**5. Conclusions**

*Oral Diseases*

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 expression* levels 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

Interestingly, some studies have focused on the potential prognostic importance

of *VEGF* polymorphisms in head and neck cancers [14, 20, 21]. Results showed the association between −1154GG *VEGF* genotype, 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 *VEGF* polymorphism 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 *VEGF* gene, in the −1154G/A polymorphism of the *VEGF* [27]. Moreover, the polymorphism −1154G/A *VEGF* has been shown to be associated with differential expression of

compared to when there were a stage 3 and 4 tumors [63].

VEGF *in vitro*. However, some of the data are contradictory.

**therapeutic strategies for oral squamous cell carcinoma**

ribozymes, VEGF toxin conjugates, and soluble VEGF receptors.

**4.4 Vascular endothelial growth factor and advances in developing novel** 

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 [13, 14]. 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 cyclophosphamideinduced 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

**4.3 The role of VEGF in prognosis**

**126**

Angiogenesis is *essential* for the growth and metastasis of solid *tumors*, including oral squamous cell *carcinoma*. The main factor responsible for angiogenesis is *VEGF* and its receptors. Specifically, *VEGF*-A is known to be a *key* angiogenic 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.
