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Hum. Reprod. Advance Access originally published online on March 8, 2007
Human Reproduction 2007 22(6):1705-1713; doi:10.1093/humrep/dem037
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© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Lymphangiogensis of normal endometrium and endometrial adenocarcinoma

Jacqueline F. Donoghue1, Fiona L. Lederman1, Beatrice J. Susil2 and Peter A.W. Rogers1,3

1 Centre for Women's Health Research, Monash University Department of Obstetrics and Gynaecology, Clayton, Victoria, Australia 2 Department of Anatomical Pathology, Monash Medical Centre, Clayton, Victoria, Australia

3 To whom correspondence should be addressed at: Centre for Women's Health Research, Monash University Department of Obstetrics and Gynaecology, Monash Medical Centre, Level 5, 246 Clayton Road, Clayton, 3168 Victoria, Australia. E-mail: peter.rogers{at}med.monash.edu.au

BACKGROUND: Information about lymphatics and lymphangiogenesis in the human endometrium is limited. We investigated the distribution of endometrial lymphatic vessels during the normal menstrual cycle and in association with endometrial adenocarcinoma and investigated the expression of lymphangiogenic growth factors, vascular endothelial growth factor (VEGF)-C, VEGF-D and VEGF receptor-3 (VEGF-R3).

METHODS AND RESULTS: Full thickness uterine samples (n = 23 proliferative; n = 23 secretory) and endometrial adenocarcinoma samples (n = 7 grade I; n = 10 grade III) were collected for the study and analysed by immunohistochemistry and western blotting. Lymphatic vessels of the functionalis were significantly reduced compared with basalis (P = 0.001) across the menstrual cycle with lymphatics of the basalis sometimes intimately associated with spiral arterioles. Lymphatic vessels of endometrial adenocarinomas were located intra-tumoural and peri-tumoural with significant increases in the peri-tumoural lymphatic vessels compared with normal basalis (P = 0.02). Interestingly, high-grade adenocarcinoma vessels containing tumour emboli demonstrated a mixed blood/lymphatic endothelial cell phenotype. VEGF-C and VEGF-D were immunolocalized in glandular epithelium and some stromal cells with the staining intensity of this localization increasing in endometrial adenocarcinoma. Protein analysis identified VEGF-C (58, 41, 31 and 21 kD) and VEGF-D (56, 41, 31 and 21 kD) and VEGF-R3 (148 and 65 kD) peptides in normal endometrium, with significant increases in several of these peptides for VEGF-C and VEGF-D and no changes in protein expression for VEGF-R3 in endometrial adenocarcinoma.

CONCLUSION: Endometrial lymphatics are significantly reduced in the functionalis, and increases in endometrial adenocarcinoma peri-tumoural lymphatics are associated with increases in VEGF-C and VEGF-D peptides.

Key words: endometrial adenocarcinoma/endometrium/lymphangiogenesis/vascular endothelial growth factor C/vascular endothelial growth factor D


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