Expression of kisspeptin and KISS1 receptor in pituitary neuroendocrine tumours — an immunohistochemical study
Abstract
Introduction: Pituitary neuroendocrine tumours (PitNETs), traditionally designated as pituitary adenomas, show elatively frequent invasive growth with exceptional metastatic potential, the causes of which are not entirely elucidated. Kisspeptins, which perform their activity through KISS1 receptor (KISS1R), are recognised as metastatic suppressors in many malignant tumours. This study aimed to investigate the immunohistochemical expression of kisspeptin and KISS1R in different types of PitNETs and to compare it with the expression in the normal anterior pituitary, using tissue microarray.
Material and methods: The experimental group consisted of 101 patients with PitNETs, with 45 (37.3%) being of gonadotroph, 40 (33.9%) somatotroph, 4 (3.4%) corticotroph, 4 (3.4%) thyrotroph, 3 (2.5%) lactotroph, and 6 (5.1%) null-cell type. The control group consisted of anterior pituitary tissue accidentally removed during the surgery for PitNETs in 17 patients.
Results: Kisspeptin expression was observed in both experimental and control groups, without statistically significant differences in the staining intensity. Negative kisspeptin staining was detected in 10 (9.9%), weak in 79 (78.2%), and moderate in 12 tumours (11.9%); none of the tumours had strong staining intensity. The weak staining intensity was predominant in all PitNET types except thyrotroph tumours. Significant statistical difference in terms of kisspeptin expression between types of PitNET and the control group was not observed. Immunohistochemical expression of KISS1R was not observed in the control group or in the experimental group.
Conclusions: We conclude that immunohistochemistry, as a method, cannot confirm the involvement of kisspeptin in tumourigenesis and aggressiveness of PitNETs, but potentially supports its antimetastatic role. The absence of KISS1R immunohistochemical expression in all anterior pituitaries and PitNETs in our cohort needs verification through the use of different procedures designed for the detection of the presence and localisation of proteins in the cell.
Keywords: kisspeptinKISS1 receptorpituitary adenomaPitNETimmunohistochemistry
References
- Asa SL, Casar-Borota O, Chanson P, et al. attendees of 14th Meeting of the International Pituitary Pathology Club, Annecy, France, November 2016. From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal. Endocr Relat Cancer. 2017; 24(4): C5–C8.
- Raverot G, Burman P, McCormack A, et al. European Society of Endocrinology. European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol. 2018; 178(1): G1–G24.
- Yang Qi, Li X, Yang Qi, et al. Molecular Network Basis of Invasive Pituitary Adenoma: A Review. Front Endocrinol (Lausanne). 2019; 10: 7.
- Lloyd RV, Osamura RY, Kloppel G, Rosai J. World Health Organization classification of tumours of endocrine organs. 4th ed. IARC Press, Lyon 2017.
- Trouillas J, Burman P, McCormack A, et al. Aggressive pituitary tumours and carcinomas: two sides of the same coin? Eur J Endocrinol. 2018; 178(6): C7–C9.
- Lee JH, Miele ME, Hicks DJ, et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst. 1996; 88(23): 1731–1737.
- West A, Vojta PJ, Welch DR, et al. Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISS1). Genomics. 1998; 54(1): 145–148.
- Kotani M, Detheux M, Vandenbogaerde A, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 2001; 276(37): 34631–34636.
- Lee DK, Nguyen T, O'Neill GP, et al. Discovery of a receptor related to the galanin receptors. FEBS Lett. 1999; 446(1): 103–107.
- Harihar S, Ray S, Narayanan S, et al. Role of the tumor microenvironment in regulating the anti-metastatic effect of KISS1. Clin Exp Metastasis. 2020; 37(2): 209–223.
- Schmid K, Wang X, Haitel A, et al. KiSS-1 overexpression as an independent prognostic marker in hepatocellular carcinoma: an immunohistochemical study. Virchows Arch. 2007; 450(2): 143–149.
- Marot D, Bieche I, Aumas C, et al. High tumoral levels of Kiss1 and G-protein-coupled receptor 54 expression are correlated with poor prognosis of estrogen receptor-positive breast tumors. Endocr Relat Cancer. 2007; 14(3): 691–702.
