Prox 1, VEGF-C and VEGFR3 expression during cervical neoplasia progression as evidence of an early lymphangiogenic switch.

Abstract

Prox1 is a key regulator of lymphatic endothelial cell commitment during embryonic development. No correlations between Prox1 and VEGF-C/VEGFR3 expression in cervical cancer has been done until now. The aim of the present study was to evaluate the peculiarities of Prox1, VEGF-C and VEGFR3 expression during uterine cervix neoplasia progression. Material and methods. One hundred and four specimens taken from women with macroscopically detectable lesions were classified by histopathology and analyzed by immunohistochemistry for Prox1, VEGFR3 and VEGF-C expression. Results. The presence of Prox1 nuclear expression was detected starting from CIN2 and CIN3 lesions to microinvasive carcinoma, in the nuclei of lymphatic and venous endothelial cells and scattered stromal cells. All Prox1 positive lymphatic vessels were positive for VEGFR3. A significant correlation was found between expression of VEGF-C in tumor cells and nuclear density of Prox1 positive lymphatic cells (p=0.044). Conclusion. The commitment of Prox1 positive cells through a lymphatic lineage is an early event for cervical neoplastic progression, being present starting with intraepithelial cervical lesions, and is strongly associated with VEGFR3 and VEGF-C expression. These findings suggest an early active lymphangiogenesis during cervical neoplasia progression and explain, in part, the early presence of lymph node metastasis in cervical cancer. By the detection of Prox1 expression in lymphatic and venous endothelial cells, and also in stromal cells, it has been suggested that there are at least three different mechanism of lymph vessel development during cervical neoplasia progression.