The expression of neural cell adhesion molecule and the microenvironment of pituitary neuroendocrine tumours.
Cells, Cultured
Cohort Studies
Female
Humans
Immunohistochemistry
Lymphocytes, Tumor-Infiltrating
/ metabolism
Male
Neoplasm Invasiveness
/ pathology
Neural Cell Adhesion Molecules
/ metabolism
Neuroendocrine Tumors
/ metabolism
Pituitary Gland
/ metabolism
Pituitary Neoplasms
/ metabolism
Tumor Microenvironment
neural cell adhesion molecule
pituitary adenoma
pituitary neuroendocrine tumour
tumour microenvironment
Journal
Journal of neuroendocrinology
ISSN: 1365-2826
Titre abrégé: J Neuroendocrinol
Pays: United States
ID NLM: 8913461
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
revised:
09
09
2021
received:
17
07
2021
accepted:
06
10
2021
pubmed:
29
10
2021
medline:
22
3
2022
entrez:
28
10
2021
Statut:
ppublish
Résumé
The neural cell adhesion molecule (NCAM) has previously been studied in pituitary neuroendocrine tumours (PitNETs), but its role in tumour biology and aggressiveness remains controversial, and its relationship with the tumour microenvironment remains unknown. We aimed to characterise NCAM expression in PitNETs, to correlate this with clinico-pathological features, and to assess the role of various microenvironment components on NCAM expression. NCAM and immune cells were investigated by immunohistochemistry in 16 human non-functioning-PitNETs (NF-PitNETs) and eight somatotrophinomas, including macrophages (CD68, CD163, HLA-DR), cytotoxic (CD8) and T helper (CD4) lymphocytes, regulatory T cells (FOXP3), B cells (CD20), and neutrophils (neutrophil elastase). Five normal pituitaries were included for comparison. The cytokine secretome from these PitNETs and from PitNET-derived tumour-associated fibroblasts (TAFs) were assessed on culture supernatants using a multiplex immunoassay panel. There were no significant NCAM expression differences between PitNETs and normal pituitary, and no difference between types of pituitary tumours (NF-PitNETs vs. somatotrophinomas). There was no association between NCAM expression and different clinico-pathological features, including cavernous sinus invasion and Ki-67, nor with serum hormone levels. NCAM immunoreactivity correlated negatively with PitNET-derived CXCL10 (rho = -0.417; p = .042) and CX3CL1 (rho = -0.423; p = .040) levels. NCAM immunoreactivity was negatively correlated with TAF-derived fibroblast growth factor (FGF)-2 (rho = -0.632; p = .009), but not with other TAF-derived cytokines. Within the PitNET cohort, there were no correlations between NCAM immunoreactivity and immune infiltrates or ratios, although, within NF-PitNETs, NCAM expression was higher in tumours with more FOXP3+ cells. NCAM expression does not differ between PitNETs and normal pituitary, and does not appear to relate to tumour invasiveness or proliferation. However, our data suggest a possible role for cytokines in the modulation of NCAM expression in PitNETs, particularly CXCL10, CX3CL1 and FGF-2, but not for immune cell infiltrates.
Substances chimiques
Neural Cell Adhesion Molecules
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13052Subventions
Organisme : Medical Research Council
ID : MR/M018539/1
Pays : United Kingdom
Organisme : Medical Research Council (UK)
Informations de copyright
© 2021 British Society for Neuroendocrinology.
Références
Molitch ME. Diagnosis and treatment of pituitary adenomas: a review. JAMA. 2017;317(5):516-524.
Kasuki L, Raverot G. Definition and diagnosis of aggressive pituitary tumors. Rev Endocr Metab Disord. 2020;21(2):203-208.
Trouillas J, Jaffrain-Rea ML, Vasiljevic A, Raverot G, Roncaroli F, Villa C. How to classify the Pituitary Neuroendocrine Tumors (PitNET)s in 2020. Cancers (Basel). 2020;12(2):514.
Barbieri F, Bajetto A, Stumm R, et al. Overexpression of stromal cell-derived factor 1 and its receptor CXCR4 induces autocrine/paracrine cell proliferation in human pituitary adenomas. Clin Cancer Res. 2008;14(16):5022-5032.
