Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma correlates with lymph node metastasis

Abstract

BACKGROUND The expression of vascular endothelial growth factor (VEGF)‐A isoforms (121, 165, 189, 206), VEGF‐B, VEGF‐C and VEGF‐D in both experimental and clinical models of head and neck squamous cell carcinoma (HNSCC) was determined and correlated with conventional clinicopathologic parameters, with particular reference to cervical nodal metastasis. METHODS The mRNA expression of VEGFs in 14 HNSCC cell lines was compared with 4 normal keratinocyte cultures and 10 fibroblast cultures using a semiquantitative reverse transcription polymerase chain reaction (RT‐PCR) assay. Protein levels were determined by Western blotting and enzyme‐linked immunosorbent assay (ELISA). The authors then examined the expression of VEGFs in tissues from 54 patients including histologically normal epithelium (n = 32), early invasive squamous cell carcinomas (SCCs) (n = 23), advanced primary SCCs (n = 31), and lymph node metastases (n = 27). RESULTS Increased levels of VEGF‐A (all four isoforms) and VEGF‐C were found in tumor cell lines compared with normal cells, whereas no differences in VEGF‐B levels were found. VEGF‐D expression, however, was lower in HNSCC cells. Studies in clinical samples showed highly significant increases in mRNA expression of all four isoforms of VEGF‐A and VEGF‐C in tumors versus normal epithelium. In contrast, the levels of VEGF‐D were significantly decreased in tumors, and VEGF‐B expression appeared similar in both normal and malignant tissues. Multivariate analysis demonstrated that an infiltrative mode of invasion and enhanced expression of VEGF‐A (isoforms 121 and 165) and VEGF‐C had predictive value for the presence of cervical nodal metastases. CONCLUSIONS Up‐regulation of VEGF‐A (two isoforms) and VEGF‐C and down‐regulation of VEGF‐D have been common features in HNSCC. Thus VEGF‐A and VEGF‐C appeared to play a vital role in the metastatic process of HNSCC. Cancer 2001;92:556–68. © 2001 American Cancer Society.

Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis

“…The current study also found that such tumours behaved more aggressively, as they were significantly associated with the presence of LN metastasis (Po0.001), distant metastasis (P ¼ 0.01) and a poorer survival (P ¼ 0.029). These findings are similar to others, both in breast cancer and other tumour types (Toi et al, 1995b;Linderholm et al, 1999;O-Charoenrat et al, 2001). Although the effect of VEGF-A expression can be mediated by an increased vascular network, it should be noted that the growth factor has also been shown to increase breast cancer cell survival through direct action on VEGFR-2 that has been found to be expressed on the surface of the breast cancer cells.…”

“…It has been reported to be significantly associated with high LVD, LN metastasis and poorer survival in gastric (Shida et al, 2005), endometrial (Yokoyama et al, 2003) and colorectal carcinomas (White et al, 2002). In head and neck tumours (O-Charoenrat et al, 2001), such relationships have not been found. In other studies in breast and in lung carcinoma, low levels of expression of VEGF-D was associated with poorer prognosis (Niki et al, 2000;Koyama et al, 2003).…”

β-Catenin Inversely Regulates Vascular Endothelial Growth Factor-D mRNA Stability

“…In light of the present results, it will also be important for the future analysis of VEGF-D expression in tumors to take into account that VEGF-D might be expressed as a late marker of tumor progression and only in cells that have lost or reduced expression of ␤-catenin. These analyses will probably clarify the apparent discrepancy of VEGF-D expression in tumors reported by different authors (31)(32)(33)(34)(35)(36)(37).…”

“…Because constitutive ␤-catenin signaling has been correlated with colorectal cancer formation (57), its regulation of VEGF-D mRNA is particularly important considering that the expression of this factor has been correlated with tumor progression (33,34,36,37,58). In this respect, it is worth noting that ␤-catenin has been described as a master gene for cell proliferation (55), but its role in tumor progression is less clear.…”

Regulation of Vascular Endothelial Growth Factor D by Orphan Receptors Hepatocyte Nuclear Factor-4α and Chicken Ovalbumin Upstream Promoter Transcription Factors 1 and 2

“…In line with their proposed role in cancer pathobiology, the expression of VEGF-C, VEGF-D, and/or VEGFR-3 has been shown to correlate with lymphatic spread, tissue invasion, and/or poor prognosis in solid malignancies (3) including gastric cancer (4). In other studies, however, conflicting observations were made (5,6) indicating that the role of the VEGF-C/VEGF-D/VEGFR-3 system in cancer is complex and may differ between malignancies.…”