ABSTRACT
OBJECTIVES: To evaluate the role of trkA receptor as a potential tumor marker in serous epithelial ovarian cancer and its relationship with the angiogenic factors expression as vascular endothelial growth factor (VEGF) and nerve growth factor (NGF). Additionally, to examine whether NGF and VEGF secreted by epithelial ovarian cancer (EOC) explants and from epithelial ovarian cancer cell line (A2780) are involved in the process of angiogenesis, such as cellular proliferation, migration and differentiation of the human endothelial cell line (EA.hy926). METHODS: The mRNA levels of VEGF, NGF and trkA receptors were measured using PCR in 60 ovarian samples. Cellular localization and semi-quantitative estimation of VEGF, NGF, total trkA and p-trkA was performed using IHC in epithelial cells. NGF, total trkA and p-trkA protein were also evaluated in endothelial cells from the same tissues. Human endothelial cell line EA.hy926 was cultured with conditioned media obtained from both EOC explants and from the A2780 cell line, with or without NGF stimulus. RESULTS: Significantly higher levels of NGF, total trkA and p-trkA protein expressions were observed in epithelial and endothelial cells in poorly differentiated EOC versus normal ovary. Interestingly, the p-trkA receptor expression level showed the most significant difference and its presence was only found in borderline tumor and EOC samples indicating the importance of trkA receptor in EOC as a potential tumor marker. A significant increase in proliferation, migration and differentiation of EA.hy926 cells was observed with NGF, and this effect was significantly reverted when NGF was immuno-blocked and when a trkA inhibitor was used, showing that NGF is an important angiogenic factor in EOC by activating its trkA receptor. CONCLUSION: These results indicate that p-trkA may be considered as a new potential tumor marker in EOC, and that NGF may also act as a direct angiogenic factor in EOC.
Subject(s)
Biomarkers, Tumor/biosynthesis , Receptor, trkA/biosynthesis , Aged , Biomarkers, Tumor/genetics , Carcinoma, Ovarian Epithelial , Cell Differentiation/physiology , Cell Growth Processes/physiology , Cell Line, Tumor , Cell Movement/physiology , Female , Humans , Immunohistochemistry , Middle Aged , Neoplasms, Glandular and Epithelial/enzymology , Neoplasms, Glandular and Epithelial/genetics , Neoplasms, Glandular and Epithelial/pathology , Nerve Growth Factor/biosynthesis , Nerve Growth Factor/genetics , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptor, trkA/genetics , Vascular Endothelial Growth Factor A/biosynthesis , Vascular Endothelial Growth Factor A/geneticsABSTRACT
OBJECTIVES: To compare the expression of nerve growth factor (NGF) and its high-affinity receptor trkA in normal ovaries and in epithelial ovarian carcinomas. Given NGF acts as an angiogenic factor through a vascular endothelial growth factor (VEGF)-mediated mechanism in several types of tissues, we examined whether NGF regulates the expression of VEGF isoforms in epithelial ovarian cancer (EOC). METHODS: The expression and localization of NGF and tyrosine kinase receptor A (trkA) in normal ovarian samples and in ovarian cancer samples were analyzed by RT-PCR and immunohistochemistry. NGF regulates the expression of three VEGF isoforms (VEGF(121), VEGF(165) and VEGF(189)); these were examined using RT-PCR in explants of EOC and ELISA in culture media. RESULTS: TrkA mRNA levels were over-expressed in ovarian cancer compared to normal ovarian samples, whereas NGF mRNA levels remained unchanged. NGF and trkA proteins were absent or found in very low levels in normal ovarian surface epithelium (OSE), whereas they were highly expressed in epithelial cells of EOC. Additionally, NGF stimulated the expression of VEGF isoforms in cancer explants. The effect was dose-dependent and inhibited by a NGF antibody and by K(252a), a trk receptor inhibitor. CONCLUSION: The abundance of NGF and trkA receptors in epithelial cells of EOC, together with the ability of NGF to increase VEGF expression strongly suggests an autocrine role of NGF in EOC. These findings suggest that blocking neurotrophin action could be a therapeutic target in treating ovarian cancer.
Subject(s)
Nerve Growth Factor/metabolism , Ovarian Neoplasms/metabolism , Receptor, trkA/metabolism , Vascular Endothelial Growth Factor A/biosynthesis , Adult , Female , Humans , Immunohistochemistry , Middle Aged , Nerve Growth Factor/biosynthesis , Nerve Growth Factor/genetics , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/genetics , Ovary/enzymology , Ovary/metabolism , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptor, trkA/biosynthesis , Receptor, trkA/genetics , Reverse Transcriptase Polymerase Chain Reaction , Vascular Endothelial Growth Factor A/geneticsABSTRACT
BACKGROUND: Tibolone is a synthetic steroid with estrogenic, androgenic and progestogenic properties, which has been used as an alternative to estrogen replacement therapy in several countries. One of its outstanding features is that it does not stimulate endometrial proliferation. CASES: We report four cases of histologically diagnosed adenocarcinoma of the endometrium in women using tibolone. CONCLUSIONS: Although we do not suggest causality between the use of tibolone and the development of endometrial malignancy, the association described should alert physicians to thorough investigation in patients presenting with vaginal bleeding while on tibolone, despite the absence of endometrial thickness by sonogram.
Subject(s)
Adenocarcinoma/chemically induced , Endometrial Neoplasms/chemically induced , Norpregnenes/adverse effects , Aged , Anabolic Agents/adverse effects , Anabolic Agents/therapeutic use , Androgen Antagonists/adverse effects , Androgen Antagonists/therapeutic use , Estrogen Receptor Modulators/adverse effects , Estrogen Receptor Modulators/therapeutic use , Female , Humans , Middle Aged , Norpregnenes/therapeutic useABSTRACT
Se reportan 90 pacientes con cáncer de endometrio evaluadas en el Instituto Nacional del Cáncer entre enero 1981 y septiembre de 1993. Todas las pacientes fueron tratadas inicialmente con cirugía. El análisis retrospectivo mostró 51 pacientes consideradas como "No etapificadas" de las cuales 37 (72 por ciento) recibieron radioterapia complementaria y 39 consideradas "Etapificadas", 20 (51 por ciento) de las cuales recibieron radioterapia complementaria. La sobrevida sin evidencia de enfermedad del grupo total en estudio fue 75 por ciento, con una mediana de seguimiento de 48,9 meses
