ECE2022 Rapid Communications Rapid Communications 6: Endocrine-Related Cancer (8 abstracts)
The clinical and molecular evaluation of the GIP/GIPR axis in Medullary Thyroid Cancer (MTC)
Gianluca Occhi 1 , Loris Bertazza 2 , Susi Barollo 2 , Eva Galletta 1 , Alberto Mondin 2 , Stefania Zovato 3 , Maurizio Iacobone 4 , Eleonora Zilio 1 , Serena Avallone 2 , Konstantions Lefkimmiatis 5,6 , Giulietta Di Benedetto 6,7 , Caterina Mian 2 , Carla Scaroni 2 & Daniela Regazzo 2
1University of Padova, Department of Biology, Padova, Italy; 2Padova University Hospital, Department of Medicine - Endocrinology Unit, Padova, Italy; 3Veneto Institute of Oncology-IOV-IRCCS, Hereditary Tumors Unit, Padova, Italy; 4Padova University Hospital, Department of Surgery, Oncology and Gastroenterology - Endocrine Surgery Unit, Padova, Italy; 5University of Pavia, Department of Molecular Medicine, Pavia, Italy; 6Foundation for Advanced Biomedical Research, Veneto Institute of Molecular Medicine (VIMM), Padova, Italy; 7National Research Council, Neuroscience Institute - Padova Section, Padova, Italy
The glucose-dependent insulinotropic polypeptide receptor (GIPR) is a 7-transmembrane class B G-protein coupled receptor that mediates the incretin response after nutrient stimulation. Although mostly involved in metabolic disorders, in the last years an improper activation of the GIP/GIPR axis has been increasingly recognized in endocrine tumors, with a potential diagnostic and prognostic value. In Medullary Thyroid Cancer (MTC), a neuroendocrine tumor of the parafollicular C cells, a high tumor-to-normal tissue ratio (T/N ratio) of GIPR was reported both in human and in rat. In this latter, a direct link between the neoplastic transformation and the mechanism of receptor overexpression has been proposed. In this work, we aimed at evaluating the potential diagnostic and prognostic significance of GIPR expression in a large cohort of MTC by correlating GIPR mRNA steady-state level with patients’ clinical features. Moreover, given the paucity of data on the GIP/GIPR axis in this tumor type, an additional aim of this study was to molecularly dissect the signaling pathways associated with GIPR stimulation in MTC-derived cells with particular attention to cell proliferation and calcitonin secretion. By Droplet Digital PCR (ddPCR) technology, we observed a GIPR positive expression (GIPR+) of nearly 80% (38/49) of MTC tumoral specimens and more frequently in larger, advanced-stage cancer with higher Ki-67 values and sporadic rather than familial manifestation. In MTC-derived cells (i.e., MZ-CRC-1, and a primary culture originating from a regional metastatic lymph node of a GIPR+ MTC patient), GIPR stimulation induced cAMP elevation – with the consequent activation of the PKA cascade – and a small but significant fluctuation in Ca2+, both likely associated with increased calcitonin secretion. GIP has instead no effects on cell viability nor on PI3K-Akt and MAPK-ERK1/2 signalling pathways. The data emerging from this study confirmed the high T/N GIPR ratio in MTC tumors and demonstrate for the first time that it may represent an index of the degree of advancement of the malignant process. The observation that GIP stimulated the adenylyl cyclase and activate the downstream cAMP pathway in MTC-derived cellular models confirms the correct coupling of GIPR to Gas which was ultimately related to an increased CT secretion. Further studies with specific provocative tests, however, will be mandatory to establish the real involvement of GIP/GIPR axis in regulating calcitonin secretion in MTC.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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