Materiały źródłowe

• #1 Pathogenesis of pituitary tumors. – Document – Gale OneFile: Health and Medicine

  https://go.gale.com/ps/i.do?id=GALE%7CA254971548&sid=googleScholar&v=2.1&it=r&linkaccess=abs&issn=17595029&p=HRCA&sw=w

  Pituitary adenomas may hypersecrete hormones (including prolactin, growth hormone and adrenocorticotropic hormone, and rarely follicle-stimulating hormone, luteinizing hormone or TSH) or may be nonfunctional. […] Pathogenesis of dysregulated pituitary cell proliferation and unrestrained hormone hypersecretion may be mediated by hypothalamic, intrapituitary and/or peripheral factors. […] Altered expression of pituitary cell cycle genes, activation of pituitary selective oncoproteins or loss of pituitary suppressor factors may be associated with aberrant growth factor signaling. […] Understanding subcellular mechanisms that underlie pituitary tumorigenesis will enable development of tumor aggression markers as well as novel targeted therapies.

• #2 Pathogenesis of pituitary tumors | Nature Reviews Endocrinology

  https://www.nature.com/articles/nrendo.2011.40

  Pituitary adenomas may hypersecrete hormones (including prolactin, growth hormone and adrenocorticotropic hormone, and rarely follicle-stimulating hormone, luteinizing hormone or TSH) or may be nonfunctional. […] Pathogenesis of dysregulated pituitary cell proliferation and unrestrained hormone hypersecretion may be mediated by hypothalamic, intrapituitary and/or peripheral factors. […] The pathogenetic mechanisms that underlie pituitary tumorigenesis may be genetic or epigenetic and result in cell cycle dysregulation, signaling defects or loss of tumor suppressor factors.

• #3 Mechanisms for pituitary tumorigenesis: the plastic pituitary

  https://pmc.ncbi.nlm.nih.gov/articles/PMC281651/

  The anterior pituitary gland integrates the repertoire of hormonal signals controlling thyroid, adrenal, reproductive, and growth functions. The gland responds to complex central and peripheral signals by trophic hormone secretion and by undergoing reversible plastic changes in cell growth leading to hyperplasia, involution, or benign adenomas arising from functional pituitary cells. […] Discussed herein are the mechanisms underlying hereditary pituitary hypoplasia, reversible pituitary hyperplasia, excess hormone production, and tumor initiation and promotion associated with normal and abnormal pituitary differentiation in health and disease. […] The pituitary gland responds to complex central and peripheral signals by two mechanisms. First, trophic hormone secretion is exquisitely controlled to regulate homeostasis. Second, developmental or acquired pituitary signals may elicit plastic pituitary growth responses, consisting of either hypoplasia, hyperplasia, or adenoma formation. […] Pituitary proliferative changes are usually accompanied by functional disorders of hormone secretion, leading to syndromes of hormone deficiency or excess.

• #4 Mechanisms for pituitary tumorigenesis: the plastic pituitary

  https://pmc.ncbi.nlm.nih.gov/articles/PMC281651/

  Excess pituitary hormone secretion is usually associated with invariably benign monoclonal adenomas arising from a specific cell type, and although pituitary chromosome instability is an early hallmark of pituitary adenoma development and growth, pituitary carcinoma is very rare, further supporting the concept that pituitary adenomas have the capacity for reversible plasticity. […] Several characteristic hallmarks of pituitary neoplasia point to a unique growth behavior distinct from that of other endocrine and nonendocrine malignancies. […] These adenomas grow slowly, and are discovered in up to 25% of unselected autopsy specimens. […] Although the natural history of pituitary microadenoma growth is difficult to ascertain because of the intrinsic inaccessibility of pituitary tissue for study, it is clear that microadenomas do not invariably progress to macroadenomas; furthermore, macroadenomas are stable or exhibit very slow growth, and may in fact resolve spontaneously.

• #5 Mechanisms for pituitary tumorigenesis: the plastic pituitary

  https://pmc.ncbi.nlm.nih.gov/articles/PMC281651/

  Abundant evidence suggests that pituitary adenomas are derived from clonal expansion of mutated somatic cells. […] Evidence supporting this intrinsic defect hypothesis includes the observed well-circumscribed discrete adenomas surrounded by normal nonhyperplastic tissue, as well as results of X-inactivation studies and loss-of-heterozygosity (LOH) analysis.

• #6 Pituitary Tumors: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1157189-overview

  Pituitary tumors are common neoplasms that constitute approximately 15% of all intracranial tumors. Among sellar neoplasms, pituitary adenomas are the most common, accounting for up to 90% of the tumors diagnosed in this region. […] The molecular basis underlying pituitary adenoma pathogenesis encompasses several mechanisms: activating mutations, receptor signaling defects, chromosomal instability and DNA damage, as well as senescence. […] Multiple oncogene abnormalities have been involved in pituitary tumorigenesis, such as G-protein abnormalities, RAS gene mutations, or p53 gene deletions, mutations, and rearrangements. […] Nonfunctioning adenomas have been associated with hypermethylation of p16. […] Galectin-3 (Gal-3), a gene involved in cell growth and apoptosis, has been described in prolactinomas and corticotrophin adenomas.

• #7 Pituitary Tumors: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1157189-overview

  Additionally, familial pituitary adenomas, such as familial gigantism and acromegaly, have been associated with mutations in the aryl hydrocarbon-interacting protein gene (AIP). […] Hereditary pituitary adenomas have also been linked to multiple endocrine neoplasia (MEN) syndromes, such as MEN types 1 and 4. […] Although pituitary tumorigenesis is heterogeneous and recurrent cell-specific oncogenic mutations are uncommon, recurrent oncogene mutations have been reported in GNAS (somatotrophin adenomas), USP8 (corticotrophin adenomas), and rarely in NR3C1. […] Most of these tumors are benign, but certain factors involved in tumorigenesis may determine their aggressiveness. For instance, the presence of p53 correlates with more aggressive tumor behavior. […] Furthermore, mutations in AIP, MEN1, and GPR101 have been found to be more frequently invasive. […] Likewise, the pituitary tumor transforming gene-1 (PTTG-1) is an oncogene that has also been implicated in pituitary tumors as a marker of invasiveness and recurrence.

