Obstetrics and Gynaecology - Research Publications
Permanent URI for this collection
Search Results
1 - 4 of 4
-
ItemLymphangiogensis of normal endometrium and endometrial adenocarcinoma(OXFORD UNIV PRESS, 2007-06)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 adenocarcinomas 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.
-
ItemEndometrial lymphangiogensis(W B SAUNDERS CO LTD, 2008-03)This article briefly summarises some of the more important recent advances in understanding of lymphangiogenesis, and then reviews current knowledge of the lymphatics and lymphangiogenesis in the endometrium. The recent identification of vascular endothelial growth factor-C (VEGF-C) and VEGF-D, as well as specific lymphatic endothelial cell (LEC) markers such as vascular endothelial growth factor receptor-3 (VEGF-R3), lymphatic endothelial hyaluronan receptor-1 (LYVE-1), podoplanin, and prospero-related homeobox-1 (PROX1), has provided the tools to characterize and investigate lymphatic development and function in a wide range of tissues. There are conflicting reports on the distribution of endometrial lymphatics, with some studies reporting lymphatics in the functional zone of human endometrium, others only in the endometrial basalis, and some reporting none at all. Using immunohistochemical methods we have shown that lymphatic vessels of the functionalis were small and sparsely distributed whereas the basalis lymphatics are larger, more frequent and often closely associated with spiral arterioles. Based on comparisons of serial sections, the majority of lymphatic vessels are positive for CD31 but not FVIII or CD34. By comparing CD31 with D2-40 (labels lymphatic endothelial cells) vessel immunostaining, it was estimated that 13% of the vessel profiles in the functionalis, 43% in the basalis and 28% in the myometrium were lymphatics. The lymphangiogenic growth factor VEGF-C is immunolocalized most prominently in the glandular cells, vascular endothelium and some stromal cells in normal cycling endometrium. There is no difference in staining intensity observed between the basalis and functionalis. VEGF-D is immunolocalized throughout the endometrial and myometrial tissues, with no difference in intensity between endometrial glands and stroma or between the basalis and functionalis across the normal cycle. In conclusion, despite an apparently similar distribution of VEGF-C, VEGF-D and VEGF-R3 in endometrial functionalis and basalis, the lymphatic vascular density is 4-5 times higher in the basalis compared to the functionalis. There is also a close association between some lymphatics in the basalis and the spiral arterioles, thus identifying a potential mechanism for a vascular control feedback loop.
-
ItemEndometrial Angiogenesis, Vascular Maturation, and Lymphangiogenesis(SAGE PUBLICATIONS INC, 2009-02)Angiogenesis, arteriogenesis or vessel maturation, and lymphangiogenesis comprise a continuum of vascular development, with overlap and interaction between the mechanisms by which they are controlled. These processes are of clinical interest because they play roles in endometrial repair, placental development, and in gynecological disorders including endometrial cancer, endometriosis and abnormal uterine bleeding. Using mouse models we have shown that estrogen can be either proangiogenic or antiangiogenic in endometrium. Progesterone alone is proangiogenic, although this can be moderated by pretreatment with estrogen. Arteriogenesis also increases in response to progesterone, and this effect is not inhibited by estrogen. Lymphatics account for 13% of all vessels in the human functionalis compared to 57% in the basalis. Many of the basalis lymphatic vessels are closely associated with spiral arterioles and this intimate connection may provide a mechanism for paracrine communication between the functionalis and the arteries supplying the endometrium.
-
ItemThe Plasticity of Oncogene Addiction: Implications for Targeted Therapies Directed to Receptor Tyrosine Kinases(ELSEVIER SCIENCE INC, 2009-05)A common mutation of the epidermal growth factor receptor (EGFR) in glioblastoma multiforme (GBM) is an extracellular truncation known as the de2-7 EGFR (or EGFRvIII). Hepatocyte growth factor (HGF) is the ligand for the receptor tyrosine kinase (RTK) c-Met, and this signaling axis is often active in GBM. The expression of the HGF/c-Met axis or de2-7 EGFR independently enhances GBM growth and invasiveness, particularly through the phosphatidylinositol-3 kinase/pAkt pathway. Using RTK arrays, we show that expression of de2-7 EGFR in U87MG GBM cells leads to the coactivation of several RTKs, including platelet-derived growth factor receptor beta and c-Met. A neutralizing antibody to HGF (AMG102) did not inhibit de2-7 EGFR-mediated activation of c-Met, demonstrating that it is ligand-independent. Therapy for parental U87MG xenografts with AMG 102 resulted in significant inhibition of tumor growth, whereas U87MG.Delta 2-7 xenografts were profoundly resistant. Treatment of U87MG.Delta 2-7 xenografts with panitumumab, an anti-EGFR antibody, only partially inhibited tumor growth as xenografts rapidly reverted to the HGF/c-Met signaling pathway. Cotreatment with panitumumab and AMG 102 prevented this escape leading to significant tumor inhibition through an apoptotic mechanism, consistent with the induction of oncogenic shock. This observation provides a rationale for using panitumumab and AMG 102 in combination for the treatment of GBM patients. These results illustrate that GBM cells can rapidly change the RTK driving their oncogene addiction if the alternate RTK signals through the same downstream pathway. Consequently, inhibition of a dominant oncogene by targeted therapy can alter the hierarchy of RTKs resulting in rapid therapeutic resistance.