Therapeutic strategy targeting the mTOR-HIF-1alpha-VEGF pathway in ovarian clear cell adenocarcinoma.
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.
Miyazawa
Masaki
M
Department of Pathology, Tokai University School of Medicine, Isehara, Japan.
Yasuda
Masanori
M
Fujita
Mariko
M
Kajiwara
Hiroshi
H
Hirabayashi
Kenichi
K
Takekoshi
Susumu
S
Hirasawa
Takeshi
T
Murakami
Masaru
M
Ogane
Naoki
N
Kiguchi
Kazushige
K
Ishiwata
Isamu
I
Mikami
Mikio
M
Osamura
R Yoshiyuki
RY
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
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