• #8 KoreaMed Synapse

  https://synapse.koreamed.org/articles/1086027

  The aryl hydrocarbon receptor interacting protein (AIP) gene dominant mutations are most frequently implicated in the pathogenesis of familial isolated pituitary adenomas with a prevalence of 15%. In addition, the germline mutation of this gene has been found in all types of sporadic pituitary adenomas, either functioning of nonfunctioning subtypes, with predominance in somatotrophinomas. Furthermore, AIP mutations seem to be more prominent in patients with young age and large tumors. The multiple endocrine neoplasia syndrome type 1 (MEN1) gene localizes on the chromosome 11q13, usually acts a tumor suppressor. MEN1 syndrome is an autosomal dominant familial disorder, about 70% of which bear the MEN1 gene mutation. However, only 3.5% of the sporadic pituitary adenomas have been found to contain a MEN1 mutation. Therefore, mutation of MEN1 may play limited role in sporadic pituitary adenomas.

• #9 Mechanisms of Disease: the pathogenesis of pituitary tumors | Nature Reviews Endocrinology

  https://www.nature.com/articles/ncpendmet0159

  Abnormal hormone receptor signaling contributes to dysfunctional responses to feedback inhibition; however, apart from one subtype of growth-hormone-secreting adenomas, hormone receptor alterations do not seem to be common events that can be implicated in the etiology and pathogenesis of the majority of pituitary adenomas. […] Altered signaling by proteins such as the G-protein oncogene that are involved in signal transduction of hormones and growth factors might be implicated in pituitary tumorigenesis, in a subset of pituitary somatotroph adenomas. […] There is emerging convincing evidence for the important role of growth factors, and in particular, the fibroblast growth factor system, in pituitary development and tumor formation. […] Cell-cycle control proteins are commonly dysregulated in pituitary tumors, usually by epigenetic silencing of inhibitors of cell proliferation.

• #10 Pituitary Tumorigenesis—Implications for Management

  https://www.mdpi.com/1648-9144/59/4/812

  Moreover, the mutations in several other tumor suppressor genes, such as menin and CDKN1B, are responsible for the MEN1 and MEN4 syndromes and succinate dehydrogenase (SDHx) in the context of the 3PAs syndrome. […] Furthermore, the pituitary stem cells and miRNAs hold an essential role in pituitary tumorigenesis and may represent new molecular targets for their diagnosis and treatment. […] Different conserved signaling pathways, such as the MAPK, PI3K/Akt, and Wnt pathways, have been associated with pituitary tumorigenesis, while their regulation seems to be tissue-specific. […] Recently, Hippo signaling has been linked to pituitary development and stem cell regulation, as well as poorly differentiated pituitary tumors. […] In the current review we summarized the already existing mechanisms contributing to the pathogenesis of the PitNETs in an attempt to understand their implications for management.

• #11 KoreaMed Synapse

  https://synapse.koreamed.org/articles/1086027

  The pRb/E2F pathway plays a critical role in pituitary tumorigenesis, as it has been clearly shown by experimental mouse models. Progress from G1 to S phrase of the cell cycle is restrained by the hypophosphorylated Rb, which is in turn mediated by upstream CDKs and its inhibitors, CDKIs. A number of cell cycle regulators have been supposed to play a role in pituitary tumorigenesis, including Rb1, p16, p21, p27, cyclin D1, and cyclin E. CDK4 and its inhibitor p16 play a vital role in cell cycle control by mediating Rb1 pathway. Both p16 and Rb1 are tumor suppressors, and usually silenced by genetic alternation in nonendocrine neoplasms. However, both of their diminished expressions are ascribed to promoter methylation in pituitary adenomas. […] MiRNAs are a class of short noncoding RNAs that posttranscriptionally regulate the target mRNAs translation and degradation, by binding to the sequences at 3′ untranslated regions. Increasing evidence indicates that miRNAs are commonly involved in tumor initiation, progression, as well as therapeutic outcomes. Moreover, half of the miRNA genes are located in cancer associated genomic regions, emphasizing a crucial role of miRNAs in tumor pathogenesis. Recently, deregulation of miRNAs is also revealed in pituitary adenomas.

• #12 KoreaMed Synapse

  https://synapse.koreamed.org/articles/1086027

  The term epigenetic modification refers to a process that influences the gene expression without changing the DNA sequence of the gene. DNA methylation is the most common epigenetic modification, which is restricted to the CpG dinucleotides in mammals. The sites with clustered CpG are known as CpG islands, which usually encompass the gene promoter regions. Inappropriate methylation of CpG islands is associated with histone deacetylation and gene silencing. Conversely, it is also suggested that modification of histone tails may lead to CpG island methylation, and therefore reinforce an already established silencing event. Many genes silenced by hypermethylation have been found to play a remarkable role in pituitary tumorigenesis, although the exact mechanisms governing site-specific DNA methylation, histone modification, and gene silencing remain unclear.

• #13 Genomic and molecular characterization of pituitary adenoma pathogenesis: review and translational opportunities in: Neurosurgical Focus Volume 48 Issue 6 (2020) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/48/6/article-pE11.xml

  The mechanism of this deregulation is generally epigenetic silencing (in the case of tumor suppressors), identifying aberrant epigenetic regulation as one of the master switches orchestrating pituitary tumor genesis and growth. […] The data we have discussed indicate that epigenetic silencing of tumor suppressors by methylation is a prominent mechanism in pituitary tumor pathogenesis.

