Cellular senescence role in human pituitary neuroendocrine tumors
Cellular senescence emerges as an alternative response to stress. It is determined by cell arrest which allows cells to remain viable and to have an active metabolism. This barrier in tumorigenesis could explain the slow growth rate and benign characteristic of pituitary neuroendocrine tumors (...
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Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología
2022
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| Acceso en línea: | https://revistas.unc.edu.ar/index.php/med/article/view/39012 |
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I10-R327-article-39012 |
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Universidad Nacional de Córdoba |
| institution_str |
I-10 |
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R-327 |
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Revista de la Facultad de Ciencias Médicas de Córdoba |
| format |
Artículo revista |
| topic |
senescence somatotroph PitNet 8OhdG Nrf2 oxidative stress senescencia PitNet somatotropos 8OhdG Nrf2 estrés oxidativo |
| spellingShingle |
senescence somatotroph PitNet 8OhdG Nrf2 oxidative stress senescencia PitNet somatotropos 8OhdG Nrf2 estrés oxidativo Bertetti, C Fernández, S Bernhardt, C Pautasso, M Sosa, LDV Venier, AC Grondona, E De Paul, AL Cellular senescence role in human pituitary neuroendocrine tumors |
| topic_facet |
senescence somatotroph PitNet 8OhdG Nrf2 oxidative stress senescencia PitNet somatotropos 8OhdG Nrf2 estrés oxidativo |
| author |
Bertetti, C Fernández, S Bernhardt, C Pautasso, M Sosa, LDV Venier, AC Grondona, E De Paul, AL |
| author_facet |
Bertetti, C Fernández, S Bernhardt, C Pautasso, M Sosa, LDV Venier, AC Grondona, E De Paul, AL |
| author_sort |
Bertetti, C |
| title |
Cellular senescence role in human pituitary neuroendocrine tumors |
| title_short |
Cellular senescence role in human pituitary neuroendocrine tumors |
| title_full |
Cellular senescence role in human pituitary neuroendocrine tumors |
| title_fullStr |
Cellular senescence role in human pituitary neuroendocrine tumors |
| title_full_unstemmed |
Cellular senescence role in human pituitary neuroendocrine tumors |
| title_sort |
cellular senescence role in human pituitary neuroendocrine tumors |
| description |
Cellular senescence emerges as an alternative response to stress. It is determined by cell arrest which allows cells to remain viable and to have an active metabolism. This barrier in tumorigenesis could explain the slow growth rate and benign characteristic of pituitary neuroendocrine tumors (PitNET). We aimed to establish senescence's contribution, particularly the reactive response to oxidative stress, in human somatotroph PitNet.
Paraffin-embedded PitNet samples were analyzed. These belonged to both female and male patients (n=9) and were supplied by Clínica Universitaria Reina Fabiola (REPIS 3974) and Sanatorio Allende (Córdoba). We were also provided with clinical records and immunolabeling data for growth hormone (GH) and Ki-67. The expression of 8-hydroxy-2'-deoxyguanosine (8OhdG), marker of oxidative damage in DNA, along with Nuclear factor erythroid 2-related factor 2 (Nrf2), which indicates activation of antioxidant response, was detected by immunohistochemistry. Five randomly chosen fields were selected (400x) and 1.000 cells were counted for every sample. Data is expressed as percentages of positive cells for nuclear 8OdHG in relation to the total number of cells. The intensity of cytoplasmic Nrf2 expression was classified as weak/strong and focal/diffuse regarding its distribution. Statics analysis: T-Test (p<0.05) for 8OhdG and Kruskal Wallis (p<0.05) for Nrf2.
In PiNet with Ki-67<3 (n=7) and densely granulated GH distribution (less aggressive) the percentage of positive cells for 8OdhG was 14,3%. In sparsely granulated tumors with Ki-67>3 (n=2) (more aggressive), the percentage for this marker was 9.28% (p>0.05). At the same time, in the first group Nrf2's expression was mainly focal and weak; while in the second group Nrf2's expression was diffuse and strong (p>0.05).
These results may suggest that in somatotroph PitNet an heterogeneous response to cell stress exists. The build-up of oxidative damage in DNA combined with a low antioxidant response could be the first signal to trigger senescence, which could explain the lower proliferative rate that these tumors have. Likewise, we speculate that higher expression of Nrf2 could counteract oxidative processes, enabling proliferation and promoting tumoral evolution.
