An Up-to-Date Anti-Cancer Treatment Strategy Focusing on HIF-1.ALPHA. Suppression: Its Application for Refractory Ovarian Cancer

Fujita, Mariko; Yasuda, Masanori; Kitatani, Kanae; Miyazawa, Masaki; Hirabayashi, Kenichi; Takekoshi, Susumu; Iida, Takuya; Hirasawa, Takeshi; Murakami, Masaru; Mikami, Mikio; Ishiwata, Isamu; Shimizu, Michio; Osamura, R. Yoshiyuki

doi:10.1267/ahc.07024

Cited by 14 publications

(16 citation statements)

References 23 publications

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“…Together with the fact that ovarian cancers have been reported to overexpress HIF-1α and HIF-1 protein-coding target genes, it was plausible to predict that ovarian cancers would also overexpress miR-210 as a potential oncogene. 35,36 The opposite, however, turned out to be true. Ovarian cancers demonstrate deletions and reduced expression of miR-210 when compared to healthy donors, evidence that supports a tumor suppressor role for miR-210.…”

Section: Hypoxic Regulation Of Mir-210mentioning

confidence: 94%

Hypoxic regulation of miR-210: Shrinking targets expand HIF-1’s Influence

Corn

2008

Cancer Biology & Therapy

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Section: Hypoxic Regulation Of Mir-210mentioning

confidence: 94%

Hypoxic regulation of miR-210: Shrinking targets expand HIF-1’s Influence

Corn

2008

Cancer Biology & Therapy

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“…16 Because it promotes malignant transformation and development of histological tumor characteristics 7 including angiogenesis, 16 inhibition of Glut-1 is currently being evaluated as a therapeutic strategy. 15,17 Cantuaria et al studied the IHC expression of Glut-1 in 113 primary ovarian carcinomas. 18 Glut-1 was more frequently expressed in the poorly differentiated tumors compared with the more differentiated counterparts.…”

Section: Recently Kurman Et Al Proposed a New Classification Ofmentioning

confidence: 99%

Molecular typing of epithelial ovarian carcinomas using inflammatory markers

Ali-Fehmi

Semaan

Sethi

et al. 2010

Cancer

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BACKGROUND: Ovarian epithelial carcinomas have recently been classified as slow growing type I tumors and rapidly growing highly aggressive type II tumors. The present study sought to molecularly characterize type I and II tumors using known molecular markers. METHODS: Specimens from 213 patients with ovarian carcinoma were categorized as type I or type II, and evaluated by immunohistochemistry for the inflammatory markers glucose transporter protein-1 (Glut-1), inducible nitric oxide synthase (iNOS), cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and nuclear factor kappa B. Statistical analysis was performed to investigate whether these molecular markers could distinguish between type I and type II tumors. Kaplan-Meier survival curves and COX regression analysis were used to determine the prognostic effect of these markers on survival in the 2 types of tumors. RESULTS: Overexpression of COX-1, COX-2, iNOS, and Glut-1 was significantly higher in type II tumors (P < .05). Women with type II tumors had a poorer median survival (60 months) as compared with those with type I tumors (141 months) (P ¼.0001). Multivariate analysis revealed type II tumors, late stage, and age >60 years as significant predictors of poor survival. For type II tumors, median survival of patients with tumors overexpressing COX-2 was 44 compared with 85 months for those with tumors with low COX-2 expression (P ¼.029). Looking at both type I and II tumors, the number of markers simultaneously overexpressed in each tumor was a significant predictor of poor patient survival (P ¼.005). CONCLUSIONS: The present study demonstrates that the new proposed histologic classification of ovarian epithelial carcinomas correlates with a distinct expression of inflammatory pathway proteins. High expression of these markers may explain the different biologic behavior of these 2 tumor types and provide targets for therapy. Cancer 2011;117:301-9.

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“…13,16,17 In our studies so far, HIF-1a expression profiles differed to some extent depending on the histological type of the ovarian carcinoma, 20,21 and the decrease in expression of HIF-1a and VEGF was demonstrated in the rapamycin-treated cell line from refractory CLA. 22 These results motivated us to clarify the status of HIF-1a-related factors in ovarian carcinomas and explore the clinicopathological significance of HIF-1a inhibition from the point view of anti-cancer therapy. In the present study using surgical specimens, CLA was found to be characterized by overexpression of HIF-1a in the nucleus and also aberrant activation of the mTOR signaling pathway, compared to SEA.…”

mentioning

confidence: 99%

Therapeutic strategy targeting the mTOR–HIF‐1α–VEGF pathway in ovarian clear cell adenocarcinoma

Miyazawa¹,

Yasuda

Fujita³

et al. 2008

Pathology International

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Malignant tumors usually involve a relatively hypoxic state, which induces overexpression of hypoxia-inducible factor-1alpha (HIF-1alpha) to satisfactorily enable the tumor to survive. Thus, inhibition of the mammalian target of rapamycin (mTOR) pathway including HIF-1alpha is expected to play a major role in suppression of tumor cell growth, having recently drawn much attention as an anti-cancer therapeutic strategy for various malignant tumors. In the present study, which compared clear cell adenocarcinoma (CLA) of the ovary with serous adenocarcinoma (SEA), the immunohistochemical expression of mTOR, phosphorylated-mTOR (p-mTOR), HIF-1alpha, and vascular endothelial growth factor (VEGF) was examined in surgically resected specimens of 29 SEA and 47 CLA. There were no significant differences in expression of mTOR, HIF-1alpha and VEGF between SEA and CLA, but it was noted that p-mTOR expression was more prominent in CLA than SEA. Then, using the cell lines of CLA (RMG-1 and W3uF), an experimental study was designed to clarify whether tumor suppression due to downregulation of mTOR activity could represent a promising therapeutic strategy for CLA. After treatment of an analogue of rapamycin (everolimus), expression of mTOR, p-mTOR, HIF-1alpha and VEGF was examined on western blot. As a result, although mTOR expression remained unchangeable, expression of p-mTOR, HIF-1alpha and VEGF was shown to be sharply depressed. The same expression alterations were demonstrated in the xenograft model treated with everolimus. In conclusion, mTOR-targeted therapy through usage of drugs such as everolimus may be more effective for CLA of the ovary because of its significant expression of p-mTOR.

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An Up-to-Date Anti-Cancer Treatment Strategy Focusing on HIF-1.ALPHA. Suppression: Its Application for Refractory Ovarian Cancer

Cited by 14 publications

References 23 publications

Hypoxic regulation of miR-210: Shrinking targets expand HIF-1’s Influence

Hypoxic regulation of miR-210: Shrinking targets expand HIF-1’s Influence

Molecular typing of epithelial ovarian carcinomas using inflammatory markers

Therapeutic strategy targeting the mTOR–HIF‐1α–VEGF pathway in ovarian clear cell adenocarcinoma

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