- Jarzabek K, Koda M, Kozlowski L, et al. Immunohistochemical study of KiSS1 and KiSS1R expression in human primary breast cancer: Association with breast cancer receptor status, proliferation markers and clinicopathological features. Histol Histopathol. 2015; 30(6): 715–723.
- Trevisan CM, Montagna E, de Oliveira R, et al. Kisspeptin/GPR54 System: What Do We Know About Its Role in Human Reproduction? Cell Physiol Biochem. 2018; 49(4): 1259–1276.
- Martínez-Fuentes AJ, Molina M, Vázquez-Martínez R, et al. Expression of functional KISS1 and KISS1R system is altered in human pituitary adenomas: evidence for apoptotic action of kisspeptin-10. Eur J Endocrinol. 2011; 164(3): 355–362.
- Yaron M, Renner U, Gilad S, et al. KISS1 receptor is preferentially expressed in clinically non-functioning pituitary tumors. Pituitary. 2015; 18(3): 306–311.
- Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998; 4(7): 844–847.
- Kostakis ID, Agrogiannis G, Vaiopoulos AG, et al. A clinicopathological analysis of KISS1 and KISS1R expression in colorectal cancer. APMIS. 2015; 123(7): 629–637.
- Sun YB, Xu S. Expression of KISS1 and KISS1R (GPR54) may be used as favorable prognostic markers for patients with non-small cell lung cancer. Int J Oncol. 2013; 43(2): 521–530.
- Sanchez-Carbayo M, Capodieci P, Cordon-Cardo C. Tumor suppressor role of KiSS-1 in bladder cancer: loss of KiSS-1 expression is associated with bladder cancer progression and clinical outcome. Am J Pathol. 2003; 162(2): 609–617.
- Fratangelo F, Carriero MV, Motti ML. Controversial Role of Kisspeptins/KiSS-1R Signaling System in Tumor Development. Front Endocrinol (Lausanne). 2018; 9: 192.
- Ringel MD, Hardy E, Bernet VJ, et al. Metastin receptor is overexpressed in papillary thyroid cancer and activates MAP kinase in thyroid cancer cells. J Clin Endocrinol Metab. 2002; 87(5): 2399.
- Savvidis C, Papaoiconomou E, Petraki C, et al. The role of KISS1/KISS1R system in tumor growth and invasion of differentiated thyroid cancer. Anticancer Res. 2015; 35(2): 819–826.
- Manojlovic-Gacic E, Bollerslev J, Casar-Borota O. Invited Review: Pathology of pituitary neuroendocrine tumours: present status, modern diagnostic approach, controversies and future perspectives from a neuropathological and clinical standpoint. Neuropathol Appl Neurobiol. 2020; 46(2): 89–110.
- Nash KT, Phadke PA, Navenot JM, et al. Requirement of KISS1 secretion for multiple organ metastasis suppression and maintenance of tumor dormancy. J Natl Cancer Inst. 2007; 99(4): 309–321.
- Richard N, Galmiche G, Corvaisier S, et al. KiSS-1 and GPR54 genes are co-expressed in rat gonadotrophs and differentially regulated in vivo by oestradiol and gonadotrophin-releasing hormone. J Neuroendocrinol. 2008; 20(3): 381–393.
- Hershey JWB, Sonenberg N, Mathews MB. Principles of Translational Control. Cold Spring Harb Perspect Biol. 2019; 11(9).
- Torlakovic EE, Cheung CC, D'Arrigo C, et al. From the International Society for Immunohistochemistry and Molecular Morphology (ISIMM) and International Quality Network for Pathology (IQN Path). Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine. Part 3: Technical Validation of Immunohistochemistry (IHC) Assays in Clinical IHC Laboratories. Appl Immunohistochem Mol Morphol. 2017; 25(3): 151–159.
- Taylor CR. Milestones in Immunohistochemistry and Molecular Morphology. Appl Immunohistochem Mol Morphol. 2020; 28(2): 83–94.
