Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly

Martín‐Rodríguez, Juan Francisco; Muñoz-Bravo, José Luis; Ibáñez‐Costa, Alejandro; Fernández-Maza, Laura; Balcerzyk, Marcin; Leal‐Campanario, Rocío; Luque, Raúl M.; Castaño, Justo P.; Soto‐Moreno, Alfonso; Leal‐Cerro, Alfonso; Cano, David A.

doi:10.1038/srep16298

Cited by 9 publications

(12 citation statements)

References 69 publications

(98 reference statements)

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“…The tumour‐resected group of animals was monitored daily after the removal of the tumour to make sure it did not reappear. As already reported and further confirmed here, tumour‐bearing rats increased their body weight significantly more than the other two groups (Figure B) and presented higher circulating levels of GH (Figure C) and IGF‐I (Figure D). In addition, tumour resection in the tumour‐resected group stopped the abnormal increase in animals’ body weight (Figure B), and reverted GH (Figure C, blue bar A) and IGF‐I (Figure D, blue bar A) levels to control values.…”

Section: Resultssupporting

confidence: 89%

“…Our study aims to analyse the putative effects of chronic GH/IGF‐I hypersecretion in adult rats on instrumental learning—a function usually ascribed to prefrontal and related circuits—LTP evoked in hippocampal CA3‐CA1 synapses in behaving animals, and neurogenesis determined at the dentate nucleus . For this, we used Wistar Furth rats implanted with a GC cell line which resulted in the formation of solid, functional tumours . This animal model let us study the effects on associative learning, long‐term memories, LTP and neurogenesis of GH hypersecretion, as well as those following surgical resection of the tumour.…”

Section: Introductionmentioning

confidence: 99%

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Chronic adult‐onset of growth hormone/IGF‐I hypersecretion improves cognitive functions and LTP and promotes neuronal differentiation in adult rats

et al. 2019

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Aim:Besides their metabolic and endocrine functions, the growth hormone (GH) and its mediated factor, the insulin-like growth factor I (IGF-I), have been implicated in different brain functions, including neurogenesis. Long-lasting elevated GH and IGF-I levels result in non-reversible somatic, endocrine and metabolic morbidities.However, the subcutaneous implantation of the GH-secreting (GH-S) GC cell line in rats leads to the controllable over-secretion of GH and elevated IGF-I levels, allowing the experimental study of their short-term effects on brain functions. Methods: Adult rats were implanted with GC cells and checked 10 weeks later, when a GH/IGF-I-secreting tumour was already formed. Results: Tumour-bearing rats acquired different operant conditioning tasks faster and better than controls and tumour-resected groups. They also presented better retentions of long-term memories in the passive avoidance test. Experimentally evoked long-term potentiation (LTP) in the hippocampus was also larger and longer lasting in the tumour bearing than in the other groups. Chronic adult-onset of GH/IGF-I hypersecretion caused an acceleration of early progenitors, facilitating a faster neural differentiation, maturation and integration in the dentate gyrus, and increased the complexity of dendritic arbours and spine density of granule neurons. Conclusion: Thus, adult-onset hypersecretion of GH/IGF-I improves neurocognitive functions, long-term memories, experimental LTP and neural differentiation, migration and maturation.

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Section: Resultssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Chronic adult‐onset of growth hormone/IGF‐I hypersecretion improves cognitive functions and LTP and promotes neuronal differentiation in adult rats

et al. 2019

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“…Experiments with mice were carried out according to the European Regulations for Animal Care under the approval of the university/ regional government research ethics committees. Ten-week-old male athymic BALB/cAnNRj-Foxn1nu mice (Janvier Labs, Le Genest-Saint-Isle, France) were s.c. grafted in both flanks with 2 3 10 6 mock-transfected (n = 5 mice; n = 10 tumors) or stably sst5TMD4-transfected PC3 cells (n = 5 mice; n = 10 tumors) that were resuspended in 100 ml of basement membrane extract (Trevigen, Gaithersburg, MD, USA) (24). Tumor growth was monitored once per week for 3 mo by using a digital caliper.…”

Section: Xenograft Modelmentioning

confidence: 99%

“…After euthanization of mice, each tumor was dissected, fixed, and sectioned for histopathologic examination after hematoxylin and eosin staining for the examination of necrosis by expert pathologists. Additional pieces from the tumor were kept at 280°C for later RNA extraction by using Trizol reagent (Thermo Fisher Scientific) or protein extraction using SDS-DTT buffer as previously reported (24).…”

Section: Xenograft Modelmentioning

confidence: 99%

The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer

et al. 2017

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sst5TMD4, a splice variant of the sst5 gene, is overexpressed and associated with aggressiveness in various endocrine-related tumors, but its presence, functional role, and mechanisms of actions in prostate cancer (PCa)-the most common cancer type in males-is completely unexplored. In this study, formalin-fixed, paraffin-embedded prostate pieces from patients with localized PCa, which included tumoral and nontumoral adjacent regions ( = 45), fresh biopsies from patients with high-risk PCa ( = 52), and healthy fresh prostates from cystoprostatectomies ( = 14) were examined. In addition, PCa cell lines and xenograft models were used to determine the presence and functional role of sst5TMD4. Results demonstrated that sst5TMD4 is overexpressed (mRNA/protein) in PCa samples, and this is especially drastic in metastatic and/or high Gleason score tumor samples. Remarkably, sst5TMD4 expression was associated with an altered frequency of 2 single-nucleotide polymorphisms: rs197055 and rs12599155. In addition, PCa cell lines and xenograft models were used to demonstrate that sst5TMD4 overexpression increases cell proliferation and migration in PCa cells and induces larger tumors in nude mice, whereas its silencing decreased proliferation and migration. Remarkably, sst5TMD4 overexpression activated multiple intracellular pathways (ERK/JNK, MYC/MAX, WNT, retinoblastoma), altered oncogenes and tumor suppressor gene expression, and disrupted the normal response to somatostatin analogs in PCa cells. Altogether, we demonstrate that sst5TMD4 is overexpressed in PCa, especially in those patients with a worse prognosis, and plays an important pathophysiologic role in PCa, which suggesting its potential as a biomarker and/or therapeutic target.-Hormaechea-Agulla, D., Jiménez-Vacas, J. M., Gómez-Gómez, E., L.-López, F., Carrasco-Valiente, J., Valero-Rosa, J., Moreno, M. M., Sánchez-Sánchez, R., Ortega-Salas, R., Gracia-Navarro, F., Culler, M. D., Ibáñez-Costa, A., Gahete, M. D., Requena, M. J., Castaño, J. P., Luque, R. M. The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer.

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“…The responses are variable depending on cell lines as they may miss some key components of SST pathway. For example, GH3 cells do not always express all SSTRs, sometimes not even SSTR2 (Garcia & Myers 1994, Kim et al 2005 or p27kip in the case of GH3 or GC cells (Qian et al 2000, Martín-Rodriguez et al 2015, p27kip being an effector of certain antiproliferative SST-mediated responses (Pages et al 1999, Hubina et al 2006, Grant et al 2008, Aoki et al 2014, KiseljakVassiliades et al 2015.…”

Section: The Use Of Somatostatin Analogues For Acromegaly Treatmentmentioning

confidence: 99%

AIP and the somatostatin system in pituitary tumours

Ibáñez‐Costa

Korbonits

2017

Journal of Endocrinology

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Classic somatostatin analogues aimed at somatostatin receptor type 2, such as octreotide and lanreotide, represent the mainstay of medical treatment for acromegaly. These agents have the potential to decrease hormone secretion and reduce tumour size. Patients with a germline mutation in the aryl hydrocarbon receptor-interacting protein gene, AIP, develop young-onset acromegaly, poorly responsive to pharmacological therapy. In this review, we summarise the most recent studies on AIP-related pituitary adenomas, paying special attention to the causes of somatostatin resistance; the somatostatin receptor profile including type 2, type 5 and truncated variants; the role of G proteins in this pathology; the use of first and second generation somatostatin analogues; and the role of ZAC1, a zinc-finger protein with expression linked to AIP in somatotrophinoma models and acting as a key mediator of octreotide response.

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Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly

Cited by 9 publications

References 69 publications

Chronic adult‐onset of growth hormone/IGF‐I hypersecretion improves cognitive functions and LTP and promotes neuronal differentiation in adult rats

Chronic adult‐onset of growth hormone/IGF‐I hypersecretion improves cognitive functions and LTP and promotes neuronal differentiation in adult rats

The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer

AIP and the somatostatin system in pituitary tumours

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