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The hallmarks of cancer… in pituitary tumors?

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Abstract

Over 20 years ago, Hanahan and Weinberg published a seminal review that addressed the biological processes that underly malignant transformation. This classical review, along with two revisions published in 2011 and 2022, has remain a classic of the oncology literature. Since many of the addressed biological processes may apply to non-malignant tumorigenesis, we evaluated to what extent these hallmarks pertain to the development of pituitary adenomas.

Some of the biological processes analyzed in this review include genome instability generated by somatic USP8 and GNAS mutations in Cushing’s diseases and acromegaly respectively; non-mutational epigenetic reprograming through changes in methylation; induction of angiogenesis through alterations of VEGF gene expression; promotion of proliferative signals mediated by EGFR; evasion of growth suppression by disrupting cyclin dependent kinase inhibitors; avoidance of immune destruction; and the promotion of inflammation mediated by alteration of gene expression of immune check points. We also elaborate further on the existence of oncogene induced senescence in pituitary tumors. We conclude that a better understanding of these processes can help us dilucidated why pituitary tumors are so resistant to malignant transformation and can potentially contribute to the development of novel anticancer treatments.

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Abbreviations

PA:

Pituitary Adenoma

CNFPA:

Clinically Non-Functioning Pituitary Adenoma

GH:

Growth Hormone

PRL:

Prolactin

TSH:

Thyroid Stimulating Hormone

ACTH:

Adrenocorticotrophic Hormone

POU1F1 / Pit-1:

Pituitary-specific Positive Transcription factor-1

TBX19 / T-Pit:

T-Box Transcription Factor 19

LH:

Luteinizing Hormone

FSH:

Follicle-Stimulating Hormone

NR5A1 / SF-1:

Nuclear Receptor Subfamily 5 Group A Member 1 / Steroidogenic Factor-1

MEN:

Multiple Endocrine Neoplasia

CDKN:

Cyclin Dependent Kinase

PRKAR1A:

Regulatory Alpha-subunit of Protein Kinase A

SDNH:

Succinate-Dehydrogenase

RNAse:

Ribonuclease

FIPA:

Familial Isolated Pituitary Adenoma

AIP:

Aryl-hydrocarbon receptor Interacting Protein

X-LAG:

X-Linked Acrogigantism

GPR101:

G Protein-coupled Receptor 101

USP8:

Ubiquitin Specific peptidase 8

EGFR:

Epidermal Growth Factor Receptor

POMC:

Proopiomelanocortin

GNAS:

Guanine Nucleotide binding protein Alpha Subunit

GHRH:

Growth Hormone Releasing Hormone

CREB:

CAMP Response Element Binding protein

CNV:

Copy number variation

CACNA2D4:

Calcium Voltage-Gated Channel Auxiliary Subunit Alpha2delta 4

GRIA2 / GRIA4:

Glutamate Ionotropic Receptor AMPA Type Subunit 2 / Subunit 4

AVPR1B:

Arginine Vasopressin Receptor 1B

EPHA4:

EPH Receptor A4

GRIN2B:

Glutamate Receptor subiunit epsilon 2

TMEM233:

Transmembrane Protein 233

miRNA:

MicroRNA (miR)

UTR:

Untranslated Regions

mRNA:

Messenger RNA

lncRNA:

Long non-coding RNAs

LINC00473:

Long Intergenic Non-Protein Coding RNA 473

KMT5A:

Lysine Methyltransferase 5A

RPSAP52:

Ribosomal protein SA pseudogene 52

HMGA1 / 2:

High Mobility Group AT-Hook 1 / 2

XIST:

X-Inactive Specific Transcript

VEGF:

Vascular Endothelial Growth Factor

BCL-2:

B Cell Lymphoma 2

FGF2:

Fibroblast Growth Factor 2

CD31 / PECAM-1:

Cluster of Differentiation 31 / Platelet Endothelial Cell Adhesion Molecule

BAX:

Bcl-2-Associated X protein 4

SSTR2 / 5:

Somatostatin Receptor 2 / 5

TP53 / p53:

Tumor Protein 53

FGFR1-4:

Fibroblast growth factor receptor 1 / 2 / 3 / 4

STAT3:

Signal transducer and activators of transcription type 3

mTOR:

Mammalian Target Of Rapamycin

IGF-1:

Insulin like Growth Factor-1

PTTG-1:

Pituitary Tumor Transforming Gene protein-1

MAPK:

Mitogen Activated Protein Kinases

ETNK2:

Ethanolamine Kinase 2

MERTK:

Proto-oncogene tyrosine-protein kinase MER

PIP5K1B:

Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Beta

CDK:

Cyclin-dependent Kinases

CDKN1A / 2A / 1B / 2C:

Cyclin-dependent kinase inhibitor 1A / 2A / 1B / 2C

GADD45:

Growth Arrest and DNA Damage-inducible protein 45

CABLES1:

Cdk5 And Abl Enzyme Substrate 1

TERT:

Telomerase reverse transcriptase

TERC:

Telomerase RNA Component

CD27 / 28 / 37:

Cluster of Differentiation 27 / 28 / 37

ICOS:

Inducible T cell co-stimulator

OX40:

Tumor necrosis factor receptor superfamily 4

CTLA-4:

Cytotoxic T lymphocyte associated protein 4

PD1:

Programmed Death 1

PD-L1:

PD Ligand 1

IL8 / 6 / 1ß:

Interlukin 8 / 6 / 1ß

CCL2 / 3 / 4 / 10 / 22:

C-C Motif Chemokine Ligand 2 / 3 / 4 / 10 / 22

CX3CL1:

C-X3-C motif Chemokine Ligand 1

CXCL1:

C-X-C motif Chemokine Ligand 1

CD8 + T Lymphocytes:

Cytotoxic T Lymphocytes

CD4 + T Lymphocytes:

T-helper cells

NK cells:

Natural Killer cells

M2 macrophages:

Alternative activated macrophages

LDHA:

Lactate Dehydrogenase A

NAD:

Nicotinamide Adenine Dinucleotide

GLUT-1:

Glucose Transporter 1

MMP2 / 9 :

Matrix Metalloproteinase 2 / 9

FASN:

Fatty Acid Synthase

p21:

Cyclin-dependent kinase inhibitor 1

p16:

Cyclin-dependent kinase inhibitor 2A

pRB:

Retinoblastoma protein

E2F:

E2 Factor

TGFß:

Transforming Growth Factor ß

p19:

Teratocarcinoma cell line P19

E-CAD:

E-cadherin

EMT:

Epithelial-Mesenchymal Transition

N-CAD:

N-cadherin / Cadherin-2 / Neural Cadherin

EPCAM:

Epithelial Cell Adhesion Molecule

SMAD3:

Mothers Against Decapentaplegic homolog 3

SNAI2:

Snail Family Transcriptional Repressor 2

PITX2:

Paired Like Homeodomain 2

ECM:

Extracellular Matrix

PKC:

Protein Kinase C

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  1. Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, México, D.F., 06720, Mexico City, Mexico

    Daniel Marrero-Rodríguez, Keiko Taniguchi-Ponciano, Jacobo Kerbel, Amayrani Cano-Zaragoza, Ilan Remba-Shapiro, Gloria Silva-Román, Sandra Vela-Patiño, Sergio Andonegui-Elguera, Alejandra Valenzuela-Perez & Moisés Mercado

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All authors contributed to the writing. KTP and MM performed the literature search and revised the work. DMR, JK, ACZ, IRS, GSR, SVP, AES, AVP performed the literature search. All authors read and approved the final manuscript.

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Marrero-Rodríguez, D., Taniguchi-Ponciano, K., Kerbel, J. et al. The hallmarks of cancer… in pituitary tumors?. Rev Endocr Metab Disord 24, 177–190 (2023). https://doi.org/10.1007/s11154-022-09777-y

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