• #14 Mechanisms of Disease: The Pathogenesis of Pituitary Tumors

  https://www.medscape.com/viewarticle/530480

  Cell-cycle control proteins are commonly dysregulated in pituitary tumors, usually by epigenetic silencing of inhibitors of cell proliferation. […] Loss of the reticulin network represents the morphological hallmark of the transition from hyperplasia to adenoma in the pituitary gland; this seems at least in part to be caused by disruption of a multiprotein complex involving fibroblast growth factor receptor 4, N-cadherin (a cell adhesion molecule) and neural cell adhesion molecule 1.

• #15 KoreaMed Synapse

  https://synapse.koreamed.org/articles/1086027

  The pRb/E2F pathway plays a critical role in pituitary tumorigenesis, as it has been clearly shown by experimental mouse models. Progress from G1 to S phrase of the cell cycle is restrained by the hypophosphorylated Rb, which is in turn mediated by upstream CDKs and its inhibitors, CDKIs. A number of cell cycle regulators have been supposed to play a role in pituitary tumorigenesis, including Rb1, p16, p21, p27, cyclin D1, and cyclin E. CDK4 and its inhibitor p16 play a vital role in cell cycle control by mediating Rb1 pathway. Both p16 and Rb1 are tumor suppressors, and usually silenced by genetic alternation in nonendocrine neoplasms. However, both of their diminished expressions are ascribed to promoter methylation in pituitary adenomas. […] MiRNAs are a class of short noncoding RNAs that posttranscriptionally regulate the target mRNAs translation and degradation, by binding to the sequences at 3′ untranslated regions. Increasing evidence indicates that miRNAs are commonly involved in tumor initiation, progression, as well as therapeutic outcomes. Moreover, half of the miRNA genes are located in cancer associated genomic regions, emphasizing a crucial role of miRNAs in tumor pathogenesis. Recently, deregulation of miRNAs is also revealed in pituitary adenomas.

• #16 The Molecular Pathogenesis of Pituitary Adenomas: An Update

  https://www.e-enm.org/journal/view.php?doi=10.3803/enm.2013.28.4.245

  MiRNAs are a class of short noncoding RNAs that posttranscriptionally regulate the target mRNAs translation and degradation, by binding to the sequences at 3′ untranslated regions. Increasing evidence indicates that miRNAs are commonly involved in tumor initiation, progression, as well as therapeutic outcomes. […] MEG3 represents the first and the only recognized lncRNA tumor suppressor in pituitary adenomas.

• #17 lncRNA MEG3 inhibits pituitary tumor development by participating in cell proliferation, apoptosis and EMT processes

  https://www.spandidos-publications.com/10.3892/or.2021.7991

  MEG3, a maternally expressed imprinted gene, encodes an lncRNA with a length of ~1,600 nt. […] In the present study, patients with stage IIIIV pituitary tumor exhibited lower MEG3 mRNA expression levels than those with III pituitary tumor. Therefore, lncRNA MEG3 was considered to be a critical inhibitor of pituitary tumor development. […] In conclusion, MEG3 inhibited pituitary tumor development by participating in cell proliferation, apoptosis and the EMT process, which may be a novel target for treatment of pituitary tumors.

• #18 Pituitary Tumors: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1157189-overview

  Additionally, familial pituitary adenomas, such as familial gigantism and acromegaly, have been associated with mutations in the aryl hydrocarbon-interacting protein gene (AIP). […] Hereditary pituitary adenomas have also been linked to multiple endocrine neoplasia (MEN) syndromes, such as MEN types 1 and 4. […] Although pituitary tumorigenesis is heterogeneous and recurrent cell-specific oncogenic mutations are uncommon, recurrent oncogene mutations have been reported in GNAS (somatotrophin adenomas), USP8 (corticotrophin adenomas), and rarely in NR3C1. […] Most of these tumors are benign, but certain factors involved in tumorigenesis may determine their aggressiveness. For instance, the presence of p53 correlates with more aggressive tumor behavior. […] Furthermore, mutations in AIP, MEN1, and GPR101 have been found to be more frequently invasive. […] Likewise, the pituitary tumor transforming gene-1 (PTTG-1) is an oncogene that has also been implicated in pituitary tumors as a marker of invasiveness and recurrence.

• #19 Spontaneous Pituitary Tumors in Rats: A Review

  https://www.jscimedcentral.com/jounal-article-info/Annals-of-Clinical-Pathology/Spontaneous-Pituitary-Tumors-in-Rats%3A-A-Review-6766

  For many years, the mechanism of pituitary tumor pathogenesis was a controversial issue in the science world. Two theories describing the pathogenesis of these tumors have arisen – one of them is based on the participation of hormones and growth factors, the other on the spontaneous mutation of a single progenitor cell. Currently, it is known that the reason lies on both sides, and the formation of pituitary tumors is a multi-stage process of carcinogenesis, in which the event initiating the transformation of cells is created by molecular genetic changes, while hormones and growth factors play an important role in stimulating cell proliferation. […] The task of PTTG is regulation of the cell cycle and separation of sister chromatids in anaphase of mitosis. As a result of its overexpression, there are disorders of chromatid separation, aneuplody, chromosome instability and, as a consequence – cell cycle disorders. In addition, PTTG acts on pituitary growth and angiogenesis via VEGF and bFGF. Studies in rats have shown that estrogen-induced adenomas increase PTTG expression in the pre-tumor stage. This proves that PTTG is involved in both the initiation and promotion of pituitary tumors.