Mei YU, Bi WL, Greenwald NF, et al. Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors. Oncotarget. 2016;7(47):76565-76576.
Lupi I, Manetti L, Caturegli P, et al. Tumor infiltrating lymphocytes but not serum pituitary antibodies are associated with poor clinical outcome after surgery in patients with pituitary adenoma. J Clin Endocrinol Metab. 2010;95(1):289-296.
Xing B, Kong YG, Yao Y, Lian W, Wang RZ, Ren ZY. Study on the expression levels of CXCR4, CXCL12, CD44, and CD147 and their potential correlation with invasive behaviors of pituitary adenomas. Biomed Environ Sci. 2013;26(7):592-598.
Yoshida D, Koketshu K, Nomura R, Teramoto A. The CXCR4 antagonist AMD3100 suppresses hypoxia-mediated growth hormone production in GH3 rat pituitary adenoma cells. J Neurooncol. 2010;100(1):51-64.
Marques P, Barry S, Carlsen E, et al. Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours. Acta Neuropathol Commun. 2019;7(1):172.
Marques P, Barry S, Carlsen E, et al. Pituitary tumour fibroblast-derived cytokines influence tumour aggressiveness. Endocr Relat Cancer. 2019;26(12):853-865.
Weledji EP, Assob JC. The ubiquitous neural cell adhesion molecule (N-CAM). Ann Med Surg (Lond). 2014;3(3):77-81.
Rubinek T, Yu R, Hadani M, et al. The cell adhesion molecules N-cadherin and neural cell adhesion molecule regulate human growth hormone: a novel mechanism for regulating pituitary hormone secretion. J Clin Endocrinol Metab. 2003;88(8):3724-3730.
Trouillas J, Daniel L, Guigard M-P, et al. Polysialylated neural cell adhesion molecules expressed in human pituitary tumors and related to extrasellar invasion. J Neurosurg. 2003;98(5):1084-1093.
Van Acker HH, Capsomidis A, Smits EL, Van Tendeloo VF. CD56 in the immune system: more than a marker for cytotoxicity? Front Immunol. 2017;8:892.
Langley OK, Aletsee-Ufrecht MC, Grant NJ, Gratzl M. Expression of the neural cell adhesion molecule NCAM in endocrine cells. J Histochem Cytochem. 1989;37(6):781-791.
Schmid R-S, Graff RD, Schaller MD, et al. NCAM stimulates the Ras-MAPK pathway and CREB phosphorylation in neuronal cells. J Neurobiol. 1999;38(4):542-558.
Hinsby AM, Berezin V, Bock E. Molecular mechanisms of NCAM function. Front Biosci. 2004;9:2227-2244.
Cavallaro U, Christofori G. Multitasking in tumor progression: signaling functions of cell adhesion molecules. Ann N Y Acad Sci. 2004;1014:58-66.
Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer. 2004;4(2):118-132.
Raveh S, Gavert N, Ben-Ze'ev A. L1 cell adhesion molecule (L1CAM) in invasive tumors. Cancer Lett. 2009;282(2):137-145.
Daniel L, Bouvier C, Chetaille B, et al. Neural cell adhesion molecule expression in renal cell carcinomas: relation to metastatic behavior. Hum Pathol. 2003;34(6):528-532.
Prag S, Lepekhin EA, Kolkova K, et al. NCAM regulates cell motility. J Cell Sci. 2002;115(Pt 2):283-292.
Crnic I, Strittmatter K, Cavallaro U, et al. Loss of neural cell adhesion molecule induces tumor metastasis by up-regulating lymphangiogenesis. Cancer Res. 2004;64(23):8630-8638.
Pyo JS, Kim DH, Yang J. Diagnostic value of CD56 immunohistochemistry in thyroid lesions. Int J Biol Markers. 2018;33(2):161-167.
Berardi M, Hindelang C, Laurent-Huck FM, et al. Expression of neural cell adhesion molecules, NCAMs, and their polysialylated forms, PSA-NCAMs, in the developing rat pituitary gland. Cell Tissue Res. 1995;280(2):463-472.
