{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T01:33:32Z","timestamp":1777253612744,"version":"3.51.4"},"reference-count":64,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T00:00:00Z","timestamp":1775952000000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100009863","name":"Neuroendocrine Tumor Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009863","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005032","name":"Funda\u00e7\u00e3o Bial","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005032","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Neuroendocrinology"],"published-print":{"date-parts":[[2026,4]]},"abstract":"Abstract<\/jats:title>\n \n The chemokine network in the microenvironment of pituitary neuroendocrine tumours (PitNETs) may modulate tumour biology, aggressiveness, and treatment responses. We aimed to study the role of various chemokines and chemokine receptors in defining PitNET phenotype and clinical outcomes. We included 96 patients (51 females) with available snap\u2010frozen PitNET tissue from surgery between 2014 and 2020. Chemokine and chemokine receptors were studied by RT\u2010qPCR. Fold difference in mRNA expression was calculated using the \u0394\u0394Ct method; chemokine and receptor expression levels were normalised to the expression of the control gene\n TBP<\/jats:italic>\n , and expressed relative to a reference sample. Ten chemokines and receptors were studied (\n CCL2<\/jats:italic>\n ,\n CCL3<\/jats:italic>\n ,\n CCL4<\/jats:italic>\n ,\n CXCL8<\/jats:italic>\n ,\n CX3CL1<\/jats:italic>\n ,\n CCR2<\/jats:italic>\n ,\n CCR4<\/jats:italic>\n ,\n CCR5<\/jats:italic>\n ,\n CXCR1<\/jats:italic>\n ,\n CXCR2<\/jats:italic>\n ), and their expression correlated with clinico\u2010pathological and outcome data, as well as other available microenvironment\u2010related data. We found strong positive correlations between all chemokines and chemokine receptors. Higher chemokine and receptor expression levels were seen in patients who had pituitary apoplexy (\n CCR2<\/jats:italic>\n ,\n CXCR1<\/jats:italic>\n ), hypopituitarism at diagnosis (\n CCL2<\/jats:italic>\n ,\n CCR4<\/jats:italic>\n ), Ki\u201067 >3% (\n CCL4<\/jats:italic>\n ,\n CXCR2<\/jats:italic>\n ), as well as in patients who required re\u2010operation (\n CCL3<\/jats:italic>\n ,\n CXCL8<\/jats:italic>\n ,\n CXCR2<\/jats:italic>\n ), multimodal therapy (\n CCL2<\/jats:italic>\n ), and had active disease at last\u2010follow\u2010up (\n CCL2<\/jats:italic>\n ). There was a positive correlation between the number of pituitary surgeries and expression levels of\n CCL3<\/jats:italic>\n ,\n CXCL8<\/jats:italic>\n ,\n CX3CL1<\/jats:italic>\n ,\n CXCR1<\/jats:italic>\n , and\n CXCR2<\/jats:italic>\n . Compared to nonfunctioning\u2010PitNETs, somatotropinomas had higher expression of\n CCL2, CCL4<\/jats:italic>\n , and\n CCR2<\/jats:italic>\n , and lower expression of\n CX3CL1<\/jats:italic>\n and\n CCR4<\/jats:italic>\n . Expression of\n CDH1<\/jats:italic>\n (encoding E\u2010cadherin) correlated negatively with\n CCL2<\/jats:italic>\n ,\n CCL4<\/jats:italic>\n ,\n CCR2<\/jats:italic>\n ,\n CCR4<\/jats:italic>\n , and\n CXCR2<\/jats:italic>\n , while the expression of\n ZEB1<\/jats:italic>\n (mesenchymal marker) positively correlated with\n CCL3<\/jats:italic>\n ,\n CCL4<\/jats:italic>\n , and\n CX3CL1<\/jats:italic>\n . PitNETs expressing higher levels of\n CCL4<\/jats:italic>\n ,\n CX3CL1<\/jats:italic>\n ,\n CCR4<\/jats:italic>\n ,\n CCR5<\/jats:italic>\n , and\n CXCR1<\/jats:italic>\n had more and bigger vessels. Somatotropinomas treated pre\u2010operatively with somatostatin analogues were associated with higher expression of\n CCL2<\/jats:italic>\n ,\n CCR4<\/jats:italic>\n ,\n CXCR1<\/jats:italic>\n , and\n CXCR2<\/jats:italic>\n , while nonfunctioning\u2010PitNETs pre\u2010surgically treated with dopamine agonists were associated with lower expression of\n CCL3<\/jats:italic>\n ,\n CCL4<\/jats:italic>\n ,\n CX3CL1<\/jats:italic>\n ,\n CCR5<\/jats:italic>\n ,\n CXCR1<\/jats:italic>\n , and\n CXCR2<\/jats:italic>\n . Our data suggests that chemokines and chemokine receptors may be involved in the modulation of different tumorigenic mechanisms in PitNETs, including tumour proliferation, epithelial\u2010to\u2010mesenchymal transition, and angiogenesis, and may be associated with more aggressive and difficult\u2010to\u2010treat disease.\n <\/jats:p>","DOI":"10.1111\/jne.70184","type":"journal-article","created":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T22:54:46Z","timestamp":1776034486000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The emerging role of chemokines and chemokine receptors in the biological and clinical behaviour of pituitary neuroendocrine tumours: An exploratory transcriptomic study"],"prefix":"10.1111","volume":"38","author":[{"given":"Ana Lu\u00edsa","family":"Silva","sequence":"first","affiliation":[{"name":"Faculdade de Medicina Universidade Cat\u00f3lica Portuguesa Lisbon 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