VEGF-C contributes to head and neck squamous cell carcinoma growth and motility

Philips Institute of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Oral Oncology (Impact Factor: 3.61). 03/2010; 46(4):e19-24. DOI: 10.1016/j.oraloncology.2010.02.006
Source: PubMed


Previous work from our laboratory has demonstrated overexpression of chemokines in head and neck cancer and the utility of targeting these proteins for tumor therapy in a preclinical model. However, the mechanisms involved are unexplored. Through gene expression analysis, we found that expression of vascular endothelial growth factor (VEGF-C) was elevated in HN12 cells expressing high levels of CXCL5. In the present study, we have investigated the contribution of VEGF-C to tumor cell growth and motility. RNAi-mediated knockdown of VEGF-C expression in HN12 cells, which express high levels of CXCL5, resulted in a decrease in proliferation. Conversely, forced expression of VEGF-C in HN4 tumor cells with low endogenous CXCL5 levels increased cell growth. Suppression of VEGF-C inhibited migration of HN12 cells. Similarly, HN4 cells showed reduced migration towards conditioned media collected from HN12 cells with VEGF-C knockdown compared to controls, while HN4/VEGF-C conditioned media stimulated cell migration. Moreover, tumor growth in vivo was markedly reduced when VEGF-C expression was blocked by shRNA. Finally, determination of VEGF-C expression in squamous carcinoma cell lines revealed universal overexpression compared to normal keratinocytes. These findings support a role for VEGF-C in head and neck squamous cell carcinogenesis.

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    • "Here we have shown that depletion of αB-crystallin decreased the motility of UT-SCC cells, indicating also in these types of cells αB-crystallin may affect cell migration. VEGF also plays a role in cell migration [38], potentially by enhancing invadopodia formation [39]. The effect of αB-crystallin on cell migration may thus be mediated by VEGF, although other mechanisms are also possible, as for example by the influence of αB-crystallin on actin filaments dynamics [39,40]. "
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    ABSTRACT: Background αB-crystallin is able to modulate vascular endothelial growth factor (VEGF) secretion. In many solid tumors VEGF is associated with angiogenesis, metastasis formation and poor prognosis. We set out to assess whether αB-crystallin expression is correlated with worse prognosis and whether this is related to VEGF secretion and cell motility in head and neck squamous cell carcinoma (HNSCC). Methods αB-crystallin expression was determined immunohistochemically in tumor biopsies of 38 HNSCC patients. Locoregional control (LRC) and metastasis-free survival (MFS) of the patients were analyzed in relation to αB-crystallin expression. Additionally, the effects of αB-crystallin knockdown on VEGF secretion and cell motility were studied in vitro. Results Patients with higher staining fractions of αB-crystallin exhibited a significantly shorter MFS (Log-Rank test, p < 0.005). Under normoxic conditions αB-crystallin knockdown with two different siRNAs in a HNSCC cell line reduced VEGF secretion 1.9-fold and 2.1-fold, respectively. Under hypoxic conditions, a similar reduction of VEGF secretion was observed, 1.9-fold and 2.2-fold, respectively. The effect on cell motility was assessed by a gap closure assay, which showed that αB-crystallin knockdown decreased the rate by which HNSCC cells were able to close a gap by 1.5- to 2.0-fold. Conclusions Our data suggest that αB-crystallin expression is associated with distant metastases formation in HNSCC patients. This association might relate to the chaperone function of αB-crystallin in mediating folding and secretion of VEGF and stimulating cell migration.
    BMC Cancer 03/2013; 13(1):128. DOI:10.1186/1471-2407-13-128 · 3.36 Impact Factor
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    • "A probable explanation could be that nutrition is necessary for the initial establishment and growth of tumor mass but, eventually, the differentiating tumor houses a number of various modulating factors such as VEGF isoforms (VEGF-C and VEGF-D),[18] iNOS,[413] endothelins,[1920] CXCL-5, CXCL-8,[1821] and COX-2,[422] with various oncogenes like ras[23] and tumor suppressor genes like p53[7] acting upon it. As stated by several authors,[212425] activated oncogenes and/or inactivated tumor suppressor genes bring about increased VEGF expression, firstly, through the ras-raf-MAPK pathway and, secondly, through progressive tumor growth, which eventually induces hypoxia. "
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    ABSTRACT: Significant increase in vascularity occurs during the transition from normal oral mucosa, through differing degrees of dysplasia, to invasive squamous cell carcinoma (SCC). To evaluate microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression in oral tumorigenesis and correlate it with the clinicopathological characteristics. VEGF expression and MVD were quantified immunohistochemically using anti-VEGF and anti-CD34 antibody. 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. 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. 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. These findings indicate that VEGF expression is upregulated during head and neck tumorigenesis.
    Journal of Oral and Maxillofacial Pathology 03/2012; 16(1):22-6. DOI:10.4103/0973-029X.92968
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    • "So doctors are aiming to find a new way of treatment, that is gene therapy (Tangney, 2010). VEGF-C is a specific lymphatic endothelial cell growth factor, its roles of promoting tumor cell growth and angiogenesis have been reported in more literatures( Mandriota et al., 2001; Benke et al., 2010) .In this study, VEGF-C ASODN was transfected into A-549 cell lines, its invasive ability and expression of VEGF-C were examined, maybe the gene VEGF-C will be a new target in treatment of lung cancer. "
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    ABSTRACT: Vascular endothelial growth factor C (VEGF-C), a member of the VEGF family, has been reported to promote angiogenesis and tumor cell growth. In this study, we analyzed inhibitory action of a VEGF-C antisense oligoxydeonucleotide (ASODN) on a lung carcinoma cell line A-549 and its invasive ability in vitro. Liposomes, liposome-mediated sense oligoxydeonucleotide (SODN) and ASODN were transfected into A-549 cells, with a blank control group. The expression of VEGF-C was examined by western blotting and invasive ability of cells was detected at four levels. Lower expression of VEGF-C and lower invasive ability to recombinate basal membranes were apparent in the ASOND group (P<0.01). However, there were no significant differences among the other three groups (P>0.05). In the invasion assay, the number of transmembrane cells was significantly reduced in the ASODN group after 48 hours (58.6±9.2 P<0.01), but there was no variation among control, LIP and SOND groups (132.5±15.6, 129.7±16.1, 118.2±12.5, P>0.05). VEGF-C ASODN can downregulate the expression of VEGF-C in cell lines and can obviously inhibit invasive ability in vitro.
    Asian Pacific journal of cancer prevention: APJCP 01/2011; 12(8):2097-9. · 2.51 Impact Factor
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