Aletsee-Ufrecht MC, Langley K, Gratzl O, Gratzl M. Differential expression of the neural cell adhesion molecule NCAM 140 in human pituitary tumors. FEBS Lett. 1990;272(1-2):45-49.
Kleinschmidt-DeMasters BK, Conway DR, Franklin WA, Lillehei KO, Kruse CA. Neural cell adhesion molecule expression in human pituitary adenomas. J Neurooncol. 1995;25(3):205-213.
De Jong I, Aylwin SJB, Olabiran Y, et al. Expression and secretion of neural cell adhesion molecules by human pituitary adenomas. Ann Clin Biochem. 1999;36(Pt 5):660-665.
Daniel L, Trouillas J, Renaud W, et al. Polysialylated-neural cell adhesion molecule expression in rat pituitary transplantable tumors (spontaneous mammotropic transplantable tumor in Wistar-Furth rats) is related to growth rate and malignancy. Cancer Res. 2000;60(1):80-85.
Mendes GA, Haag T, Trott G, et al. Expression of E-cadherin, Slug and NCAM and its relationship to tumor invasiveness in patients with acromegaly. Braz J Med Biol Res. 2017;51(2):1-8. https://doi.org/10.1590/1414-431X20176808
Mantovani A, Schioppa T, Porta C, Allavena P, Sica A. Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev. 2006;25(3):315-322.
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549-555.
Singhal S, Stadanlick J, Annunziata MJ, et al. Human tumor-associated monocytes/macrophages and their regulation of T cell responses in early-stage lung cancer. Sci Transl Med. 2019;11(479):eaat1500.
Troiano G, Caponio VCA, Adipietro I, et al. Prognostic significance of CD68(+) and CD163(+) tumor associated macrophages in head and neck squamous cell carcinoma: a systematic review and meta-analysis. Oral Oncol. 2019;93:66-75.
Trouillas J, Roy P, Sturm N, et al. A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up. Acta Neuropathol. 2013;126(1):123-135.
Melmed S. Pituitary tumors. Endocrinol Metab Clin North Am. 2015;44(1):1-9.
Raverot G, Dantony E, Beauvy J, et al. Risk of recurrence in pituitary neuroendocrine tumors: a prospective study using a five-tiered classification. J Clin Endocrinol Metab. 2017;102(9):3368-3374.
Ongaratti BR, Haag T, D'Ávila MF, et al. Gene and protein expression of E-cadherin and NCAM markers in non-functioning pituitary adenomas. Ann Diagn Pathol. 2019;38:59-61.
Ramsdell JS, Tashjian AH Jr. GH4 pituitary cell variants selected as nonresponsive to thyrotropin-releasing hormone-enhanced substratum adhesion are nonresponsive to epidermal growth factor: evidence for a common signaling defect. J Cell Physiol. 1989;141(3):565-572.
Meager A. Cytokine regulation of cellular adhesion molecule expression in inflammation. Cytokine Growth Factor Rev. 1999;10(1):27-39.
Harjunpaa H, Llort Asens M, Guenther C, Fagerholm SC. Cell adhesion molecules and their roles and regulation in the immune and tumor microenvironment. Front Immunol. 2019;10:1078.
Chavarria A, Cardenas G. Neuronal influence behind the central nervous system regulation of the immune cells. Front Integr Neurosci. 2013;7:64.
Suzumura A, Sawada M, Yamamoto H, Marunouchi T. Transforming growth factor-beta suppresses activation and proliferation of microglia in vitro. J Immunol. 1993;151(4):2150-2158.
Balzarini P, Benetti A, Invernici G, et al. Transforming growth factor-beta1 induces microvascular abnormalities through a down-modulation of neural cell adhesion molecule in human hepatocellular carcinoma. Lab Invest. 2012;92(9):1297-1309.
Cave DD, Di Guida M, Costa V, et al. TGF-beta1 secreted by pancreatic stellate cells promotes stemness and tumourigenicity in pancreatic cancer cells through L1CAM downregulation. Oncogene. 2020;39(21):4271-4285.
Geertsen R, Zenklusen R, Kamarashev J, Burg G, Dummer R. Inverse regulation of neuronal cellular adhesion molecule (NCAM) by IFN-gamma in melanoma cell cultures established from CNS lesions. Int J Cancer. 1999;83(1):135-140.
