Heparanase expression in endometrial cancer: analysis of immunohistochemistry.

The human enzyme heparanase has been shown to function in tumour progression, metastatic spread and tumour angiogenesis. The aim of the present study was to assess heparanase expression assessed by immunohistochemical staining (IHC) in endometrial cancer in correlation with clinicopathological factors. A total of 52 endometrial cancers were obtained from previously untreated patients (median age, 56 years, range, 35-80 years). The expression of heparanase was evaluated by using IHC with anti-heparanase polyclonal antibody. This antibody was raised by immunising a rabbit with a peptide containing the amino acid residues from 238 to 250 of the heparanase. The IHC data were used to determine the relationship between heparanase expression, and clinicopathological parameters. IHC showed that the heparanase was expressed in 23 of 52 (44.2%) endometrial cancers. Heparanase was abundantly and equally expressed in both the cytoplasm and the cell membrane of the cells in endometrial cancer. Strong heparanase-positive staining was also seen at the invasive front of the tumour into myometrium. The expression was significantly related to lymph-vascular space involvement (p = 0.0028), depth of myometrial invasion (p = 0.0026), and histological tumour grade (p = 0.0135). In six tumours with positive lymph nodes, the heparanase expression was observed as being higher compared with tumours with negative lymph nodes, which was not significant (p = 0.2349). In terms of peritoneal cytology, ovarian metastasis, and cervical invasion, we observed no significant difference in the heparanase expression assessed by IHC. These results suggest that the expression of heparanase may promote tumour invasion into myometrium and lymph vascular space in endometrial cancer.

Neoadjuvant chemotherapy followed by extended-field concurrent chemoradiotherapy in squamous cell carcinoma of the cervix with positive paraaortic lymph nodes: two cases.

PURPOSE: To report the feasibility of neoadjuvant chemotherapy (NAC) followed by extended-field concurrent chemoradiotherapy (EF-CCRT) for squamous cell carcinoma of the cervix (CC) with paraaortic lymph node (PAN) metastasis. METHODS: Two patients were diagnosed with CC with positive PAN, and received two courses of cisplatin (120 mg/m2) in a neoadjuvant setting. They then received extended-field, external-beam radiotherapy (50.4 Gy) followed by intracavitary brachytherapy concurrently with cisplatin (20 mg/m2 x 5 days) at 21-day intervals. RESULTS: EF-CCRT was interrupted in one patient for five days because of grade 4 neutropenia. No severe late toxicities were observed. The two patients are alive with no evidence of recurrence at present. CONCLUSIONS: NAC followed by EF-CCRT is feasible and may improve the survival outcome of patients with CC with positive PAN.

Recurrent juvenile granulosa cell tumor of the ovary managed by palliative radiotherapy.

Prognosis in the few patients with advanced-stage juvenile granulosa cell tumor (JGCT) of the ovary has traditionally been unfavorable. We report a recurrent JGCT patient managed by palliative radiotherapy. A 37-year-old woman with recurrent JGCT received a combination of paclitaxel-carboplatin chemotherapy and then single-agent docetaxel, but her disease progressed with multiple abdominal masses and ascites. We chose palliative radiation therapy to relieve her complaints. Whole-abdominal external beam radiotherapy with pelvic boost was delivered. She tolerated the treatment well. After the completion of radiotherapy, ultrasonography showed shrinkage of the tumor, and the ascites disappeared. We should consider using radiation therapy in a palliative setting for such patients with recurrent JGCT suffering from abdominal complaints.

TGF-beta attenuates the transactivation activity of Ets-1 despite its induction via the inhibition of DNA binding.

