Evaluation of estrogen receptor expression in low-grade and high-grade astrocytomas

Tavares, Cléciton Braga; Braga, Francisca das Chagas Sheyla Almeida Gomes; Sousa, Emerson Brandão; Borges, Umbelina Soares; Escórcio-Dourado, Carla Solange; Silva‐Sampaio, João Paulo da; Silva, Benedito Borges da

doi:10.1590/1806-9282.64.12.1129

Cited by 6 publications

(5 citation statements)

References 16 publications

(10 reference statements)

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“…Based on our present findings, we formulated the idea that the inhibitory effect of LOS on the EMT process in GBM cells may also be indirectly reinforced by its inhibitory action on local estrogen production [ 45 , 46 ]. Indeed, estradiol not only stimulates glioblastoma cell proliferation well-fitting with our present data [ 47 ] but also induces a change in cell morphology displaying an elongated cell phenotype correlated with actin filaments rearrangements, together with an increase of cell migration, invasion, and upregulation of EMT markers such as Vimentin and N-Cadherin in GBM cell lines [ 47 , 48 , 49 , 50 ].…”

Section: Discussionsupporting

confidence: 83%

Novel Insights into the Antagonistic Effects of Losartan against Angiotensin II/AGTR1 Signaling in Glioblastoma Cells

Panza

Malivindi

Caruso

et al. 2021

Cancers

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New avenues for glioblastoma therapy are required due to the limited mortality benefit of the current treatments. The renin-angiotensin system (RAS) exhibits local actions and works as a paracrine system in different tissues and tumors, including glioma. The glioblastoma cell lines U-87 MG and T98G overexpresses Angiotensin II (Ang II)/Angiotensin II type I receptor (AGTR1) signaling, which enhances in vitro and in vivo local estrogen production through a direct up-regulation of the aromatase gene promoters p I.f and p I.4. In addition, Ang II/AGTR1 signaling transactivates estrogen receptor-α in a ligand-independent manner through mitogen-activated protein kinase (MAPK) activation. The higher aromatase mRNA expression in patients with glioblastoma was associated with the worst survival prognostic, according to The Cancer Genome Atlas (TCGA). An intrinsic immunosuppressive glioblastoma tumor milieu has been previously documented. We demonstrate how Ang II treatment in glioblastoma cells increases programmed death-ligand 1 (PD-L1) expression reversed by combined exposure to Losartan (LOS) in vitro and in vivo. Our findings highlight how LOS, in addition, antagonizes the previously documented neoangiogenetic, profibrotic, and immunosuppressive effects of Ang II and drastically inhibits its stimulatory effects on local estrogen production, sustaining glioblastoma cell growth. Thus, Losartan may represent an adjuvant pharmacological tool to be repurposed prospectively for glioblastoma treatment.

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Section: Discussionsupporting

confidence: 83%

Novel Insights into the Antagonistic Effects of Losartan against Angiotensin II/AGTR1 Signaling in Glioblastoma Cells

Panza

Malivindi

Caruso

et al. 2021

Cancers

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“…Both ER subtypes are predominantly expressed through healthy CNS; however, in human astrocytomas, both ER-α [ 45 , 47 , 48 , 49 ] and ER-β [ 44 ] expression decreases as the grade of tumor malignancy increases. Therefore, different researchers have proposed that ER expression may be reduced or lost during tumor development, although it is not clear if this represents a cause or consequence of tumor development.…”

Section: Discussionmentioning

confidence: 99%

“…ER expression status in GBM is controversial. Some studies have reported the absence of ER in GBM [ 40 , 41 ], while other researchers have determined that ER expression varies according to malignancy degree, suggesting that these receptors are involved in GBM malignant progression [ 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. ER subtypes have shown different effects in GBMs.…”

Section: Introductionmentioning

confidence: 99%

Estradiol Induces Epithelial to Mesenchymal Transition of Human Glioblastoma Cells

Hernández-Vega

Moral-Morales

Zamora-Sánchez

et al. 2020

Cells

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The mesenchymal phenotype of glioblastoma multiforme (GBM), the most frequent and malignant brain tumor, is associated with the worst prognosis. The epithelial–mesenchymal transition (EMT) is a cell plasticity mechanism involved in GBM malignancy. In this study, we determined 17β-estradiol (E2)-induced EMT by changes in cell morphology, expression of EMT markers, and cell migration and invasion assays in human GBM-derived cell lines. E2 (10 nM) modified the shape and size of GBM cells due to a reorganization of actin filaments. We evaluated EMT markers expression by RT-qPCR, Western blot, and immunofluorescence.We found that E2 upregulated the expression of the mesenchymal markers, vimentin, and N-cadherin. Scratch and transwell assays showed that E2 increased migration and invasion of GBM cells. The estrogen receptor-α (ER-α)-selective agonist 4,4’,4’’-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT, 10 nM) affected similarly to E2 in terms of the expression of EMT markers and cell migration, and the treatment with the ER-α antagonist methyl-piperidino-pyrazole (MPP, 1 μM) blocked E2 and PPT effects. ER-β-selective agonist diarylpropionitrile (DNP, 10 nM) and antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazole[1,5-a]pyrimidin-3-yl]phenol (PHTPP, 1 μM) showed no effects on EMT marker expression. These data suggest that E2 induces EMT activation through ER-α in human GBM-derived cells.

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“…An immunohistochemical study of low-and high-grade astrocytomas sought to characterize the expression of ERα in these two groups using the NCL-ER-6F11 ERα antibody. The expression of ERα correlated with the grade of the tumor: unlike the low grades, the high grades no longer expressed ERα [103]. Conversely, two publications recently reported the high expression ERα36 in U87 and U251 GBM cell lines [104,105].…”

Section: Estrogen Receptors Complex and Interconnected Signaling Patmentioning

confidence: 95%

Astrocytoma: A Hormone-Sensitive Tumor?

Hirtz

Rech

Dubois-Pot-Schneider

et al. 2020

IJMS

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Astrocytomas and, in particular, their most severe form, glioblastoma, are the most aggressive primary brain tumors and those with the poorest vital prognosis. Standard treatment only slightly improves patient survival. Therefore, new therapies are needed. Very few risk factors have been clearly identified but many epidemiological studies have reported a higher incidence in men than women with a sex ratio of 1:4. Based on these observations, it has been proposed that the neurosteroids and especially the estrogens found in higher concentrations in women’s brains could, in part, explain this difference. Estrogens can bind to nuclear or membrane receptors and potentially stimulate many different interconnected signaling pathways. The study of these receptors is even more complex since many isoforms are produced from each estrogen receptor encoding gene through alternative promoter usage or splicing, with each of them potentially having a specific role in the cell. The purpose of this review is to discuss recent data supporting the involvement of steroids during gliomagenesis and to focus on the potential neuroprotective role as well as the mechanisms of action of estrogens in gliomas.

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Evaluation of estrogen receptor expression in low-grade and high-grade astrocytomas

Cited by 6 publications

References 16 publications

Novel Insights into the Antagonistic Effects of Losartan against Angiotensin II/AGTR1 Signaling in Glioblastoma Cells

Novel Insights into the Antagonistic Effects of Losartan against Angiotensin II/AGTR1 Signaling in Glioblastoma Cells

Estradiol Induces Epithelial to Mesenchymal Transition of Human Glioblastoma Cells

Astrocytoma: A Hormone-Sensitive Tumor?

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