Serum levels of cytoplasmic melanoma-associated antigen at diagnosis may predict clinical relapse in neuroblastoma patients
- 156 Downloads
The high molecular weight melanoma-associated antigen (HMW-MAA) and the cytoplasmic melanoma-associated antigen (cyt-MAA/LGALS3BP) are expressed in melanoma. Their serum levels are increased in melanoma patients and correlate with clinical outcome. We investigated whether these molecules can serve as prognostic markers for neuroblastoma (NB) patients. Expression of cyt-MAA and HMW-MAA was evaluated by flow cytometry in NB cell lines, patients’ neuroblasts (FI-NB), and short-term cultures of these latter cells (cNB). LGALS3BP gene expression was evaluated by RT–qPCR on FI-NB, cNB, and primary tumor specimens. Soluble HMW-MAA and cyt-MAA were tested by ELISA. Cyt-MAA and HMW-MAA were expressed in NB cell lines, cNB, and FI-NB samples. LGALS3BP gene expression was higher in primary tumors and cNB than in FI-NB samples. Soluble cyt-MAA, but not HMW-MAA, was detected in NB cell lines and cNBs supernatants. NB patients’ serum levels of both antigens were higher than those of the healthy children. High cyt-MAA serum levels at diagnosis associated with higher incidence of relapse, independently from other known risk factors. In conclusion, both HMW-MAA and cyt-MAA antigens, and LGALS3BP gene, were expressed by NB cell lines and patients’ neuroblasts, and both antigens’ serum levels were increased in NB patients. Elevated serum levels of cyt-MAA at diagnosis correlated with relapse, supporting that cyt-MAA may serve as early serological biomarker to individuate patients at higher risk of relapse that may require a more careful follow-up, after being validated in a larger cohort of patients at different time-points during follow-up. Given its immunogenicity, cyt-MAA may also be a potential target for NB immunotherapy.
KeywordsCytoplasmic melanoma-associated antigen Neuroblastoma Clinical relapse Serum biomarkers
This work has been supported by grants from Ministero della Salute, Progetti di Ricerca Corrente. BC is recipient of a Fondazione Italiana per la Lotta al Neuroblastoma fellowship. SS is recipient of a fellowship from Ministero della Salute/Regione Liguria. We thank Mrs Chiara Bernardini and Camilla Valentino for excellent secretarial assistance, Dr. Mirco Ponzoni, Genoa, for providing us the G2a anti-GD2 antibody and Mrs Barbara Galleni at the Italian NB registry, Genoa, for the excellent work aimed at providing clinical data on NB patients.
Conflict of interest
The authors disclose any conflict of interest.
- 3.Giacomini P, Veglia F, Cordiali Fei P, Rehle T, Natali PG, Ferrone S (1984) Level of a membrane-bound high-molecular-weight melanoma-associated antigen and a cytoplasmic melanoma-associated antigen in surgically removed tissues and in sera from patients with melanoma. Cancer Res 44(3):1281–1287PubMedGoogle Scholar
- 11.Wagner S, Krepler C, Allwardt D, Latzka J, Strommer S, Scheiner O, Pehamberger H, Wiedermann U, Hafner C, Breiteneder H (2008) Reduction of human melanoma tumor growth in severe combined immunodeficient mice by passive transfer of antibodies induced by a high molecular weight melanoma-associated antigen mimotope vaccine. Clin Cancer Res 14(24):8178–8183PubMedCrossRefGoogle Scholar
