Melatonin Reduces Angiogenesis in Serous Papillary Ovarian Carcinoma of Ethanol-Preferring Rats.

Angiogenesis is a hallmark of ovarian cancer (OC); the ingrowth of blood vessels promotes rapid cell growth and the associated metastasis. Melatonin is a well-characterized indoleamine that possesses important anti-angiogenic properties in a set of aggressive solid tumors. Herein, we evaluated the role of melatonin therapy on the angiogenic signaling pathway in OC of an ethanol-preferring rat model that mimics the same pathophysiological conditions occurring in women. OC was chemically induced with a single injection of 7,12-dimethylbenz(a)anthracene (DMBA) under the ovarian bursa. After the rats developed serous papillary OC, half of the animals received intraperitoneal injections of melatonin (200 µg/100 g body weight/day) for 60 days. Melatonin-treated animals showed a significant reduction in OC size and microvessel density. Serum levels of melatonin were higher following therapy, and the expression of its receptor MT1 was significantly increased in OC-bearing rats, regardless of ethanol intake. TGFß1, a transforming growth factor-beta1, was reduced only after melatonin treatment. Importantly, vascular endothelial growth factor (VEGF) was severely reduced after melatonin therapy in animals given or not given ethanol. Conversely, the levels of VEGF receptor 1 (VEGFR1) was diminished after ethanol consumption, regardless of melatonin therapy, and VEGFR2 was only reduced following melatonin. Hypoxia-inducible factor (HIF)-1α was augmented with ethanol consumption, and, notably, melatonin significantly reduced their levels. Collectively, our results suggest that melatonin attenuates angiogenesis in OC in an animal model of ethanol consumption; this provides a possible complementary therapeutic opportunity for concurrent OC chemotherapy.

Angiogenesis in endometrial carcinoma: correlation with survival and clinicopathologic risk factors.

Association among angiogenesis, survival and clinicopathologic parameters in endometrial carcinoma was evaluated. Sixty patients who had been diagnosed as endometrial carcinoma, from 1993 to 1998, were included in the study. All patients had been surgically staged with bilateral pelvic and para-aortic lymph node dissection. All hysterectomy specimens were stained immunohistologically for factor VIII-related antigen. The area with the most intensified microvasculature was determined under low-power (x100) magnification, and the microvessel count of this area under high-power (x200) magnification was determined as the microvessel density (MVD) of the tumor. The mean MVD was 26.2 +/- 13.0 (range 6-68), and it was considered as high (n = 24; 40%), moderate (n = 19; 31.7%) and low (n = 17; 28.3%) when the MVD was >30, between 15-30 and <15, respectively. Statistical analysis included Mann-Whitney, Kruskal-Wallis and Spearman rank correlation tests. The Kaplan-Meier method was used to evaluate the difference between angiogenesis and survival. Multivariate analysis with the Cox regression model was used in MVD values and different clinicopathological parameters. There was positive correlation between MVD increase and surgicopathological stage (p < 0.05). A significant difference was seen between MVD increase and lymph node metastasis (p < 0.05). There were no differences between MVD and age, histological type, grade and lymphovascular invasion. MVD did not change in association with myometrial invasion depth. There was a significant difference in means of survival between the low and high MVD groups (p = 0.01). However, MVD was not an independent prognostic factor in multivariate analysis. Increased angiogenesis was found to be associated with advanced stage and decreased survival in endometrial carcinoma.

Tumor angiogenesis and thymidine phosphorylase expression in ovarian carcinomas including serous surface papillary adenocarcinoma of the peritoneum.

To clarify biological and clinical significance of tumor angiogenesis in the development of ovarian carcinoma, we investigated the relationship between tumor vascularity, the expression of thymidine phosphorylase (dThdPase), which is an angiogenic factor identical to platelet-derived endothelial cell growth factor (PD-ECGF), and patient outcome in ovarian carcinoma, including serous surface papillary carcinoma (SSPC). Primary tumor specimens (stages I-IV) from 54 patients were examined. Intratumoral microvessel density (IMVD) and dThdPase expression were evaluated immunohistochemically using anti-CD34 and anti-dThdPase antibodies, and results were correlated with clinicopathologic parameters and prognosis. IMVD for the 54 tumors ranged from 22.5 to 120.7 (number/0.73686 mm2/field). Twenty-three tumors were positive, and 31 tumors were negative for dThdPase expression. IMVD positively correlated with the expression of dThdPase (p < 0.01), tumor size, and peritoneal metastases (p < 0.05). However, there was no statistical correlation between IMVD, dThdPase expression, and clinical outcome. Of the 54 patients examined, 30 were diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV primary ovarian carcinoma, and 9 were diagnosed with SSPC. There were no significant differences between the two groups with respect to clinicopathologic features, IMVD, dThdPase expression, or patient outcome. In conclusion, angiogenic activity may be necessary for the growth of metastatic implants in ovarian carcinoma and SSPC.

Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in endometrial carcinoma.

BACKGROUND: Solid tumors, including endometrial carcinomas, must induce a vascular stroma to grow beyond a minimal size. The mechanisms responsible for angiogenesis in endometrial carcinoma, however, are not well defined. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a multifunctional cytokine that is an important regulator of tumor angiogenesis. We evaluated VPF/VEGF mRNA and protein expression, as well as VPF/VEGF receptor mRNA expression, in endometrial carcinoma. METHODS: Fourteen examples of endometrial carcinoma were evaluated by in situ hybridization; in 7 cases, benign atrophic endometrium from the same patient was also examined. Histologic sections were subjected to in situ hybridization using 35S-labeled riboprobes specific for VPF/VEGF and, in a subset of cases, riboprobes specific for the VPF/VEGF receptors flt-1 and KDR. In addition, ten examples of endometrial carcinoma were evaluated for VPE/VEGF protein expression by immunohistochemistry. RESULTS: All 14 examples of endometrial carcinoma studied by in situ hybridization exhibited focal strong VPF/VEGF mRNA expression by tumor cells. In addition, the endothelial cells of surrounding microvessels strongly expressed flt-1 and KDR mRNAs in all ten cases examined. In contrast, no strong expression of VPF/VEGF, flt-1, or KDR mRNA was observed in the seven examples of benign atrophic endometrium studied. All ten cases of endometrial carcinoma studied by immunohistochemistry exhibited strong VPF/VEGF protein expression by tumor cells. CONCLUSIONS: These observations suggest that VPF/VEGF is an important angiogenic factor in endometrial carcinoma.

Papillary cystic neoplasm of the pancreas: radiological findings.

We report a series of 10 papillary cystic neoplasms of the pancreas evaluated in our institution. The lesions are analyzed in retrospect to define the existence of eventual specific imaging patterns as well as to point out the existing problems of differential diagnosis versus other pancreatic tumors.

Papillary cystic neoplasm of the pancreas: radiological findings.

We report a series of 10 papillary cystic neoplasms of the pancreas evaluated in our institution. The lesions are analyzed in retrospect to define the existence of eventual specific imaging patterns as well as to point out the existing problems of differential diagnosis versus other pancreatic tumors.