title: Therapeutic strategy targeting the mTOR-HIF-1alpha-VEGF pathway in ovarian clear cell adenocarcinoma.
abstract: 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.
authors.affiliation: Department of Pathology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyazawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Yasuda
authors.forename: Mariko
authors.initials: M
authors.lastname: Fujita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kajiwara
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hirabayashi
authors.forename: Susumu
authors.initials: S
authors.lastname: Takekoshi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirasawa
authors.forename: Masaru
authors.initials: M
authors.lastname: Murakami
authors.forename: Naoki
authors.initials: N
authors.lastname: Ogane
authors.forename: Kazushige
authors.initials: K
authors.lastname: Kiguchi
authors.forename: Isamu
authors.initials: I
authors.lastname: Ishiwata
authors.forename: Mikio
authors.initials: M
authors.lastname: Mikami
authors.forename: R Yoshiyuki
authors.initials: RY
authors.lastname: Osamura
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D000068338:Everolimus; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000187:drug effects; D007150:Immunohistochemistry; D051379:Mice; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000096:biosynthesis* / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus