Expression of SSTR2a, but not of SSTRs 1, 3, or 5 in Somatotroph Adenomas Assessed by Monoclonal Antibodies Was Reduced by Octreotide and Correlated With the Acute and Long-Term Effects of Octreotide

Casar‐Borota, Olivera; Heck, Ansgar; Schulz, Stefan; Nesland, Jahn M.; Ramm‐Pettersen, Jon; Lekva, Tove; Alafuzoff, Irina; Bollerslev, Jens

doi:10.1210/jc.2013-2145

Cited by 124 publications

(120 citation statements)

References 38 publications

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“…Numerous factors are associated with resistance to first-generation SSAs (10), including reduced expression of SSTR2a (11,12,13,14,15,16,17,18), sparsely granulated adenoma subtype (19,20,21,22) and a higher Ki-67 proliferation index (23,24). Adenomas that occur in patients with AIP mutations and AIP mutation-negative sporadic somatotroph adenomas with reduced AIP expression show increased invasiveness (25,26,27,28) and are frequently resistant to first generation SSAs (29).…”

Section: Introductionmentioning

confidence: 99%

Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study

Iacovazzo

Carlsen²,

Lugli

et al. 2016

European Journal of Endocrinology

139

109

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Aim: To gather data regarding factors predicting responsiveness to pasireotide in acromegaly. Patients and methods: SSTR2a, SSTR3, SSTR5, AIP, Ki-67 and the adenoma subtype were evaluated in somatotroph adenomas from 39 patients treated post-operatively with somatostatin analogues (SSAs). A standardized SSTR scoring system was applied (scores 0-3). All patients received first-generation SSAs, and 11 resistant patients were subsequently treated with pasireotide LAR. Results: None of the patients with negative or cytoplasmic-only SSTR2a expression (scores 0-1) were responsive to firstgeneration SSAs, as opposed to 20% (score 2) and 50% of patients with a score of 3 (PZ0.04). None of the patients with an SSTR5 score of 0-1 were responsive to pasireotide, as opposed to 5/7 cases with a score of 2 or 3 (PZ0.02). SSTR3 expression did not influence first-generation SSAs or pasireotide responsiveness. Tumours with low AIP were resistant to first-generation SSAs (100 vs 60%; PZ0.02), while they had similar responsiveness to pasireotide compared to tumours with conserved AIP expression (50 vs 40%; PZ0.74). Tumours with low AIP displayed reduced SSTR2 (SSTR2a scores 0-1 44.4 vs 6.7%; PZ0.006) while no difference was seen in SSTR5 (SSTR5 scores 0-1 33.3 vs 23.3%; PZ0.55). Sparsely granulated adenomas responded better to pasireotide compared to densely granulated ones (80 vs 16.7%; PZ0.04). Conclusion: The expression of SSTR5 might predict responsiveness to pasireotide in acromegaly. AIP deficient and sparsely granulated adenomas may benefit from pasireotide treatment. These results need to be confirmed in larger series of pasireotide-treated patients.

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Section: Introductionmentioning

confidence: 99%

Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study

Iacovazzo

Carlsen²,

Lugli

et al. 2016

European Journal of Endocrinology

139

109

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“…Sabe-se que os LRS de primeira geração apresentam maior afinidade ao SSTR2 e que a expressão desse receptor é necessária (84)(85)(86)(100)(101)(102) , porém não suficiente (110,111) para resposta a essas drogas. A despeito das diferenças nos métodos de detecção do SSTR2 (gene ou proteína), dos diversos anticorpos utilizados nos estudos com imunohistoquímica, na inclusão ou não de pacientes com tratamento clínico primário, e na utilização de diferentes critérios para controle hormonal na acromegalia, a grande maioria dos estudos confirma a correlação entre SSTR2 e resposta aos LRS (84)(85)(86)(100)(101)(102) . No único estudo prévio no qual não houve tal correlação (103) , os autores ponderam que a expressão do receptor não garantiu a resposta adequada aos LRS.…”