• #20 Mechanisms for pituitary tumorigenesis: the plastic pituitary

  https://pmc.ncbi.nlm.nih.gov/articles/PMC281651/

  The spectrum of cellular changes leading from reversible hyperplasia to a committed pituitary microadenoma and ultimately to a macroadenoma. […] Factors leading to enhanced pituicyte growth autonomy, with evasion of apoptosis and unrestrained replicative potential, are potentiated by intrapituitary changes in hormone, growth factor, or receptor functions. […] Several lines of evidence corroborate the concept of a hypothalamic role for pituitary tumorigenesis. […] True pituitary adenomas often retain the capacity to respond to hypothalamic trophic stimuli. Furthermore, pituitary adenomas, especially prolactinomas, may resolve spontaneously, demonstrating the plasticity of adenomatous pituitary cell growth. […] The etiology of these tumors is unresolved and likely involves multiple initiating and promoting factors. […] The literature is replete with heterogenous descriptions of overexpressed or underexpressed specific oncogenes or growth factors in these adenomas, and they may not necessarily be the direct cause of the tumor, especially as many of these factors are induced only after cells are transformed and may in fact be epiphenomena rather than etiologic molecules.

• #21 Mechanisms for pituitary tumorigenesis: the plastic pituitary

  https://pmc.ncbi.nlm.nih.gov/articles/PMC281651/

  The spectrum of cellular changes leading from reversible hyperplasia to a committed pituitary microadenoma and ultimately to a macroadenoma. […] Factors leading to enhanced pituicyte growth autonomy, with evasion of apoptosis and unrestrained replicative potential, are potentiated by intrapituitary changes in hormone, growth factor, or receptor functions. […] Several lines of evidence corroborate the concept of a hypothalamic role for pituitary tumorigenesis. […] True pituitary adenomas often retain the capacity to respond to hypothalamic trophic stimuli. Furthermore, pituitary adenomas, especially prolactinomas, may resolve spontaneously, demonstrating the plasticity of adenomatous pituitary cell growth. […] The etiology of these tumors is unresolved and likely involves multiple initiating and promoting factors. […] The literature is replete with heterogenous descriptions of overexpressed or underexpressed specific oncogenes or growth factors in these adenomas, and they may not necessarily be the direct cause of the tumor, especially as many of these factors are induced only after cells are transformed and may in fact be epiphenomena rather than etiologic molecules.

• #22 Pathogenesis of pituitary tumors. – Document – Gale OneFile: Health and Medicine

  https://go.gale.com/ps/i.do?id=GALE%7CA254971548&sid=googleScholar&v=2.1&it=r&linkaccess=abs&issn=17595029&p=HRCA&sw=w

  Pituitary adenomas may hypersecrete hormones (including prolactin, growth hormone and adrenocorticotropic hormone, and rarely follicle-stimulating hormone, luteinizing hormone or TSH) or may be nonfunctional. […] Pathogenesis of dysregulated pituitary cell proliferation and unrestrained hormone hypersecretion may be mediated by hypothalamic, intrapituitary and/or peripheral factors. […] Altered expression of pituitary cell cycle genes, activation of pituitary selective oncoproteins or loss of pituitary suppressor factors may be associated with aberrant growth factor signaling. […] Understanding subcellular mechanisms that underlie pituitary tumorigenesis will enable development of tumor aggression markers as well as novel targeted therapies.

• #23 Pathogenesis of pituitary tumors | Nature Reviews Endocrinology

  https://www.nature.com/articles/nrendo.2011.40

  Pituitary adenomas may hypersecrete hormones (including prolactin, growth hormone and adrenocorticotropic hormone, and rarely follicle-stimulating hormone, luteinizing hormone or TSH) or may be nonfunctional. […] Pathogenesis of dysregulated pituitary cell proliferation and unrestrained hormone hypersecretion may be mediated by hypothalamic, intrapituitary and/or peripheral factors. […] The pathogenetic mechanisms that underlie pituitary tumorigenesis may be genetic or epigenetic and result in cell cycle dysregulation, signaling defects or loss of tumor suppressor factors.

• #24 Mechanisms of Disease: the pathogenesis of pituitary tumors | Nature Reviews Endocrinology

  https://www.nature.com/articles/ncpendmet0159

  Pituitary tumors exhibit a spectrum of biology, with variable growth and hormonal behaviors. They therefore provide an opportunity to examine pathogenetic mechanisms that underlie the neoplastic process. […] These include alterations in hormone regulation, growth-factor stimulation, cell-cycle control and cell-stromal interactions that result from genetic mutations or epigenetic disruption of gene expression. […] Mouse models have validated the roles of these alterations, which can be targets for the development of therapies that can manage these lesions. […] These therapies are increasingly recognized as critical for quality of life. […] Adenohypophysiotropic hormones promote proliferation in transformed pituitary cells, but it seems that hormone excess alone does not cause pituitary tumors.

• #25 Pituitary Tumors: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1157189-overview

  Additionally, familial pituitary adenomas, such as familial gigantism and acromegaly, have been associated with mutations in the aryl hydrocarbon-interacting protein gene (AIP). […] Hereditary pituitary adenomas have also been linked to multiple endocrine neoplasia (MEN) syndromes, such as MEN types 1 and 4. […] Although pituitary tumorigenesis is heterogeneous and recurrent cell-specific oncogenic mutations are uncommon, recurrent oncogene mutations have been reported in GNAS (somatotrophin adenomas), USP8 (corticotrophin adenomas), and rarely in NR3C1. […] Most of these tumors are benign, but certain factors involved in tumorigenesis may determine their aggressiveness. For instance, the presence of p53 correlates with more aggressive tumor behavior. […] Furthermore, mutations in AIP, MEN1, and GPR101 have been found to be more frequently invasive. […] Likewise, the pituitary tumor transforming gene-1 (PTTG-1) is an oncogene that has also been implicated in pituitary tumors as a marker of invasiveness and recurrence.

• #26

  https://journals.lww.com/neurosurgery/fulltext/2023/04001/524_cytodifferentiation_of_pituitary_tumors.346.aspx

  Pituitary neuroendocrine tumors (PitNET) continue to offer unique challenges given their proximity to the cavernous sinus, whereby invasive behavior can dictate extent of resection and surgical outcome, especially in neuroendocrine-active tumors. […] Likelihood of cavernous sinus invasion differed by transcription factor expression; PIT-1 expressing somatotroph and lactotroph tumors had a higher predilection for invading the cavernous sinus compared to other tumor subtypes. This elucidates a unique cavernoinvasive behavior absent in cells from other lineages. […] These findings can have considerable implications on the surgical management and study of PitNET biology and behavior.

• #27

  https://www.jci.org/articles/view/20401

  Mechanisms for pituitary tumorigenesis: the plastic pituitary […] The anterior pituitary gland integrates the repertoire of hormonal signals controlling thyroid, adrenal, reproductive, and growth functions. The gland responds to complex central and peripheral signals by trophic hormone secretion and by undergoing reversible plastic changes in cell growth leading to hyperplasia, involution, or benign adenomas arising from functional pituitary cells. Discussed herein are the mechanisms underlying hereditary pituitary hypoplasia, reversible pituitary hyperplasia, excess hormone production, and tumor initiation and promotion associated with normal and abnormal pituitary differentiation in health and disease. […] The pituitary gland responds to complex central and peripheral signals by two mechanisms. First, trophic hormone secretion is exquisitely controlled to regulate homeostasis. Second, developmental or acquired pituitary signals may elicit plastic pituitary growth responses, consisting of either hypoplasia, hyperplasia, or adenoma formation. These clinically apparent plastic changes of pituitary mass are indicative of physiologic or pathologic responses to extrapituitary or intrapituitary signals. […] Several characteristic hallmarks of pituitary neoplasia point to a unique growth behavior distinct from that of other endocrine and nonendocrine malignancies. Pituitary tumors are invariably benign, and although aggressive local growth may occur, their general failure to proceed to true malignancy with demonstrable extracranial metastases is intriguing. […] The spectrum of cellular changes leading from reversible hyperplasia to a committed pituitary microadenoma and ultimately to a macroadenoma. Pituitary cell types undergo proliferative and secretory changes as a consequence of a graded sequence of intrinsic and extrinsic signals. […] The mechanisms involved in the oncogenic function for PTTG are still obscure. Genetic instability could therefore underly the transforming and tumorigenic effects of PTTG overexpression as well as its association with tumor aggressiveness. Chromosomal instability of hyperplastic pituitary cells could provide a growth advantage for ultimate progression of tumor growth. […] PTTG thus functions as a securin that regulates chromosome separation, and aberrant PTTG expression leading to chromosome mis-segregation appears to be an early link in the multistep initiation and progression of pituitary tumors.

• #28 A review of multiomics platforms in pituitary adenoma pathogenesis

  https://www.imrpress.com/journal/FBL/27/3/10.31083/j.fbl2703077/htm

  Nonfunctioning pituitary adenomas (NF-PitNETs) are typically benign, characterized by their absence of hormonal overproduction, and show specific molecular changes that are hallmarks to their pathogenesis. […] Two major signaling pathways at the genomic level contribute to the pathogenesis of nonfunctioning pituitary adenomas: phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK). […] The MAPK signaling can be dysregulated in NF-PitNETs through alterations in the ERK1/2, JNK, p38 and ERK5 pathways. […] Genome-wide methylation assays of functioning vs. nonfunctioning adenomas revealed that NF-PitNETs, in general, are defined by a higher frequency of gene hypermethylation. […] The most frequent somatic change in somatotroph PitNETs is the heterozygous gain-of-function mutation of the GNAS gene.

• #29

  https://link.springer.com/article/10.1007/s007010050368

  Modern theory of tumorigenesis suggests that genetic alterations may play a role in the initiation and promotion of pituitary adenomas. Gsp and MEN-1 genes play a role in the initiation event, while p53, ras, Rb and nm23 genes play some role in the progression of the tumor. Gsp gene, that may play an important role in 40% of GH-producing tumor, activation of 10% of non-functioning tumors and 6% of corticotroph adenomas, produces cAMP, which stimulates cyclin D1 and D3 which later produce cdk2 and cdk 4 respectively, and stimulates cell progression from G1 to S phase. […] MEN-1 gene, although found in some sporadic tumors, is more likely associated with familial adenoma. p53, Ras, Rb, nm23 and c-myc genes play some role in the promotion of tumors especially toward their aggressive variant. p53 gene, which is found in up to 60% of ACTH producing adenomas, through action of p21 inhibits progression of cell cycle from G1 to S phase, by inhibiting the action of cyclin D3 on cdk 4.

• #30 Spontaneous Pituitary Tumors in Rats: A Review

  https://www.jscimedcentral.com/jounal-article-info/Annals-of-Clinical-Pathology/Spontaneous-Pituitary-Tumors-in-Rats%3A-A-Review-6766

  Pituitary adenomas develop in situations where there is overproduction of hypothalamic hormones or in the case of hormone deficits secreted by peripheral endocrine organs that inhibit the production and secretion of the pituitary gland. This is one of the arguments confirming the thesis about the participation of hormones in their pathogenesis. Another proof of the validity of this thesis is the paradoxical pituitary hormonal response to exogenous hormone stimulation, which is characteristic of pituitary tumors. […] Studies have shown that in rodents high doses of estrogen induce lactotropic cell hyperplasia and the formation of prolactin adenomas. This happens as a result of increased expression of PTTG, bFGF, TGF, VEGF and galanin. A similar effect in humans was observed only in transsexual persons who were found to have receptors for estrogen alpha, beta and estrogen receptor isoforms that are activated regardless of the presence of the ligand.

• #31

  https://www.jci.org/articles/view/14264

  Pituitary hyperplasia and lactotroph replication are induced by estrogen. […] The product of the pituitary tumor transforming gene (PTTG) exhibits in vitro and in vivo transforming activity and induces basic bFGF secretion, thereby modulating pituitary angiogenesis and tumor formation. […] We demonstrated previously that pituitary pttg is induced by estrogen and bFGF, the latter being expressed in a concordant fashion with pttg in experimental and human pituitary adenomas. […] We now elucidate the role of estrogen in paracrine regulation of pituitary tumorigenesis by PTTG. […] Coincident with the circulating rat estradiol surge and maximal pituitary proliferation, pituitary pttg mRNA, bFGF, and VEGF expression increased approximately threefold during proestrus and estrus. […] Antiestrogen treatment of primary human pituitary tumor cultures reduced PTTG expression approximately 65%.

• #32 Cushing syndrome – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/cushing-syndrome/symptoms-causes/syc-20351310

  Cushing syndrome is caused by having too much cortisol in the body. Cortisol is a hormone that is made in the adrenal glands. It helps the body respond to stress and plays many other important roles, including: […] A hormone made in the pituitary gland controls how much cortisol the body makes. This is called adrenocorticotropic hormone (ACTH). Some tumors make ACTH, which creates more cortisol and can cause Cushing syndrome. Problems with the adrenal glands also can affect cortisol and cause Cushing syndrome. […] ACTH-producing pituitary adenoma. Pituitary adenomas are tumors that grow in the pituitary gland. They are found at the base of the brain and are usually not cancer. These tumors sometimes make too much ACTH. This causes the adrenal glands to make extra cortisol. When Cushing syndrome happens this way, it’s called Cushing disease. It happens more often in women and is the most common type of endogenous Cushing syndrome.

• #33

  https://link.springer.com/article/10.1007/s007010050368

  Modern theory of tumorigenesis suggests that genetic alterations may play a role in the initiation and promotion of pituitary adenomas. Gsp and MEN-1 genes play a role in the initiation event, while p53, ras, Rb and nm23 genes play some role in the progression of the tumor. Gsp gene, that may play an important role in 40% of GH-producing tumor, activation of 10% of non-functioning tumors and 6% of corticotroph adenomas, produces cAMP, which stimulates cyclin D1 and D3 which later produce cdk2 and cdk 4 respectively, and stimulates cell progression from G1 to S phase. […] MEN-1 gene, although found in some sporadic tumors, is more likely associated with familial adenoma. p53, Ras, Rb, nm23 and c-myc genes play some role in the promotion of tumors especially toward their aggressive variant. p53 gene, which is found in up to 60% of ACTH producing adenomas, through action of p21 inhibits progression of cell cycle from G1 to S phase, by inhibiting the action of cyclin D3 on cdk 4.

• #34 A review of multiomics platforms in pituitary adenoma pathogenesis

  https://www.imrpress.com/journal/FBL/27/3/10.31083/j.fbl2703077/htm

  Nonfunctioning pituitary adenomas (NF-PitNETs) are typically benign, characterized by their absence of hormonal overproduction, and show specific molecular changes that are hallmarks to their pathogenesis. […] Two major signaling pathways at the genomic level contribute to the pathogenesis of nonfunctioning pituitary adenomas: phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK). […] The MAPK signaling can be dysregulated in NF-PitNETs through alterations in the ERK1/2, JNK, p38 and ERK5 pathways. […] Genome-wide methylation assays of functioning vs. nonfunctioning adenomas revealed that NF-PitNETs, in general, are defined by a higher frequency of gene hypermethylation. […] The most frequent somatic change in somatotroph PitNETs is the heterozygous gain-of-function mutation of the GNAS gene.

• #35 A review of multiomics platforms in pituitary adenoma pathogenesis

  https://www.imrpress.com/journal/FBL/27/3/10.31083/j.fbl2703077/htm

  Although most pituitary tumors are sporadic in nature, 5% of PitNETs are driven by monogenic germline mutations. […] The familial subset of PitNETs can be divided into isolated (only pituitary affected) and syndromic, such as multiple endocrine neoplasia 1 and 4 (MEN1/4), neurofibromatosis type 1, and Carney complex.

• #36 Revista Española Endocrinología Pediátrica – Advances in the diagnosis, treatment and molecular genetics of pituitary tumors in childhood

  https://www.endocrinologiapediatrica.org/modules.php?name=articulos&idarticulo=45&idlangart=ES

  Pituitary tumors are rare in childhood and adolescence, with a reported prevalence of up to 1 per million children. […] Although pituitary tumors in children are almost never malignant and hormonal secretion is rare, these tumors may result in significant morbidity. […] The study of pituitary tumorigenesis in the context of these genetic syndromes has advanced our knowledge of the molecular basis of pituitary tumors and may lead to new therapeutic developments. […] In general, mutations in genes involved in genetic syndromes associated with pituitary tumors are not a common finding in sporadic lesions. […] In contrast MEN1 and AIP mutations may be more frequent among specific subgroups of patients, such as in children and young adults with growth hormone-producing adenomas. […] The majority of pituitary tumors are sporadic; however in children more commonly than in adults, they can be part of a genetic condition predisposing to pituitary and other tumors.

• #37 Revista Española Endocrinología Pediátrica – Advances in the diagnosis, treatment and molecular genetics of pituitary tumors in childhood

  https://www.endocrinologiapediatrica.org/modules.php?name=articulos&idarticulo=45&idlangart=ES

  Most pituitary tumors are monoclonal lesions and modifications in expression of various oncogenes or tumor suppressor genes, including GNAS, PTTG, HMGA2, and FGFR-4 have been identified. […] Pituitary tumor development and cell growth are likely influenced by both pituitary and hypothalamic factors. […] Other factors and genetic events seem to be implicated in pituitary cell clonal expansion, and oncogene activation is necessary to propagate tumor growth. […] An example of this secondary phenomenon is the widespread presence of GNAS activating mutations in sporadic GH-secreting pituitary tumors (in up to 40% of all such lesions). […] Four genetic conditions associated with pituitary tumors include: Carney complex (CNC), McCune Albright syndrome (MAS), multiple endocrine neoplasia type 1 (MEN1), and familial isolated pituitary adenomas (FIPA) provide useful models to advance our knowledge of the molecular basis of pituitary tumors.

• #38 Revista Española Endocrinología Pediátrica – Advances in the diagnosis, treatment and molecular genetics of pituitary tumors in childhood

  https://www.endocrinologiapediatrica.org/modules.php?name=articulos&idarticulo=45&idlangart=ES

  Genetic defects in one of the regulatory subunits of protein kinase A (PKA) (regulatory subunit type 1 alpha, PRKAR1A) causes CNC. […] Somatic mutations on the adenylate cyclase-stimulating G alpha protein (GNAS complex locus, GNAS) are found in McCune Albright syndrome. […] The disorder is due to inactivating mutations in the menin gene, a tumor suppressor, which has been localized to chromosome 11q(13). […] Inactivation mutations of the gene encoding aryl hydrocarbon receptor-interacting protein (AIP) were found in patients with pituitary tumors (typically acromegaly) in both sporadic and familial settings. […] Significant improvements in the diagnosis and interventions for pituitary tumors in childhood and adolescence have resulted from advances in diagnostic testing, neuroimaging, microneurosurgery, and pharmacological interventions.

• #39 Mechanisms of Disease: The Pathogenesis of Pituitary Tumors

  https://www.medscape.com/viewarticle/530480

  Adenohypophysiotropic hormones promote proliferation in transformed pituitary cells, but it seems that hormone excess alone does not cause pituitary tumors. […] Abnormal hormone receptor signaling contributes to dysfunctional responses to feedback inhibition; however, apart from one subtype of growth-hormone-secreting adenomas, hormone receptor alterations do not seem to be common events that can be implicated in the etiology and pathogenesis of the majority of pituitary adenomas. […] Altered signaling by proteins such as the G-protein oncogene that are involved in signal transduction of hormones and growth factors might be implicated in pituitary tumorigenesis, in a subset of pituitary somatotroph adenomas. […] There is emerging convincing evidence for the important role of growth factors, and in particular, the fibroblast growth factor system, in pituitary development and tumor formation.

• #40 Pathogenesis of pituitary tumors. – Document – Gale OneFile: Health and Medicine

  https://go.gale.com/ps/i.do?id=GALE%7CA254971548&sid=googleScholar&v=2.1&it=r&linkaccess=abs&issn=17595029&p=HRCA&sw=w

  Pituitary adenomas may hypersecrete hormones (including prolactin, growth hormone and adrenocorticotropic hormone, and rarely follicle-stimulating hormone, luteinizing hormone or TSH) or may be nonfunctional. […] Pathogenesis of dysregulated pituitary cell proliferation and unrestrained hormone hypersecretion may be mediated by hypothalamic, intrapituitary and/or peripheral factors. […] Altered expression of pituitary cell cycle genes, activation of pituitary selective oncoproteins or loss of pituitary suppressor factors may be associated with aberrant growth factor signaling. […] Understanding subcellular mechanisms that underlie pituitary tumorigenesis will enable development of tumor aggression markers as well as novel targeted therapies.

• #41 Genomic and molecular characterization of pituitary adenoma pathogenesis: review and translational opportunities in: Neurosurgical Focus Volume 48 Issue 6 (2020) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/48/6/article-pE11.xml

  Although not currently a prominent aspect in the clinical management of pituitary adenomas, genomics and epigenomic studies may become essential in refining patient care and developing novel pharmacological agents. Future basic science investigations should aim at elucidating mechanistic understandings unique to each pituitary adenoma subtype, which will facilitate rational drug design. […] The fundamental cellular processes underlying pituitary adenoma pathogenesis are aberrant epigenetic regulation, cell cycle dysregulation, and growth signaling imbalance. […] Uncontrolled progression through the cell cycle is a primary driver of pituitary adenoma growth. […] Overall, deregulation in the Rb/p16/cyclin D1/CDK4 pathway is present in up to 80% of pituitary adenomas. […] One of the hallmarks of tumorigenesis is an imbalance in pro- versus antiproliferative cellular signaling. This aberration can be seen in pituitary adenoma cell signaling, which reveals both a decrease in growth suppression signals and an excess of progrowth signaling.

• #42 Mechanisms of Disease: the pathogenesis of pituitary tumors | Nature Reviews Endocrinology

  https://www.nature.com/articles/ncpendmet0159

  Pituitary tumors exhibit a spectrum of biology, with variable growth and hormonal behaviors. They therefore provide an opportunity to examine pathogenetic mechanisms that underlie the neoplastic process. […] These include alterations in hormone regulation, growth-factor stimulation, cell-cycle control and cell-stromal interactions that result from genetic mutations or epigenetic disruption of gene expression. […] Mouse models have validated the roles of these alterations, which can be targets for the development of therapies that can manage these lesions. […] These therapies are increasingly recognized as critical for quality of life. […] Adenohypophysiotropic hormones promote proliferation in transformed pituitary cells, but it seems that hormone excess alone does not cause pituitary tumors.

