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      Expression of vascular endothelial growth factor and microvessel density in oral tumorigenesis

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          Abstract

          Context:

          Significant increase in vascularity occurs during the transition from normal oral mucosa, through differing degrees of dysplasia, to invasive squamous cell carcinoma (SCC).

          Aims:

          To evaluate microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression in oral tumorigenesis and correlate it with the clinicopathological characteristics.

          Settings and Design:

          VEGF expression and MVD were quantified immunohistochemically using anti-VEGF and anti-CD34 antibody.

          Materials and Methods:

          For this study we used a total of 60 archival specimens, including 10 normal oral mucosa (NOM), 7 mild epithelial dysplasia (Mild ED), 8 moderate epithelial dysplasia (Mod ED), 5 severe epithelial dysplasia (SED), 14 well-differentiated SCC, 11 moderately-differentiated SCC, and 5 poorly-differentiated SCC. VEGF expression was assessed in relation to the localization, intensity, and area of the immunohistochemically stained cells. MVD was evaluated using the Image-Pro ® Plus software.

          Statistical Analysis:

          One-way ANOVA (F test) was carried out for comparing the parameters for multiple groups such as different histopathological grades of dysplasia and carcinoma. Comparison between groups was carried out using the Student's ‘ t’ test. Correlations between VEGF score and MVD were estimated using the Karl Pearson coefficient of correlation.

          Results:

          VEGF and MVD appeared to increase with disease progression and were statistically higher in oral SCC than in epithelial dysplasia and normal buccal mucosa. There was significant correlation between VEGF expression and MVD.

          Conclusions:

          These findings indicate that VEGF expression is upregulated during head and neck tumorigenesis.

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          Most cited references25

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          Mechanism and its regulation of tumor-induced angiogenesis.

          Tumor angiogenesis is the proliferation of a network of blood vessels that penetrates into cancerous growths, supplying nutrients and oxygen and removing waste products. The process of angiogenesis plays an important role in many physiological and pathological conditions. Solid tumors depend on angiogenesis for growth and metastasis in a hostile environment. In the prevascular phase, the tumor is rarely larger than 2 to 3 mm(3) and may contain a million or more cells. Up to this size, tumor cells can obtain the necessary oxygen and nutrient supplies required for growth and survival by simple passive diffusion. The properties of tumors to release and induce several angiogenic and anti-angiogenic factors which play crucial roles in regulating endothelial cell (EC) proliferation, migration, apoptosis or survival, cell-cell and cell-matrix adhesion through different intracellular signaling are thought to be the essential mechanisms during tumor-induced angiogenesis. Tumor angiogenesis actually starts with tumor cells releasing molecules that send signals to surrounding normal host tissue. This signaling activates certain genes in the host tissue that, in turn, make proteins to encourage growth of new blood vessels. In this review, we focus the mechanisms of tumor-induced angiogenesis, with an emphasis on the regulatory role of several angiogenic and anti-angiogenic agents during the angiogenic process in tumors. Advances in understanding the mechanisms of tumor angiogenesis have led to the development of several most effective anti-angiogenic and anti-metastatic therapeutic agents and also have provided several techniques for the regulation of cancer's angiogenic switch. The suggestion is made that standard cytotoxic chemotherapy and angiogenesis inhibitors used in combination may produce complementary therapeutic benefits in the treatment of cancer.
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            Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis.

            The growth of solid tumors in vivo beyond 1-2 mm in diameter requires induction and maintenance of an angiogenic response. This can occur through the release of various angiogenic growth factors from tumor cells. One such factor is vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), a secreted and specific mitogen for vascular endothelial cells. We show that one of the most commonly encountered genetic changes detected in human cancer, i.e., expression of mutant ras oncogenes, is associated with marked up-regulation of VEGF/VPF in transformed epithelial cells. Thus, elevation of the levels of both VEGF/VPF mRNA and secreted functional protein were detected in human and rodent tumor cell lines expressing mutant K-ras or H-ras oncogenes, respectively. Genetic disruption of the mutant K-ras allele in human colon carcinoma cells was associated with a reduction in VEGF/VPF activity. Furthermore, pharmacological disruption of mutant RAS protein function in H-ras transformed rat intestinal epithelial cells by treatment with L-739,749 (a protein farnesyltransferase inhibitor) caused a significant suppression of VEGF/VPF. The results suggest that dominantly acting ras oncogenes may contribute to the growth of solid tumors in vivo not only by a direct effect on tumor cell proliferation but also indirectly, i.e., by facilitating tumor angiogenesis. Hence, pharmacologically targeting mutant ras oncogenes could conceivably suppress solid tumor growth in vivo, in part, by inhibiting tumor-induced angiogenesis.
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              Increase of mast cells and tumor angiogenesis in oral squamous cell carcinoma.

              Although mast cells (MCs) have been implicated in promoting angiogenesis in some malignant tumors, especially of the aerodigestive tract, little is known in oral squamous cell carcinoma (SCC). A retrospective study was conducted to elaborate upon the correlation between MCs and tumor angiogenesis in 26 cases of oral SCC, six cases of oral pre-malignant dysplasia, 10 cases of oral hyperkeratosis, and six cases of normal oral mucosa by means of immunohistochemical technique. The MCs in all lesions and normal oral mucosa strongly expressed tryptase. The densities of MCs and microvessels appeared to increase with disease progression. The MC and microvascular counts were significantly higher in oral SCC than in hyperkeratosis and normal oral mucosa (P < 0.05). A significant correlation between MC and microvascular densities was observed in oral SCC (r = 0.5; P = 0.012). These findings suggest that MCs may upregulate tumor angiogenesis in oral SCC, perhaps via MC tryptase.
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                Author and article information

                Journal
                J Oral Maxillofac Pathol
                JOMFP
                Journal of Oral and Maxillofacial Pathology : JOMFP
                Medknow Publications & Media Pvt Ltd (India )
                0973-029X
                1998-393X
                Jan-Apr 2012
                : 16
                : 1
                : 22-26
                Affiliations
                [1] Department of Oral and Maxillofacial Pathology, Pacific Dental College and Hospital, PAHER University, Udaipur, Rajasthan, India
                Author notes
                Address for correspondence: Dr. Madhusudan Astekar, Department of Oral Pathology, Pacific Dental College, Udaipur - 313 024, Rajasthan, India. E-mail: madhu.tanu@ 123456gmail.com
                Article
                JOMFP-16-22
                10.4103/0973-029X.92968
                3303517
                22434941
                3280e380-c9f9-4938-9784-a8fb9b313a77
                Copyright: © Journal of Oral and Maxillofacial Pathology

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Categories
                Original Article

                Pathology
                angiogenesis,epithelial dysplasia,vascular endothelial growth factor,image analysis,oral squamous cell carcinoma,microvessel density

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