We examined whether TGF-fl affects the transactivation activity of Ets-1. TGF-beta augmented ets-1 mRNA expression and Ets-1 protein synthesis in ECV304 cells to the level equivalent to bFGF. When the DNA binding activity of Ets-1 protein was examined, bFGF was found to enhance DNA-Ets complex formation, whereas TGF-beta attenuated basal as well as bFGF-enhanced DNA-Ets complex formation. As a result, TGF-beta attenuated the promoter activity driven by Ets-1. The DNA binding of Ets-1 protein was enhanced by the initial 4-hour bFGF treatment and the subsequent 8-hour cycloheximide treatment. When TGF-beta replaced cycloheximide in the subsequent 8-hour treatment, TGF-beta inhibited this bFGF-enhanced DNA-Ets complex formation. When TGF-beta and cycloheximide were simultaneously added in the subsequent 8-hour treatment, the inhibitory effect of TGF-beta on bFGF-enhanced DNA-Ets complex formation was completely abolished. These results suggest the possibility that TGF-beta attenuates the transactivation activity of Ets-1 by inducing a protein that interferes with the binding of Ets-1 to the DNA binding site.

Role of transcription factor Ets-1 in the apoptosis of human vascular endothelial cells.

Transcription factor Ets-1 is induced in endothelial cells (ECs) by angiogenic factors, and promotes angiogenesis by inducing angiogenesis-related genes such as MMPs and integrin beta3. Here, we examined the effect of Ets-1 on apoptosis in ECs. Overexpression of Ets-1 in human umbilical vein endothelial cells (HUVECs) induced apoptosis under the serum-deprived condition. VEGF inhibited apoptosis and augmented the DNA binding of Ets-1 in HUVECs. The inhibition of transcriptional activity of endogenous Ets-1 by a dominant negative molecule intensified the anti-apoptotic effect of VEGF. Caspase inhibitors blocked apoptosis of HUVECs induced by Ets-1. DNA array analysis showed that Ets-1 up-regulated pro-apoptotic genes such as Bid, cytochrome p450, caspase-4, p27, and p21 more than 2 fold, and down-regualted anti-apoptotic genes such as DAD-1, AXL, Cox-2, IAP-2, and MDM-2 less than 0.5 fold in HUVECs. These results indicate that Ets-1 itself is pro-apoptotic to ECs by modulating the expression of apoptosis-related genes.

Role of transcription factors in angiogenesis: Ets-1 promotes angiogenesis as well as endothelial apoptosis.

Angiogenesis is a complex phenomenon that requires at least migration, proliferation, and tubular morphogenesis of endothelial cells (ECs). Some genes are expressed in ECs during these processes, and therefore the regulation of gene expression in ECs is critical. Increasing evidence suggests that the Ets family of transcription factors plays an important role in angiogenesis. We observed that Ets-1, a prototype of the Ets family of transcription factors, promoted angiogenesis by inducing the expression of matrix metalloproteinases and integrin beta3 in ECs, and the elimination of the transactivation activity of Ets-1 by a dominant negative molecule inhibited angiogenesis. Apoptosis, a term used to describe the terminal morphological and biochemical events seen in programmed cell death, is critical for the development or reconstitution of multicellular organs. Apoptosis of ECs is observed at the initiation of angiogenesis, at the branching or communication with newly formed vessels, and at the regression of neo-vessels. The Ets family of transcription factors is generally thought to be anti-apoptotic. However, there are conflicting reports on the role of Ets-1 in apoptosis. We examined the role of Ets-1 in apoptosis of ECs and found that Ets-1 was pro-apoptotic to ECs by modulating the expression of several apoptosis-related genes.

Hyperamylasemia associated with endometrioid carcinoma of the ovary: case report and immunohistochemical study.

Hyperamylasemia was noted in a patient with a stage I well-differentiated endometrioid adenocarcinoma of the ovary. Serum levels of amylase decreased rapidly after removal of the ovarian tumor. Immunohistochemical study revealed intracytoplasmic localization of amylase in many tumor cells. Although it was strongly suspected that the tumor cells had produced amylase in the present patient, further studies are required to be sure that amylase can be considered an important tumor marker for the endometrioid type of ovarian tumors.