Dopamine receptor type 2 (<scp>DRD2</scp>) and somatostatin receptor type 2 (<scp>SSTR2</scp>) agonists are effective in inhibiting proliferation of progenitor/stem‐like cells isolated from nonfunctioning pituitary tumors

Peverelli, Erika; Giardino, Elena; Treppiedi, Donatella; Meregalli, Mirella; Belicchi, M.; Vaira, Valentina; Corbetta, Serafino; Verdelli, Chiara; Verrua, Elisa; Șerban, Adela; Locatelli, Marco; Carrabba, Giorgio; Gaudenzi, Germano; Malchiodi, Elena; Cassinelli, Letizia; Lania, Andrea; Ferrero, Stefano; Bòsari, Silvano; Mantovani, Giovanna; Torrente, Yvan; Spada, Anna

doi:10.1002/ijc.30613

Cited by 52 publications

(72 citation statements)

References 40 publications

(97 reference statements)

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“…This ability was indeed described in most of the previously mentioned studies: Xu et al reported that after up to 15 passages PASCs were still able to generate spheroids (69); Chen et al observed that, after dispersion of PAs to single cells, primary spheres are generated after 2-3 weeks in culture and that daughter cells derived from the spheres formed secondary spheres within 2-4 weeks after reseeding (71); Peverelli et al showed that cells from 46 PAs form primary spheres after about 2 weeks in stem cell-permissive medium, with sphere-forming efficiency (SFE), calculated in a subset of tumors, in about 2-5% of the plated cells. Cells derived from primary spheres and re-plated as single cell were able to generate secondary spheres with a SFE of about 4-8%, while no tertiary spheres were obtained (78). In our study, sphere formation occurred after 7-10 days in 14 out of 16 GHoma and NFPA cell cultures, but proliferation within spheroids lasted for several weeks (77).…”

Section: In Vitro Self-renewal Activitymentioning

confidence: 45%

“…For example, glioblastoma CSCs, grown in the absence of growth factors and in the presence of fetal bovine serum (FBS), are able to differentiate into astrocyte-and/or neuron-like cells (114). Contrasting results were reported as far as PASC differentiation ability: in most studies this PA subpopulation does not express pituitary hormones (69,70,77), while, in others, the immunohistochemical detection of LH in Sox2 + cells within spheroids was reported, although evidence of co-localization in the same cells was not provided (78). However, relevant to the CSC ability to originate all the cell populations composing the tumor, few studies actually showed that PASCs, isolated from hormone-producing tumors, can differentiate into hormonereleasing cells in vitro.…”

Section: Differentiation Abilitymentioning

confidence: 94%

“…In the study of Xu et al two out of eight of the tested PAs gave rise to stemlike cell cultures (69). In another study, 69.6% of cultured nonfunctioning PAs (NFPAs) (n = 46) showed the formation of non-adherent spheroids after 2 weeks of culture in stem cellpermissive medium; sphere generation was significantly higher in aggressive tumors as assessed by cavernous sinus invasion (78). In our lab, we developed a similar protocol to isolate and expand in vitro putative PASCs from GH-secreting PAs (GHomas) and NFPAs post-surgical specimens (81), obtaining a similar success rate.…”

Section: Isolation Of Putative Pituitary Adenoma Stem Cellsmentioning

confidence: 94%

“…In another report (78), putative PASCs were isolated from 46 NFPAs and characterized for the expression of SOX2, OCT4, and KLF4 mRNAs. SOX2 and NESTIN expression was also confirmed by immunohistochemistry/immunofluorescence experiments, in a subset of PASC-enriched cultures grown as spheroids.…”

Section: Pituitary Adenoma Stem Cell Markers In Enriched In Vitro Culmentioning

confidence: 99%

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Experimental Evidence and Clinical Implications of Pituitary Adenoma Stem Cells

et al. 2020

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Pituitary adenomas, accounting for 15% of diagnosed intracranial neoplasms, are usually benign and pharmacologically and surgically treatable; however, the critical location, mass effects and hormone hypersecretion sustain their significant morbidity. Approximately 35% of pituitary tumors show a less benign course since they are highly proliferative and invasive, poorly resectable, and likely recurring. The latest WHO classification of pituitary tumors includes pituitary transcription factor assessment to determine adenohypophysis cell lineages and accurate designation of adenomas, nevertheless little is known about molecular and cellular pathways which contribute to pituitary tumorigenesis. In malignant tumors the identification of cancer stem cells radically changed the concepts of both tumorigenesis and pharmacological approaches. Cancer stem cells are defined as a subset of undifferentiated transformed cells from which the bulk of cancer cells populating a tumor mass is generated. These cells are able to self-renew, promoting tumor progression and recurrence of malignant tumors, also conferring cytotoxic drug resistance. On the other hand, the existence of stem cells within benign tumors is still debated. The presence of adult stem cells in human and murine pituitaries where they sustain the high plasticity of hormone-producing cells, allowed the hypothesis that putative tumor stem cells might exist in pituitary adenomas, reinforcing the concept that the cancer stem cell model could also be applied to pituitary tumorigenesis. In the last few years, the isolation and phenotypic characterization of putative pituitary adenoma stem-like cells was performed using a wide and heterogeneous variety of experimental models and techniques, although the role of these cells in adenoma initiation and progression is still not completely definite. The assessment of possible pituitary adenoma-initiating cell population would be of extreme relevance to better understand pituitary tumor biology and to identify novel potential diagnostic markers and pharmacological targets. In this review, we summarize the most updated studies focused on the definition of pituitary adenoma stem cell phenotype and functional features, highlighting the biological processes and intracellular pathways potentially involved in driving tumor growth, relapse, and therapy resistance.

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Section: In Vitro Self-renewal Activitymentioning

confidence: 45%

Section: Differentiation Abilitymentioning

confidence: 94%

Section: Isolation Of Putative Pituitary Adenoma Stem Cellsmentioning

confidence: 94%

Section: Pituitary Adenoma Stem Cell Markers In Enriched In Vitro Culmentioning

confidence: 99%

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Experimental Evidence and Clinical Implications of Pituitary Adenoma Stem Cells

et al. 2020

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“…These actions are inhibited by activation of SSTR2 on the somatotropes. The importance of SSTR2 activation on the control of GH release is highlighted by the fact that SSTR2 agonists are used clinically for treatment of acromegaly, which is caused by excessive release of GH from pituitary adenomas (Cheung and Boyages, 1995; Lopez et al, 1996; Peverelli et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Regulated resurfacing of a somatostatin receptor storage compartment fine-tunes pituitary secretion

Alshafie

Francis

Bednarz

et al. 2019

Journal of Cell Biology

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The surfacing of the glucose transporter GLUT4 driven by insulin receptor activation provides the prototypic example of a homeostasis response dependent on mobilization of an intracellular storage compartment. Here, we generalize this concept to a G protein–coupled receptor, somatostatin receptor subtype 2 (SSTR2), in pituitary cells. Following internalization in corticotropes, SSTR2 moves to a juxtanuclear syntaxin-6–positive compartment, where it remains until the corticotropes are stimulated with corticotropin releasing factor (CRF), whereupon SSTR2 exits the compartment on syntaxin-6–positive vesicular/tubular carriers that depend on Rab10 for their fusion with the plasma membrane. As SSTR2 activation antagonizes CRF-mediated hormone release, this storage/resurfacing mechanism may allow for a physiological homeostatic feedback system. In fact, we find that SSTR2 moves from an intracellular compartment to the cell surface in pituitary gland somatotropes, concomitant with increasing levels of serum growth hormone (GH) during natural GH cycles. Our data thus provide a mechanism by which signaling-mediated plasma membrane resurfacing of SSTR2 can fine-tune pituitary hormone release.

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