Granulosa cell tumor with activated mTOR‐HIF‐1α‐VEGF pathway

Abstract

The DNA-binding activity of hypoxia-inducible factor-1 alpha (HIF-1alpha) has been analyzed for various gynecological tumors. Among the tumors that were studied, there was a finding of a high level of DNA-binding HIF-1alpha activity, although it was limited to one case of adult type granulosa cell tumor (GCT). In this case a 60-year-old female had marked immunohistochemical expression of HIF-1alpha. The expressions of the mammalian target of rapamycin (mTOR) and phosphorylated-mTOR (p-mTOR) were also marked, and vascular endothelial growth factor (VEGF) was moderately expressed. To compare the expression profiles, 11 consecutive cases with adult type GCT were used. All cases showed marked expressions of HIF-1alpha and mTOR, but p-mTOR expression was moderately to markedly observed in four of the 12 cases. VEGF was expressed in all cases in varying degrees. Based on the evidence that downregulation of the mTOR pathway due to treatment with rapamycin (everolimus) would suppress tumor cell growth, an experimental study using the GCT cell line was designed to clarify whether HIF-1alpha and VEGF expressions decline. As a result, the expressions of p-mTOR, HIF-1alpha and VEGF were suppressed, but those of mTOR were not. It was concluded that mTOR-targeted therapy may represent a promising strategy for some GCT with an activated mTOR-HIF-1alpha-VEGF pathway.

Expression of hypoxia-inducible factor-1α during ovarian follicular growth and development in Sprague-Dawley rats

“…Furthermore, HIF-1α antagonism may allow for the development of novel treatments for fertility control for some types of ovarian dysfunction such as polycystic ovarian syndrome, ovarian hyperstimulation syndrome, and ovarian neoplasia (Galanis et al, 2008;Miyazawa et al, 2009Miyazawa et al, , 2010Seeber et al, 2011;Zhang et al, 2012b;Wang et al, 2012).…”

Expression and contribution of the HIF‑1α/VEGF signaling pathway to luteal development and function in pregnant rats

“…This HIF-1α-mediated expression of VEGF may be an important mechanism regulating luteal development and function in the mammalian ovary. HIF-1α antagonism may be useful for the development of novel treatments for fertility control and for certain types of ovarian dysfunction (11,43,46), particularly those conditions characterized by pathological angiogenesis and excessive vascular permeability, including polycystic ovarian syndrome, ovarian hyperstimulation syndrome and ovarian neoplasia.…”

“…HIF-1, a helix-loop-helix transcriptional factor, which consists of HIF-1α and HIF-1β, has been cloned and characterized as a transcriptional activator of several oxygen-sensitive genes, including erythropoietin, heme oxygenases, transferrin and several glycolytic enzymes (27)(28)(29)40), whose protein products are important in developmental and physiological processes, including angiogenesis, erythropoiesis, glycolysis, iron transport and cell proliferation/survival (2,5,11,(41)(42)(43). It has been reported that HIF-1α protein is inducible by a decrease of O 2 concentration in tissue or cells.…”

“…The ruptured follicle, which occurs immediately following ovulation is considered to be under hypoxia conditions due to bleeding and immature vasculature (6). Previous studies have indicated that hypoxia is important for establishing the vascular system during luteal development (5), which induces the expression of hypoxia-inducible factor (HIF)-1α in luteal cells (7)(8)(9)(10)(11). When vascular endothelial factor (VEGF) is regulated by hypoxia, there is an upregulation of specific transcription factors, notably HIF-1α (7,8,12).…”

Effects of pantoprazole as a HIF-1α inhibitor on human gastric adenocarcinoma sgc-7901 cells

“…However, whether HIF-1α is able to promote or inhibit tumor growth remains controversial. Between the two opponent points of view, one is that HIF-1α is a positive factor in tumor growth, and its positive adjustment effect seems to be achieved by the expression of VEGF [16][17][18]; on the contrary, a slice of experiments elucidate that HIF-1α may inhibit tumor growth through its capacity of association with p53, which is a mediator of genotoxic apoptosis [19,20]. Our conclusions based on this study seem to be more supportive of the former, which is HIF-1α can promote tumor growth, in spite of absence of detecting VEGF.…”