The accumulating evidence that erythropoietin and erythropoietin receptor are expressed in various non-haematopoietic organs suggests that erythropoietin signalling might be involved in the growth of tumours, but this possibility has never been examined. We found that mRNAs for erythropoietin and erythropoietin receptor are expressed in malignant tumours of female reproductive organs, where erythropoietin levels are higher than in normal tissues. Furthermore, tumour cells and capillary endothelium showed erythropoietin receptor immunoreactivity. To investigate the role of the erythropoietin/erythropoietin receptor pathway in these tumours, we injected mouse monoclonal antibody against erythropoietin or the soluble form of erythropoietin receptor into blocks of tumour specimens and cultured the blocks. After 12 h of injections, these blocks were examined and compared with control blocks injected with mouse monoclonal antibody, heat denatured soluble form of erythropoietin receptor, mouse serum or saline. Tumour cells and capillaries were markedly decreased in a dose-dependent manner after either injection. A marked increase of the cells containing fragmented DNA and the histopathological characteristics of these cells suggest that the decrease in tumour cells and capillary endothelial cells was due to apoptotic cell death. The co-existence of JAK2 and phosphorylated-JAK2, and STAT5 and phosphorylated STAT5, all of which are involved in the mitogenic signalling of erythropoietin, was found frequently in tumour cells and capillary endothelial cells in the untreated blocks. In contrast, most of the phosphorylated-JAK2- or phosphorylated-STAT5-positive cells had disappeared in the experimental blocks. Moreover, reduced tyrosine phosphorylation of STAT5 in the experimental blocks was confirmed by western blotting analysis. The results strongly indicate that erythropoietin signalling contributes to the growth and/or survival of both transformed cells and capillary endothelial cells in these tumours. Thus, deprivation of erythropoietin signalling may be a useful therapy for erythropoietin-producing malignant tumours.

SummaryWe assessed the therapeutic significance of systematic aortic and pelvic lymphadenectomy followed by adjuvant therapy in nodepositive endometrial carcinoma. Among 173 stage lll patients, 30 (17%) had positive nodes: ten in the pelvic region alone (group P) and 20 in the aortic region alone or in both regions (group A). The adjuvant therapy was administered as follows: subjects in group P received 50 Gy pelvic radiation, including three post-surgical T3 (pT3) patients who received either one or three cycles of cisplatin-based chemotherapy before radiation. Subjects in group A were given three cycles of chemotherapy followed by 50 Gy pelvic and 50 Gy extended field periaortic radiation using a four-field or conformational technique. Five-year survival was 95% for 143 patients with negative nodes and 84% for 30 patients with positive nodes (100% for group P and 75% for group A). In group A, 5-year survival was 38% for eight patients with both pT3 and histology other than endometrioid type Gl, and 91% for the remaining 12 patients. Either way, both group P and group A patients had a better prognosis than previously reported. In summary, aortic and pelvic lymphadenectomy and subsequent chemotherapy and radiation therapy based on node status seem to improve the survival of endometrial cancer patients with positive nodes.

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