Janiszewska M, Primi MC, Izard T. Cell adhesion in cancer: beyond the migration of single cells. J Biol Chem. 2020;295(8):2495-2505.
Downer EJ, Cowley TR, Lyons A, et al. A novel anti-inflammatory role of NCAM-derived mimetic peptide, FGL. Neurobiol Aging. 2010;31(1):118-128.
Ray D, Melmed S. Pituitary cytokine and growth factor expression and action. Endocr Rev. 1997;18(2):206-228.
Spoletini M, Taurone S, Tombolini M, et al. Trophic and neurotrophic factors in human pituitary adenomas (Review). Int J Oncol. 2017;51(4):1014-1024.
Renner U, Paez-Pereda M, Arzt E, Stalla GK. Growth factors and cytokines: function and molecular regulation in pituitary adenomas. Front Horm Res. 2004;32:96-109.
Ezzat S. The role of hormones, growth factors and their receptors in pituitary tumorigenesis. Brain Pathol. 2001;11(3):356-370.
Ezzat S, Melmed S. The role of growth factors in the pituitary. J Endocrinol Invest. 1990;13(8):691-698.
Missale C, Fiorentini C, Finardi A, Spano P. Growth factors in pituitary tumors. Pituitary. 1999;1(3-4):153-158.
Saeger W. Expression of growth factors in normal and neoplastic pituitary tissues. Endocr Pathol. 2000;11(4):295-300.
Spada A, Lania A. Growth factors and human pituitary adenomas. Mol Cell Endocrinol. 2002;197(1-2):63-68.
Kiselyov VV, Soroka V, Berezin V, Bock E. Structural biology of NCAM homophilic binding and activation of FGFR. J Neurochem. 2005;94(5):1169-1179.
Walmod PS, Kolkova K, Berezin V, Bock E. Zippers make signals: NCAM-mediated molecular interactions and signal transduction. Neurochem Res. 2004;29(11):2015-2035.
Takase N, Koma Y-I, Urakawa N, et al. NCAM- and FGF-2-mediated FGFR1 signaling in the tumor microenvironment of esophageal cancer regulates the survival and migration of tumor-associated macrophages and cancer cells. Cancer Lett. 2016;380(1):47-58.
Ditlevsen DK, Povlsen GK, Berezin V, Bock E. NCAM-induced intracellular signaling revisited. J Neurosci Res. 2008;86(4):727-743.
Zecchini S, Bombardelli L, Decio A, et al. The adhesion molecule NCAM promotes ovarian cancer progression via FGFR signalling. EMBO Mol Med. 2011;3(8):480-494.
Griffioen AW, Damen CA, Martinotti S, Blijham GH, Groenewegen G. Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: the role of angiogenic factors. Cancer Res. 1996;56(5):1111-1117.
Akl MR, Nagpal P, Ayoub NM, et al. Molecular and clinical significance of fibroblast growth factor 2 (FGF2 /bFGF) in malignancies of solid and hematological cancers for personalized therapies. Oncotarget. 2016;7(28):44735-44762.
Woodbury ME, Ikezu T. Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration. J Neuroimmune Pharmacol. 2014;9(2):92-101.
Chae YK, Choi WM, Bae WH, et al. Overexpression of adhesion molecules and barrier molecules is associated with differential infiltration of immune cells in non-small cell lung cancer. Sci Rep. 2018;8(1):1023.
Crawford JM, Watanabe K. Cell adhesion molecules in inflammation and immunity: relevance to periodontal diseases. Crit Rev Oral Biol Med. 1994;5(2):91-123.
Goridis C, Brunet JF. NCAM: structural diversity, function and regulation of expression. Semin Cell Biol. 1992;3(3):189-197.
Ren G, Roberts AI, Shi Y. Adhesion molecules: key players in Mesenchymal stem cell-mediated immunosuppression. Cell Adh Migr. 2011;5(1):20-22.
Rodrigues E, Macauley MS. Hypersialylation in cancer: modulation of inflammation and therapeutic opportunities. Cancers (Basel). 2018;10(6):207.