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| publisher |
Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología |
| publishDate |
2022 |
| url |
https://revistas.unc.edu.ar/index.php/med/article/view/39012 |
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I10-R327-article-390122024-04-15T16:14:45Z Cellular senescence role in human pituitary neuroendocrine tumors Participación de la senescencia celular en tumores neuroendócrinos hipofisarios humanos Bertetti, C Fernández, S Bernhardt, C Pautasso, M Sosa, LDV Venier, AC Grondona, E De Paul, AL senescence somatotroph PitNet 8OhdG Nrf2 oxidative stress senescencia PitNet somatotropos 8OhdG Nrf2 estrés oxidativo Cellular senescence emerges as an alternative response to stress. It is determined by cell arrest which allows cells to remain viable and to have an active metabolism. This barrier in tumorigenesis could explain the slow growth rate and benign characteristic of pituitary neuroendocrine tumors (PitNET). We aimed to establish senescence's contribution, particularly the reactive response to oxidative stress, in human somatotroph PitNet. Paraffin-embedded PitNet samples were analyzed. These belonged to both female and male patients (n=9) and were supplied by Clínica Universitaria Reina Fabiola (REPIS 3974) and Sanatorio Allende (Córdoba). We were also provided with clinical records and immunolabeling data for growth hormone (GH) and Ki-67. The expression of 8-hydroxy-2'-deoxyguanosine (8OhdG), marker of oxidative damage in DNA, along with Nuclear factor erythroid 2-related factor 2 (Nrf2), which indicates activation of antioxidant response, was detected by immunohistochemistry. Five randomly chosen fields were selected (400x) and 1.000 cells were counted for every sample. Data is expressed as percentages of positive cells for nuclear 8OdHG in relation to the total number of cells. The intensity of cytoplasmic Nrf2 expression was classified as weak/strong and focal/diffuse regarding its distribution. Statics analysis: T-Test (p<0.05) for 8OhdG and Kruskal Wallis (p<0.05) for Nrf2. In PiNet with Ki-67<3 (n=7) and densely granulated GH distribution (less aggressive) the percentage of positive cells for 8OdhG was 14,3%. In sparsely granulated tumors with Ki-67>3 (n=2) (more aggressive), the percentage for this marker was 9.28% (p>0.05). At the same time, in the first group Nrf2's expression was mainly focal and weak; while in the second group Nrf2's expression was diffuse and strong (p>0.05). These results may suggest that in somatotroph PitNet an heterogeneous response to cell stress exists. The build-up of oxidative damage in DNA combined with a low antioxidant response could be the first signal to trigger senescence, which could explain the lower proliferative rate that these tumors have. Likewise, we speculate that higher expression of Nrf2 could counteract oxidative processes, enabling proliferation and promoting tumoral evolution. La senescencia celular emerge como una respuesta alternativa al estrés, determinada por el arresto estable del ciclo celular en el cual las células permanecen viables y metabólicamente activas. Esta barrera en la tumorigénesis explicaría el crecimiento lento y benignidad de los tumores neuroendócrinos hipofisarios (PitNet). Nos propusimos determinar la contribución de la senescencia, particularmente la activación de la respuesta al estrés oxidativo, en PitNet somatotropos humanos. Se analizaron muestras de PitNet incluidas en parafina, de pacientes de ambos sexos (n=9) provistas por la Clínica Universitaria Reina Fabiola (REPIS 3974) y Sanatorio Allende (Córdoba). Se dispuso de datos clínicos y de inmunomarcación para hormona de crecimiento (GH) y de Ki-67. La expresión de 8 Hidroxi-deoxiguanosina (8OhdG), marcador de daño oxidativo al ADN y del Factor relacionado al factor nuclear eritroide-2 (Nrf2), indicador de la activación de la respuesta antioxidante, se evaluó mediante inmunohistoquímica. Se seleccionaron aleatoriamente cinco campos (400x) y se contaron un total de 1.000 células por muestra. Datos expresados como porcentaje de células positivas para 8OhdG nuclear respecto al total. La intensidad de Nrf2 citoplasmático se clasificó como débil/fuerte y según su distribución como focal/difusa. Análisis estadístico: test-T (p <0,05) para 8OhdG y Kruskal Wallis (p <0,05) para Nrf2. En PitNet con valores de ki-67 <3 (n=7) y distribución de GH densamente granulada (menos agresivos), el porcentaje de células positivas para 8OhdG fue 14,3%; mientras que en tumores con ki-67 >3 (n=2) y distribución de GH escasamente granulada (más agresivos) el porcentaje para este marcador fue 9,28% (p >0,05). Asimismo, en el primer grupo, la expresión de Nrf2, fue predominantemente focal y débil; mientras que en segundo grupo se constató una mayor expresión Nrf2, con distribución difusa y fuerte (p >0,05). Los hallazgos obtenidos permiten sugerir que, en PitNet somatotropos, existiría una heterogeneidad en la respuesta al estrés celular. La acumulación de daño oxidativo en el ADN, junto a una menor respuesta antioxidante, constituiría la primera señal para desencadenar la respuesta senescente, explicando posiblemente la menor tasa proliferativa. Igualmente, especulamos que mayores niveles de expresión de Nrf2 contrarrestarían los procesos oxidantes facilitando la proliferación, promoviendo la evolución tumoral. Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología 2022-10-26 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion texto https://revistas.unc.edu.ar/index.php/med/article/view/39012 Revista de la Facultad de Ciencias Médicas de Córdoba.; Vol. 79 No. Suplemento JIC XXIII (2022): Suplemento JIC XXIII Revista de la Facultad de Ciencias Médicas de Córdoba; Vol. 79 Núm. Suplemento JIC XXIII (2022): Suplemento JIC XXIII Revista da Faculdade de Ciências Médicas de Córdoba; v. 79 n. Suplemento JIC XXIII (2022): Suplemento JIC XXIII 1853-0605 0014-6722 http://creativecommons.org/licenses/by-nc/4.0 |