Section: Discussionunclassified

“…No único estudo prévio no qual não houve tal correlação (103) , os autores ponderam que a expressão do receptor não garantiu a resposta adequada aos LRS. Em nossa casuística, avaliando apenas os pacientes com tratamento cirúrgico ou o grupo total, não houve diferença na expressão de SSTR2, fato que ainda é controverso na literatura (100,103) . Ainda que não tenhamos encontrado associação entre a expressão de SSTR2 e resposta aos LRS, apenas um paciente (GH08) apresentou resposta hormonal ao LRS sem a presença do SSTR2.…”

Section: Discussionunclassified

“…Há sete estudos que avaliaram a expressão de SSTR2 em portadores de acromegalia e sua relação com a resposta aos LRS, sendo positiva em seis deles (84)(85)(86)(100)(101)(102) , e negativa em um único estudo (103) . Em um dos estudos, houve maior expressão de SSTR2 nos subtipos tumorais densamente granulados, corroborando para descrição prévia que esse padrão de granulação associa-se à melhor resposta aos LRS (102) .…”

Section: Somatotropinomasunclassified

“…Através de análise por IHQ, demonstrou-se que a localização do SSTR2 e do SSTR5 é predominantemente citoplasmática (103) . No entanto, há autores preconizando que somente a presença dos receptores na membrana deva ser analisada, com a justificativa de que apenas esses refletem o seu estado funcional (104,105) , enquanto que a localização preferencialmente citoplasmática poderia estar associada à internalização dos receptores, implicando em resistência e taquifilaxia (100,106) .…”

Section: Somatotropinomasunclassified

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Análise da expressão da filamina A nos tumores hipofisários e suas implicações clínicas e terapêuticas

Sickler¹

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Dedico esta tese:Aos meus pais, Marilena e Luciano, pelo apoio incondicional, ajuda e exemplo de boas pessoas.Aos meus filhos, Lucas e Rafael, por deixarem a vida doce, e repleta de alegrias em todos os seus momentos.À minha irmã Bruna, por ser sempre sincera e amiga. E principalmente ao Gabriel, pelo amor presente em cada dia que antecedeu a realização e finalização desse estudo; sem você, eu não conseguiria...

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TGF‐β1/Smad2/3 signaling pathway modulates octreotide antisecretory and antiproliferative effects in pituitary somatotroph tumor cells

Picech

Sosa

Pérez

et al. 2021

Journal Cellular Physiology

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Octreotide (OCT) is used to inhibit hormone secretion and growth in somatotroph tumors, although a significant percentage of patients are resistant. It has also been tested in nonfunctioning (NF) tumors but with poor results, with these outcomes having been associated with SSTR2 levels and impaired signaling. We investigated whether OCT inhibitory effects can be improved by TGF‐β1 in functioning and nonfunctioning somatotroph tumor cells. OCT effects on hormone secretion and proliferation were analyzed in the presence of TGF‐β1 in WT and SSTR2‐overexpressing secreting GH3 and silent somatotroph tumor cells. The mechanism underlying these effects was assessed by studying SSTR and TGFβR signaling pathways mediators. In addition, we analyzed the effects of OCT/TGF‐β1 treatment on tumor growth and cell proliferation in vivo. The inhibitory effects of OCT on GH‐ and PRL‐secretion and proliferation were improved in the presence of TGF‐β1, as well as by SSTR2 overexpression. The OCT/TGF‐β1 treatment induced downregulation of pERK1/2 and pAkt, upregulation of pSmad3, and inhibition of cyclin D1. In vivo experiments showed that OCT in the presence of TGF‐β1 blocked tumor volume growth, decreased cell proliferation, and increased tumor necrosis. These results indicate that SSTR2 levels and the stimulation of TGF‐β1/TGFβR/Smad2/3 pathway are important for strengthening the antiproliferative and antisecretory effects of OCT.

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Expression of SSTR2a, but not of SSTRs 1, 3, or 5 in Somatotroph Adenomas Assessed by Monoclonal Antibodies Was Reduced by Octreotide and Correlated With the Acute and Long-Term Effects of Octreotide

Cited by 124 publications

References 38 publications

Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study

Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study

Análise da expressão da filamina A nos tumores hipofisários e suas implicações clínicas e terapêuticas

TGF‐β1/Smad2/3 signaling pathway modulates octreotide antisecretory and antiproliferative effects in pituitary somatotroph tumor cells

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