• #43 The clinical characteristics and molecular mechanism of pituitary adenoma associated with meningioma | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-2103-0

  In the present study, we found that lower expression of MEN1 play an important role in PAM by upregulating the mTOR signaling pathway. […] The factors involved in the AKT/mTOR pathway have been known to participate in the tumorigenesis and tumor progression of pituitary adenoma and meningioma. […] These results suggested that the low expression of MEN1 could activate the expression of factors involved in the mTOR signaling pathway. […] Therefore, these results indicated that rapamycin represent potential therapeutic strategy for PAM in the future.

• #44 Advances in the mechanism of action of metformin in pituitary tumors

  https://www.wjgnet.com/2308-3840/abstract/v11/i5/144.htm

  Pituitary tumors are common intracranial tumors, but when faced with drug-resistant or aggressive tumors, existing medical measures may not provide good control, leading to progression and deterioration. […] Metformin, a traditional hypoglycemic drug, has recently been discovered to have multiple functions including antitumor effects. […] There have been studies on the mechanism of metformin for the treatment of pituitary tumors, but it is uncertain whether it will provide new adjuvant or alternative therapies for the treatment of these tumors. […] We analyzed the potential mechanisms of action of metformin with respect to the inhibition of pituitary tumor growth and hormone secretion by reviewing the available literature. […] We analyzed the potential mechanisms of action of metformin on the inhibition of pituitary tumor growth and hormone secretion by reviewing the available literature.

• #45 Matrine inhibits the proliferation of pituitary tumor cells by decreasing Foxo3a phosphorylation and promoting Foxo3a nuclear localization

  https://www.spandidos-publications.com/10.3892/etm.2019.7365

  Pituitary tumors account for 10% of intracranial cancer, and are difficult to treat with chemotherapy. […] The aim of the present study was to explore the role of matrine on the proliferation of pituitary cancer cells, as well as the molecular mechanism of matrine in progression and development of pituitary tumors. […] Matrine significantly suppressed the proliferation of pituitary cancer cells in a dose and time-dependent manner. […] Western blotting results showed that the phosphorylation levels of AKT serine/threonine kinase (Akt) and forkhead box O3A (Foxo3a) decreased as the concentration of matrine increased. […] Matrine increased the nuclear localization of Foxo3a and the expression of pro-apoptotic genes, such as BCL2 like 11 and BCL2 associated X apoptosis regulator, and inhibited the levels of cytoplasmic Foxo3a.

• #46 Genomic and molecular characterization of pituitary adenoma pathogenesis: review and translational opportunities in: Neurosurgical Focus Volume 48 Issue 6 (2020) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/48/6/article-pE11.xml

  Innovations in genomics, epigenomics, and transcriptomics now lay the groundwork for therapeutic interventions against neoplastic disease. In the past 30 years, the molecular pathogenesis of pituitary adenomas has been characterized. This enhanced understanding of the biology of pituitary tumors has potential to impact current treatment paradigms, and there exists significant translational potential for these results. […] Pituitary adenoma growth is primarily driven by unrestrained cell cycle progression, deregulation of growth and proliferation pathways, and abnormal epigenetic regulation of gene expression. These pathways may be amenable to therapeutic intervention. A significant number of studies have attempted to establish links between gene mutations and tumor progression, but a thorough mechanistic understanding remains elusive.

• #47 Management of Pituitary Tumors: Focus on Carcinomas

  https://www.uspharmacist.com/article/management-of-pituitary-tumors-focus-on-carcinomas

  Pituitary carcinomas, which are extremely rare, are characterized by poor prognosis. […] Although various markers of molecular pathogenesis have been proposed, none are reliable predictors of disease progression or outcome. […] Pituitary carcinomas are defined by the presence of cerebrospinal and/or systemic metastasis. […] Whether carcinomas occur de novo or progress from atypical adenomas is unknown. […] However, most pituitary carcinomas are believed to arise from aggressive pituitary adenomas that transition to malignancy, leading to development of distant metastases. […] Supporting evidence comes from 1) initial presentation as macroadenoma (1 cm), with multiple recurrences despite medical therapy, surgery, and RT; 2) long latency period for progression to carcinoma (up to 18 years); and 3) progressive accumulation of genetic changes.

• #48

  https://journals.lww.com/md-journal/fulltext/2016/11220/genetic_aspects_of_pituitary_carcinoma__a.14.aspx

  Pituitary carcinoma (PC) is a rare type of malignant intracranial neoplasm defined as distant metastasis of pituitary adenoma (PA). […] The lack of efficacy of current treatments is largely caused by the limited understanding of the molecular pathogenesis of PA and the malignant transformation to PC. […] Previous studies demonstrated that many genes promote PC malignant transformation, angiogenesis, invasion, metastasis, and recurrence. […] Understanding the genetic pathogenesis of PC is essential for the accurate and effective treatment of the disease. […] The identification of PC-specific molecular biomarkers would contribute to the improvement of current diagnostic criteria and to the development of targeted therapeutic approaches, which would potentially increase the long-term survival of PC patients.

• #49 A review of multiomics platforms in pituitary adenoma pathogenesis

  https://www.imrpress.com/journal/FBL/27/3/10.31083/j.fbl2703077/htm

  The advancement of next generation sequencing genomics, including methylomics, transcriptomics, proteomics and even glycomics, have reinvigorated the discovery of disease pathogenesis. The integration of multiple platforms, termed multiomics, can be an effective way to understand disease across different levels of gene regulation. […] While the 2017 WHO classification transitioned towards the use of transcription factor use for tumor identification, there has also been a rapidly growing body of literature on the multiomic dysregulations that contribute to the pathogenesis of nonfunctioning, functioning, and familial pituitary adenomas. For each type of tumor, we discuss the genomics, epigenetic, exomic, transcriptomic, and proteomic dysregulations as well as provide their clinical correlates.

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