oxygen-sensing pathway. The Journal of Clinical Investigation. 2003;111(6):779-783
  45. 45. Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, et al. Mutant ras oncogenes upregulate VEGF/VPF expression: Implications for induction and inhibition of tumor angiogenesis. Cancer Research. 1995;55(20):4575-4580
  46. 46. Coultas L, Chawengsaksophak K, Rossant J. Endothelial cells and VEGF in vascular development. Nature. 2005;438(7070):937-945
  47. 47. Chen JC, Chang YW, Hong CC, Yu YH, Su JL. The role of the VEGF-C/VEGFRs axis in tumor progression and therapy. International Journal of Molecular Sciences. 2013;14(1):88-107
  48. 48. Abdul-Aziz MA, Amin AK, El-Rouby DH, Shaker OG. Lymphangiogenesis in oral squamous cell carcinoma: Correlation with VEGF-C expression and lymph node metastasis. International Journal of Dentistry. 2017:10. Article ID: 7285656
  49. 49. Bryne M. Is the invasive front of an oral carcinoma the most important area for prognostication? Oral Diseases. 1998;4(2):70-77
  50. 50. Abdo MM, Gaballah ET, Fikry HE, Mosbah MM. Expression of VEGF-C in oral precancerous lesions and oral squamous cell carcinoma. Mansoura Journal of Dentistry. 2014;1(3):105-108
  51. 51. Wang Z, Chen Y, Li X, Li X, Ma W, et al. Expression of VEGF-C/VEGFR-3 in human laryngeal squamous cell carcinomas and its significance for lymphatic metastasis. Asian Pacific Journal of Cancer Prevention. 2012;13(1):27-31
  52. 52. Khaleel ME, Raza A, Ehsan A, Masood R, Javed M. Clinicopathological spectrum of oral squamous cell carcinoma at a public sector health facility. Biomédica. 2015;31(1):21-26
  53. 53. Krishna A, Singh RK, Singh S, Verma P, Pal US, et al. Demographic risk factors, affected anatomical sites and Clinicopathological profile for oral squamous cell carcinoma in a north Indian population. Asian Pacific Journal of Cancer Prevention. 2014;15(16):6755-6760
  54. 54. Benke EM, Ji Y, Patel V, Wang H, Miyazaki H, et al. VEGF-C contributes to head and neck squamous cell carcinoma growth and motility. Oral Oncology. 2010;46(4):e19-e24
  55. 55. Ding MX, Lin XQ , Fu XY, Zhang N, Li JC. Expression of vascular endothelial growth factor-C and angiogenesis in esophageal squamous cell carcinoma. World Journal of Gastroenterology. 2006;12(28):4582-4585
  56. 56. Vairaktaris E, Serefoglou Z, Avgoustidis D, Yapijakis C, Critselis E, Vylliotis A, et al. Gene polymorphisms related to angiogenesis, inflammation and thrombosis that influence risk for oral cancer. Oral Oncology. 2009;45:247-253
  57. 57. Cheng CY, Chang CS, Liu CJ, Kao SY. Vascular endothelial growth factor 936 C/T polymorphism is associated with vascular invasion in oral squamous cell carcinoma. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 2008;106:79-84
  58. 58. Faratzis G, Tsiambas E, Rapdis AD, et al. VEGF and KI 67 expression in squamous cell carcinoma of tongue–An immunohistochemical and computerized image analysis study. Oral Oncology. 2009;45(7):584-588
  59. 59. Li YH, Hu CF, Shao Q , et al. Elevated expression of survival and VEGF protein are strong independent predictors of survival in advanced nasopharyngeal carcinoma. Journal of Translational Medicine. 2008;6:1
  60. 60. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocrine Reviews. 1997;18:4-25
  61. 61. Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. The Oncologist. 2004;9(Suppl 1):2-10
  62. 62. Kim SK, Park SG, Kim KW. Expression of vascular endothelial growth factor in oral squamous cell carcinoma. Journal of the Korean Association of Oral and Maxillofacial Surgeons. 2015;41(1):11-18. DOI: 10.5125/jkaoms.2015.41.1.11
  63. 63. Shang ZJ, Li JR. Expression of endothelial nitric oxide synthase and vascular endothelial growth factor in oral squamous cell carcinoma its correlation with angiogenesis and disease progression. Journal of Oral Pathology & Medicine. 2005;34(3):134-139
  64. 64. Nasr HB, Chahed K, Bouaouina N, Chouchane L. Functional vascular endothelial growth factor −2578 C/A polymorphism in relation to nasopharyngeal carcinoma risk and tumor progression. Clinica Chimica Acta. 2008;395:124-129
  65. 65. Unal ZN, Unal M, Bagdatoglu OT, Polat G, Atik U. Genetic polymorphism of VEGF-1154 (A/G) in laryngeal squamous cell carcinoma. Archives of Medical Research. 2008;39:209-211
  66. 66. Ku KT, Wan L, Peng HC, Tsai MH, Tsai CH, Tsai FJ. Vascular endothelial growth factor gene-460 C/T polymorphism. Acta Haematol. 2010;123:91-95
  67. 67. Shintani S, Li C, Ishikawa T, et al. Expression of vascular endothelial growth factor A, B, C and D in oral squamous cell carcinoma. Oral Oncology. 2004;40(1):13-20

Written By

Biagio Rapone and Elisabetta Ferrara

Submitted: October 13th, 2019 Reviewed: December 20th, 2019 Published: January 16th, 2020