Gaia Barisione1, Marina Fabbi1, Alice Gino1, Paola Queirolo1, Laura Orgiano1, Laura Spano1, Virginia Picasso1, Ulrich Pfeffer2, Carlo Mosci3, Martine J Jager4, Silvano Ferrini1, Rosaria Gangemi1. 1. Department of Integrated Oncology Therapies, Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. 2. Department of Technologically Complex Diagnostics, Pathology, and Therapy, Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. 3. Ocular Oncology Center, Galliera Hospital, Genoa, Italy. 4. Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
Abstract
IMPORTANCE: Conventional melanoma serum biomarkers (S100 and lactate dehydrogenase [LDH]) perform poorly in patients with uveal melanoma, and the search for new biomarkers is needed. A high expression of the oncoprotein c-Met in primary uveal melanoma is associated with metastatic progression, and c-Met is released as a soluble ectodomain through ADAM10- and ADAM17-mediated cleavage, suggesting a possible role as biomarker. OBJECTIVE: To determine the potential role of soluble c-Met (sc-Met) as a biomarker of uveal melanoma progression in comparison with S100 and LDH. DESIGN, SETTING, AND PARTICIPANTS: Soluble c-Met was studied in the conditioned medium of 9 uveal melanoma cell lines and in the blood serum samples of 24 mice with uveal melanoma xenografts, 57 patients with uveal melanoma (17 patients whose tumors metastasized and 40 patients whose tumors did not metastasize), and 37 healthy donors. We collected blood samples for as long as 5 years after treatment of the primary tumor. The concentration of sc-Met was measured using enzyme-linked immunosorbent assays, and the receiver operating characteristic curve was used to evaluate sensitivity and specificity in the identification of metastatic uveal melanoma. The study began on May 2, 2011, and the last samples were collected in January 2015. MAIN OUTCOMES AND MEASURES: Levels of sc-Met in uveal melanoma cell cultures and in the blood serum samples of xenotransplanted mice, of healthy donors, and of patients with uveal melanoma during follow-up. RESULTS: The conditioned medium of uveal melanoma cell lines and the blood serum samples of mice with uveal melanoma xenografts contained significant levels of sc-Met. Patients with metastatic disease had significantly higher serum levels of sc-Met (median level, 590 ng/mL [range, 246-12,856 ng/mL]) than did patients without metastatic disease (median level, 296 ng/mL [range, 201-469 ng/mL]) (P < .001) and healthy donors (median level, 285 ng/mL [range, 65-463 ng/mL]) (P < .001). Analysis of receiver operating characteristic curves for sc-Met levels in patients with nonmetastatic uveal melanoma vs patients with metastatic uveal melanoma yielded an area under the curve of 0.82 (95% CI, 0.68-0.95) (P < .001), which was superior to the areas under the curve achieved with S100 or LDH markers. Patients with progressive metastatic disease showed further increases in sc-Met level, whereas stable patients did not. CONCLUSIONS AND RELEVANCE: The present pilot study suggests that sc-Met should be further exploited as a biomarker for monitoring of uveal melanoma.
IMPORTANCE: Conventional melanoma serum biomarkers (S100 and lactate dehydrogenase [LDH]) perform poorly in patients with uveal melanoma, and the search for new biomarkers is needed. A high expression of the oncoprotein c-Met in primary uveal melanoma is associated with metastatic progression, and c-Met is released as a soluble ectodomain through ADAM10- and ADAM17-mediated cleavage, suggesting a possible role as biomarker. OBJECTIVE: To determine the potential role of soluble c-Met (sc-Met) as a biomarker of uveal melanoma progression in comparison with S100 and LDH. DESIGN, SETTING, AND PARTICIPANTS: Soluble c-Met was studied in the conditioned medium of 9 uveal melanoma cell lines and in the blood serum samples of 24 mice with uveal melanoma xenografts, 57 patients with uveal melanoma (17 patients whose tumors metastasized and 40 patients whose tumors did not metastasize), and 37 healthy donors. We collected blood samples for as long as 5 years after treatment of the primary tumor. The concentration of sc-Met was measured using enzyme-linked immunosorbent assays, and the receiver operating characteristic curve was used to evaluate sensitivity and specificity in the identification of metastatic uveal melanoma. The study began on May 2, 2011, and the last samples were collected in January 2015. MAIN OUTCOMES AND MEASURES: Levels of sc-Met in uveal melanoma cell cultures and in the blood serum samples of xenotransplanted mice, of healthy donors, and of patients with uveal melanoma during follow-up. RESULTS: The conditioned medium of uveal melanoma cell lines and the blood serum samples of mice with uveal melanoma xenografts contained significant levels of sc-Met. Patients with metastatic disease had significantly higher serum levels of sc-Met (median level, 590 ng/mL [range, 246-12,856 ng/mL]) than did patients without metastatic disease (median level, 296 ng/mL [range, 201-469 ng/mL]) (P < .001) and healthy donors (median level, 285 ng/mL [range, 65-463 ng/mL]) (P < .001). Analysis of receiver operating characteristic curves for sc-Met levels in patients with nonmetastatic uveal melanoma vs patients with metastatic uveal melanoma yielded an area under the curve of 0.82 (95% CI, 0.68-0.95) (P < .001), which was superior to the areas under the curve achieved with S100 or LDH markers. Patients with progressive metastatic disease showed further increases in sc-Met level, whereas stable patients did not. CONCLUSIONS AND RELEVANCE: The present pilot study suggests that sc-Met should be further exploited as a biomarker for monitoring of uveal melanoma.
Authors: Susan Kennedy; Michael Rice; Sinead Toomey; Noel Horgan; Bryan T Hennessey; Annemarie Larkin Journal: J Cancer Res Clin Oncol Date: 2018-07-14 Impact factor: 4.553
Authors: Martina Angi; Helen Kalirai; Samuel Prendergast; Deborah Simpson; Dean E Hammond; Michele C Madigan; Robert J Beynon; Sarah E Coupland Journal: Oncotarget Date: 2016-08-02