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. 2023 Mar 22:14:1129213.
doi: 10.3389/fendo.2023.1129213. eCollection 2023.

Molecular characterization of epithelial-mesenchymal transition and medical treatment related-genes in non-functioning pituitary neuroendocrine tumors

Joan Gil  1   2   3 , Montserrat Marques-Pamies  1   4 , Elena Valassi  1   2   3 , Guillermo Serra  5 , Isabel Salinas  6 , Gemma Xifra  7 , Paula Casano-Sancho  8 , Cristina Carrato  9 , Betina Biagetti  10 , Gemma Sesmilo  11 , Jennifer Marcos-Ruiz  1 , Helena Rodriguez-Lloveras  1 , Anna Rueda-Pujol  1 , Anna Aulinas  2   3 , Alberto Blanco  12 , Cristina Hostalot  12 , Andreu Simó-Servat  13 , Fernando Muñoz  14 , Marta Rico  14 , Javier Ibáñez-Domínguez  15 , Esteban Cordero  16 , Susan M Webb  2   3 , Mireia Jordà  1 , Manel Puig-Domingo  1   3   4
Affiliations

Molecular characterization of epithelial-mesenchymal transition and medical treatment related-genes in non-functioning pituitary neuroendocrine tumors

Joan Gil et al. Front Endocrinol (Lausanne). .

Abstract

Introduction: Different medical therapies have been developed for pituitary adenomas. However, Non-Functioning Pituitary Neuroendocrine Tumors (NF-PitNET) have shown little response to them. Furthermore, epithelial-mesenchymal transition (EMT) has been linked to resistance to medical treatment in a significant number of tumors, including pituitary adenomas.

Methods: We aimed to evaluate the expression of EMT-related markers in 72 NF-PitNET and 16 non-tumoral pituitaries. To further explore the potential usefulness of medical treatment for NF-PitNET we assessed the expression of somatostatin receptors and dopamine-associated genes.

Results: We found that SNAI1, SNAI2, Vimentin, KLK10, PEBP1, Ki-67 and SSTR2 were associated with invasive NF-PitNET. Furthermore, we found that the EMT phenomenon was more common in NF-PitNET than in GH-secreting pituitary tumors. Interestingly, PEBP1 was overexpressed in recurrent NF-PitNET, and could predict growth recurrence with 100% sensitivity but only 43% specificity. In parallel with previously reported studies, SSTR3 is highly expressed in our NF-PitNET cohort. However, SSTR3 expression is highly heterogeneous among the different histological variants of NF-PitNET with very low levels in silent corticotroph adenomas.

Conclusion: NF-PitNET showed an enhanced EMT phenomenon. SSTR3 targeting could be a good therapeutic candidate in NF-PitNET except for silent corticotroph adenomas, which express very low levels of this receptor. In addition, PEBP1 could be an informative biomarker of tumor regrowth, useful for predictive medicine in NF-PitNET.

Keywords: Epithelial-mesenchymal transition; dopamine agonists; non-functioning pituitary adenomas; somatostatin analogs; somatostatin receptor ligands.

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Conflict of interest statement

MP-D, EV, GuS, IS, GX, PC-S, BB, GeS, SW declare to have received funds from Novartis, Ipsen, and Pfizer as lecturers. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Dendrogram and unsupervised hierarchical clustering heatmap of the EMT-related genes in NF-PitNETs (NFPT), somatotropinomas (ACRO) and healthy pituitary tissue (NORMAL) using Ward’s minimum variance method and Minkowski distance.
Figure 2
Figure 2
Boxplots of SRL-related genes according to the different histological samples. Relative expression of SSTR2 (A), SSTR3 (B), SSTR5 (C), ARRB1 (D), KLK10 (E), PLAGL1 (F), E-cadherin (G), DRD2 short (H) and long (I) isoform. NT, Normal tissue.
Figure 3
Figure 3
(A) Relative expression of PEBP1 in NF-PitNETs in tumors that recurred vs. tumors that did not. (B) ROC curve for predicting recurrence using ARRB1 expression in NF-PitNETs.
Figure 4
Figure 4
Histogram and density plot of the log10 relative expression of DRD2 long and short isoform, SSTR2, SSTR3 and SSTR5 in NF-PitNETs (A) and GH-secreting pituitary neuroendocrine tumors (B). Dashed line showed the mean expression of each gene.
Figure 5
Figure 5
(A) Relative expression of SSTR3 according to the immunohistochemical expression of the pituitary hormones. (B) Relative expression of ARRB1 according to the immunohistochemical expression of the pituitary hormones. P-values for the different group comparisons regarding SSTR3 expression: ACTH+ vs. FSH/LH-+ (p=0.001), ACTH+ vs. PRL+ (p=0.418), ACTH+ vs. plurihormonal NF-PitNETs (p=0.005), ACTH+ vs. negative tumors (p=0.004), FSH/LH+ vs. PRL+ (p=0.418), FSH/LH+ vs. plurihormonal NF-PitNETs (p=0.429), FSH/LH+ vs. negative tumors (p=0.603), PRL+ vs. plurihormonal NF-PitNETs (p=1), PRL+ vs. negative tumors (p=0.795) and plurihormonal NF-PitNETs vs. negative tumors (p=0.787). P-values for the different group comparisons regarding ARRB1 expression: ACTH+ vs. FSH/LH-+ (p=0.005), ACTH+ vs. PRL+ (p=0.509), ACTH+ vs. plurihormonal NF-PitNETs (p=0.152), ACTH+ vs. negative tumors (p=0.012), FSH/LH+ vs. PRL+ (p=0.119), FSH/LH+ vs. plurihormonal NF-PitNETs (p=0.085), FSH/LH+ vs. negative tumors (p=0.147), PRL+ vs. plurihormonal NF-PitNETs (p=0.535), PRL+ vs. negative tumors (p=0.051) and plurihormonal NF-PitNETs vs. negative tumors (p=0.026). * indicates the subtypes of NF-PitNETs that showed significant differences compared to ACTH+ NF-PitNETs.
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References

    1. Melmed S. Pituitary tumors. Endocrinol Metab Clin North Am (2015) 44:1–9. doi: 10.1016/j.ecl.2014.11.004 - DOI - PMC - PubMed
    1. Ntali G, Wass JA. Epidemiology, clinical presentation and diagnosis of non-functioning pituitary adenomas. Pituitary (2018) 21:111–8. doi: 10.1007/s11102-018-0869-3 - DOI - PubMed
    1. Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A. High prevalence of pituitary adenomas: A cross-sectional study in the province of liege, Belgium. J Clin Endocrinol Metab (2006) 91:4769–75. doi: 10.1210/jc.2006-1668 - DOI - PubMed
    1. Lopes MBS. The 2017 world health organization classification of tumors of the pituitary gland: a summary. Acta Neuropathol (2017) 134:521–35. doi: 10.1007/s00401-017-1769-8 - DOI - PubMed
    1. Even-Zohar N, Greenman Y. Management of NFAs: Medical treatment. Pituitary (2018) 21:168–75. doi: 10.1007/s11102-018-0865-7 - DOI - PubMed

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