Immunohistochemical study of vascular endothelial growth factor-C/vascular endothelial growth factor receptor-3 expression in oral tongue squamous cell carcinoma: Correlation with the induction of lymphangiogenesis

Abstract

The aim of the present study was to elucidate the associations between the expression of the vascular endothelial growth factor-C (VEGF-C)/VEGF receptor-3 (VEGFR-3) axis and lymphangiogenesis, regional lymph node metastasis and clinicopathological factors in oral tongue squamous cell carcinoma (OTSCC) using immunohistochemistry. The expression of VEGF-C, VEGFR-3 and podoplanin was immunohistochemically evaluated in specimens obtained from 65 patients with OTSCC (T1-2, N0) who had undergone radical surgery alone. The associations between the expression of VEGF-C, VEGFR-3 and podoplanin, and lymphangiogenesis, regional lymph node metastasis and clinocopathological factors were determined by immunohistochemical analysis. VEGF-C, VEGFR-3 and combined VEGF-C/VEGFR-3 expression was significantly higher in cases with regional recurrence compared with those without lymph node involvement (P<0.001). As regards lymphangiogenesis, a significant correlation was observed between podoplanin expression and VEGF-C, VEGFR-3 and combined VEGF-C/VEGFR-3 expression (P<0.001). Therefore, lymphangiogenesis in the peritumoral stroma was associated with lymph node metastasis. However, podoplanin expression did not exhibit a significant correlation with the progression of lymph node metastasis. The results of the present study suggest that the VEGF-C/VEGFR-3 axis may be associated with lymph node metastasis through lymphangiogenesis. Determining the VEGF-C/VEGFR-3 expression status may help predict which patients will develop regional recurrence and provide novel targets for therapies to suppress lymph node metastasis in the treatment of OTSCC.

Correlation between podoplanin expression and extracapsular spread in squamous cell carcinoma of the oral cavity using subjective immunoreactivity scores and semiquantitative image analysis

“…Using various subjective methods of immunostaining quantification, previous studies have reported an association between high levels of podoplanin expression and the presence of lymph node metastasis in HNSCC . However, other studies did not confirm these findings . These differences are most likely due to the lack of standardized protocols for podoplanin quantification, together with an important heterogeneity between the different groups of patients included in these studies.…”

“…Although not restricted to occult neck disease, other studies have reported a significant association between podoplanin expression and the presence of lymph node metastasis . However, other recent reports did not confirm these results . Our work was conducted on a selected population of patients with squamous cell carcinoma of the oral cavity using both subjective and semiquantitative image analysis quantification of podoplanin expression.…”

Chemokine CCL4 Induces Vascular Endothelial Growth Factor C Expression and Lymphangiogenesis by miR-195-3p in Oral Squamous Cell Carcinoma

“…VEGF-C acts directly on lymphatic endothelial cells (LECs) to induce survival, proliferation, migration, and tube formation ( 14 ). VEGF-C/VEGFR3 expression is associated with lymph node metastasis in OSCC ( 15 ). It is known that various signaling systems influence tumor lymphangiogenesis through the modulation of VEGF-C. For instance, JAK/STAT3 signaling is associated with oral cancer cell proliferation, invasion and angiogenesis ( 16 ), while STAT3 signaling induces LEC migration and tube formation ( 17 ).…”

Gefitinib inhibits malignant melanoma cells through the VEGF/AKT signaling pathway

“…It can promote vascular endothelial cell proliferation, differentiation, migration and movement, and form vessel structures by enhancing blood vessel permeability and degrading extracellular matrix (19). VEGF can promote neovascularization in tumorigenesis (20). The binding of VEGF to VEGF receptor, synergized with angiogenin-2, can facilitate lymphatic vessel hyperplasia surrounding the tumor to ensure that new capillaries can provide nutrition for the tumor and promote tumor metastasis (21).…”