Simultaneous expression of furin and vascular endothelial growth factor in human oral tongue squamous cell carcinoma progression.
OBJECTIVE
Squamous cell carcinoma (SCC) of the tongue is a common malignancy of the oral cavity. Furin convertase activates several precursor matrix metalloproteinases involved in the degradation of the extracellular matrix. The pattern of expression of furin and vascular endothelial growth factor-C (VEGF-C), two key molecules in neoplasm development, was examined during the progression from normal epithelium to invasive SCC.


METHODS
We evaluated furin and VEGF-C expression and microvessel density (MVD) by immunohistochemistry in human tongue sections harboring normal epithelium, dysplastic epithelium, and/or SCC. Sections from 46 glossectomy specimens were assessed for furin expression. A selected group of 15 cases, each containing normal epithelium, precursor lesions, and invasive SCC, were further studied for furin and VEGF-C expression and MVD quantification. We also evaluated the pattern of furin expression and VEGF-C processing by Western blot analysis in three SCC cell lines with different degrees of aggressiveness.


RESULTS
Furin and VEGF-C expression was notably higher in most precursor lesions and SCCs than in normal epithelia. Approximately 60% (n = 26) and 100% (n = 15) of the normal epithelia showed low-intensity staining for furin and VEGF-C, respectively. Intense staining for furin and VEGF-C was detected in approximately 80% (n = 34) and 100% (n = 15) of the SCCs, respectively. A significant correlation was seen between the expression of these two markers (Spearman's test, P < 0.00002). We found a statistically significant increase in MVD when either dysplasia (432 +/- 19.06; P < 0.05) or SCC (546 +/- 17.24) was compared with normal epithelium (315 +/- 17.27; P < 0.0001). SCC71, the most aggressive cell line analyzed, was the one with the highest furin expression. This cell line totally processed the VEGF-C proform, whereas the less aggressive line SCC9, exhibiting the least furin expression, did not. SCC15, of intermediate aggressiveness and furin expression, showed intermediate pro-VEGF-C processing.


CONCLUSIONS
These findings suggest that furin is a useful marker of tumor progression and is responsible for VEGF-C processing. This in turn would enhance angiogenesis, leading to increased MVD associated with preinvasive and invasive neoplasia.
López de Cicco
Ricardo
R
Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Watson
James C
JC
Bassi
Daniel E
DE
Litwin
Samuel
S
Klein-Szanto
Andrés J
AJ
D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000378:metabolism; D018450:Disease Progression; D045683:Furin / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D008833:Microcirculation; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D013997:Time Factors; D014059:Tongue / Q000378:metabolism; D014062:Tongue Neoplasms / Q000378:metabolism / Q000473:pathology*; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis*
D018076:DNA, Complementary; D042582:Vascular Endothelial Growth Factor C; D045683:Furin