- 13.Tinari N, D’Egidio M, Iacobelli S, Bowen M, Starling G, Seachord C, Darveau R, Aruffo A (1997) Identification of the tumor antigen 90 K domains recognized by monoclonal antibodies SP2 and L3 and preparation and characterization of novel anti-90 K monoclonal antibodies. Biochem Biophys Res Commun 232(2):367–372PubMedCrossRefGoogle Scholar
- 17.Scambia G, Panici PB, Iacobelli S, Baiocchi G, Battaglia F, Perrone L, Sonsini C, Ferrandina G, Natoli C, Mancuso S (1990) Recombinant alpha-2b-interferon enhances the circulating levels of a 90-kilodalton (K) tumor-associated antigen in patients with gynecologic and breast malignancies. Cancer 65(6):1325–1328PubMedCrossRefGoogle Scholar
- 30.Cecchetto G, Mosseri V, De Bernardi B, Helardot P, Monclair T, Costa E, Horcher E, Neuenschwander S, Toma P, Rizzo A, Michon J, Holmes K (2005) Surgical risk factors in primary surgery for localized neuroblastoma: the LNESG1 study of the European International Society of Pediatric Oncology Neuroblastoma Group. J Clin Oncol 23(33):8483–8489. doi: 10.1200/JCO.2005.02.4661 PubMedCrossRefGoogle Scholar
- 31.Rubie H, De Bernardi B, Gerrard M, Canete A, Ladenstein R, Couturier J, Ambros P, Munzer C, Pearson AD, Garaventa A, Brock P, Castel V, Valteau-Couanet D, Holmes K, Di Cataldo A, Brichard B, Mosseri V, Marquez C, Plantaz D, Boni L, Michon J (2011) Excellent outcome with reduced treatment in infants with nonmetastatic and unresectable neuroblastoma without MYCN amplification: results of the prospective INES 99.1. J Clin Oncol 29(4):449–455. doi: 10.1200/JCO.2010.29.5196 PubMedCrossRefGoogle Scholar
- 32.Olgun N, Kansoy S, Aksoylar S, Cetingul N, Vergin C, Oniz H, Sarialioglu F, Kantar M, Uysal K, Tuncyurek M, Kargi A, Aktas S, Bayol U, Karaca I, Arikan A, Balik E, Aktug T, Elmas N, Kovanlikaya A, Kinay M, Anacak Y, Degirmenci B, Burak Z (2003) Experience of the izmir pediatric oncology group on neuroblastoma: IPOG-NBL-92 protocol. Pediatr Hematol Oncol 20(3):211–218PubMedGoogle Scholar
- 40.Gregorio A, Corrias MV, Castriconi R, Dondero A, Mosconi M, Gambini C, Moretta A, Moretta L, Bottino C (2008) Small round blue cell tumours: diagnostic and prognostic usefulness of the expression of B7–H3 surface molecule. Histopathology 53(1):73–80. doi: 10.1111/j.1365-2559.2008.03070.x PubMedCrossRefGoogle Scholar
- 42.Gordower L, Decaestecker C, Kacem Y, Lemmers A, Gusman J, Burchert M, Danguy A, Gabius H, Salmon I, Kiss R, Camby I (1999) Galectin-3 and galectin-3-binding site expression in human adult astrocytic tumours and related angiogenesis. Neuropathol Appl Neurobiol 25(4):319–330PubMedCrossRefGoogle Scholar
- 44.Hajto T, Hostanska K, Frei K, Rordorf C, Gabius HJ (1990) Increased secretion of tumor necrosis factors alpha, interleukin 1, and interleukin 6 by human mononuclear cells exposed to beta-galactoside-specific lectin from clinically applied mistletoe extract. Cancer Res 50(11):3322–3326PubMedGoogle Scholar
- 48.Ozaki Y, Kontani K, Teramoto K, Fujita T, Tezuka N, Sawai S, Watanabe H, Fujino S, Asai T, Ohkubo I (2004) Identification of antigenic epitopes recognized by Mac-2 binding protein-specific cytotoxic T lymphocytes for use in cancer immunotherapy. Biochem Biophys Res Commun 317(4):1089–1095. doi: 10.1016/j.bbrc.2004.03.155 PubMedCrossRefGoogle Scholar
- 49.Ozaki Y, Kontani K, Hanaoka J, Chano T, Teramoto K, Tezuka N, Sawai S, Fujino S, Yoshiki T, Okabe H, Ohkubo I (2002) Expression and immunogenicity of a tumor-associated antigen, 90 K/Mac-2 binding protein, in lung carcinoma. Cancer 95(9):1954–1962. doi: 10.1002/cncr.10899 PubMedCrossRefGoogle Scholar