title: Proteomic profiling of a mouse model for ovarian granulosa cell tumor identifies VCP as a highly sensitive serum tumor marker in several human cancers.
abstract: The initial aim of this study was to identify novel serum diagnostic markers for the human ovarian granulosa cell tumor (GCT), a tumor that represents up to 5% of all ovarian cancers. To circumvent the paucity of human tissues available for analyses, we used the Ctnnb1(tm1Mmt/+);Pten(tm1Hwu/tmiHwu);Amhr2(tm3(cre)Bhr/+) transgenic mouse model, which features the constitutive activation of CTNNB1 signaling combined with the loss of Pten in granulosa cells and develops GCTs that mimic aggressive forms of the human disease. Proteomic profiling by mass spectrometry showed that vinculin, enolase 1, several heat shock proteins, and valosin containing protein (VCP) were more abundantly secreted by cultured mouse GCT cells compared to primary cultured GC. Among these proteins, only VCP was present in significantly increased levels in the preoperative serum of GCT cancer patients compared to normal subjects. To determine the specificity of VCP, serum levels were also measured in ovarian carcinoma, non-Hodgkin's lymphoma and breast, colon, pancreatic, lung, and prostate cancer patients. Increased serum VCP levels were observed in the majority of cancer cases, with the exception of patients with lung or prostate cancer. Moreover, serum VCP levels were increased in some GCT, ovarian carcinoma, breast cancer, and colon cancer patients who did not otherwise display increased levels of widely used serum tumor markers for their cancer type (e.g. inhibin A, inhibin B, CA125, CEA, or CA15.3). These results demonstrate the potential use of VCP as highly sensitive serum marker for GCT as well as several other human cancers.
authors.affiliation: Centre de Recherche en Reproduction Animale, Faculté de Médecine Vétérinaire, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Laguë
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Romieu-Mourez
authors.forename: Éric
authors.initials: É
authors.lastname: Bonneil
authors.forename: Alexandre
authors.initials: A
authors.lastname: Boyer
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pouletty
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: Pierre
authors.initials: P
authors.lastname: Thibault
authors.forename: Marie-Ève
authors.initials: MÈ
authors.lastname: Nadeau
authors.forename: Derek
authors.initials: D
authors.lastname: Boerboom
mesh_terms: D000251:Adenosine Triphosphatases / Q000097:blood* / Q000235:genetics; D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics; D018797:Cell Cycle Proteins / Q000097:blood* / Q000235:genetics; D005260:Female; D006106:Granulosa Cell Tumor / Q000097:blood* / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000097:blood* / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D000074405:Valosin Containing Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D018797:Cell Cycle Proteins; D020543:Proteome; D051176:beta Catenin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse