Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma.
BACKGROUND: Hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha are essential regulatory proteins for the adaptation of tumor cells to hypoxia, and they stimulate angiogenesis through activation of the vascular endothelial growth factor (VEGF) gene. METHODS: HIF-1alpha and HIF-2alpha protei...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
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2002
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| _version_ | 1797100674684551168 |
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| author | Sivridis, E Giatromanolaki, A Gatter, K Harris, A Koukourakis, M |
| author_facet | Sivridis, E Giatromanolaki, A Gatter, K Harris, A Koukourakis, M |
| author_sort | Sivridis, E |
| collection | OXFORD |
| description | BACKGROUND: Hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha are essential regulatory proteins for the adaptation of tumor cells to hypoxia, and they stimulate angiogenesis through activation of the vascular endothelial growth factor (VEGF) gene. METHODS: HIF-1alpha and HIF-2alpha proteins were studied immunohistochemically in a group of 81 patients with Stage I endometrial adenocarcinoma of the endometrioid cell type. The results were correlated with intratumoral angiogenesis, the expression of the angiogenic factors VEGF and thymidine phosphorylase (TP), and the VEGF/receptor (VEGF/KDR) complex. Relations also were sought with estrogen receptor (ER) and progesterone receptor (PR), with the apoptosis-related proteins bcl-2 and p53, with several histopathologic parameters, and with patient prognosis. In addition, a sample of 25 normal endometria at various phases of the menstrual cycle was studied for the presence of HIF-1alpha and HIF-2alpha. RESULTS: HIF-1alpha expression was detected in 49% of endometrial carcinomas. The expression was cytoplasmic or mixed nuclear/cytoplasmic. HIF-1alpha expression was associated with up-regulation of the VEGF pathway and with increased standard microvessel density (sMVD) and activated VEGF/KDR microvessel density (aMVD). It also was associated with a poor prognosis in both univariate and multivariate analyses. HIF-2alpha protein showed a pattern of expression similar to the pattern seen in HIF-1alpha, but expression of HIF-2alpha protein occurred in only 17% of endometrial carcinomas, and it was associated with increased TP reactivity. There also was a relation of HIF-1alpha expression with well-differentiated endometrial neoplasms, and there was a marginal association of HIF-1alpha and HIF-2alpha with ER expression. With reference to normally cycling tissues, HIF-1alpha nuclear/cytoplasmic expression was particularly strong in the samples of early proliferative phase endometrium compared with HIF-2alpha protein expression, which showed a constant reaction throughout the menstrual cycle. CONCLUSIONS: The up-regulation of HIF-1alpha and, to a lesser extent, of HIF-2alpha is a common event in Stage I endometrial adenocarcinomas. In these tumors, HIF-1alpha expression is related to increased angiogenesis, through activation of the VEGF angiogenic pathway, and to an unfavorable prognosis. HIF-2alpha accumulation is associated with increased expression of the angiogenic factor TP. |
| first_indexed | 2024-03-07T05:40:57Z |
| format | Journal article |
| id | oxford-uuid:e58adde8-2cea-4a9d-86a1-a3f5837e0c7c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:40:57Z |
| publishDate | 2002 |
| record_format | dspace |
| spelling | oxford-uuid:e58adde8-2cea-4a9d-86a1-a3f5837e0c7c2022-03-27T10:24:47ZAssociation of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e58adde8-2cea-4a9d-86a1-a3f5837e0c7cEnglishSymplectic Elements at Oxford2002Sivridis, EGiatromanolaki, AGatter, KHarris, AKoukourakis, M BACKGROUND: Hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha are essential regulatory proteins for the adaptation of tumor cells to hypoxia, and they stimulate angiogenesis through activation of the vascular endothelial growth factor (VEGF) gene. METHODS: HIF-1alpha and HIF-2alpha proteins were studied immunohistochemically in a group of 81 patients with Stage I endometrial adenocarcinoma of the endometrioid cell type. The results were correlated with intratumoral angiogenesis, the expression of the angiogenic factors VEGF and thymidine phosphorylase (TP), and the VEGF/receptor (VEGF/KDR) complex. Relations also were sought with estrogen receptor (ER) and progesterone receptor (PR), with the apoptosis-related proteins bcl-2 and p53, with several histopathologic parameters, and with patient prognosis. In addition, a sample of 25 normal endometria at various phases of the menstrual cycle was studied for the presence of HIF-1alpha and HIF-2alpha. RESULTS: HIF-1alpha expression was detected in 49% of endometrial carcinomas. The expression was cytoplasmic or mixed nuclear/cytoplasmic. HIF-1alpha expression was associated with up-regulation of the VEGF pathway and with increased standard microvessel density (sMVD) and activated VEGF/KDR microvessel density (aMVD). It also was associated with a poor prognosis in both univariate and multivariate analyses. HIF-2alpha protein showed a pattern of expression similar to the pattern seen in HIF-1alpha, but expression of HIF-2alpha protein occurred in only 17% of endometrial carcinomas, and it was associated with increased TP reactivity. There also was a relation of HIF-1alpha expression with well-differentiated endometrial neoplasms, and there was a marginal association of HIF-1alpha and HIF-2alpha with ER expression. With reference to normally cycling tissues, HIF-1alpha nuclear/cytoplasmic expression was particularly strong in the samples of early proliferative phase endometrium compared with HIF-2alpha protein expression, which showed a constant reaction throughout the menstrual cycle. CONCLUSIONS: The up-regulation of HIF-1alpha and, to a lesser extent, of HIF-2alpha is a common event in Stage I endometrial adenocarcinomas. In these tumors, HIF-1alpha expression is related to increased angiogenesis, through activation of the VEGF angiogenic pathway, and to an unfavorable prognosis. HIF-2alpha accumulation is associated with increased expression of the angiogenic factor TP. |
| spellingShingle | Sivridis, E Giatromanolaki, A Gatter, K Harris, A Koukourakis, M Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma. |
| title | Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma. |
| title_full | Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma. |
| title_fullStr | Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma. |
| title_full_unstemmed | Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma. |
| title_short | Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma. |
| title_sort | association of hypoxia inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma |
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