Background: Pancreatic Ductal Adenocarcinoma (PDAC) is an highly aggressive malignancy characterized by rapid progression, invasiveness and resistance to treatments. Biomarkers for its early detection are lacking. Refined genetically engineered mouse (GEM) models of human cancer have been shown to faithfully recapitulate the molecular, biological and clinical features of human disease. Aim: In this study we have used two well-characterized GEM models of PDAC to identify antigens that elicit an early humoral response in PDAC. Methods and Results: Proteins from mouse PDAC cell line were separed by two-dimensional electrophoresis (2-DE) and the serum reactivity of 39 GEM mice at early and advanced stages of tumor development was tested by Western blot (WB) analysis and compared to matched controls. Spots specifically recognized by PDAC sera were identified by mass spectrometry and corresponded to three nuclear and four cytoskeletal proteins. Autoantibodies against these proteins were present already at the earliest stages of tumor development. According to microarray data, the mRNA of some on these proteins is over-expressed in PDAC compared to normal pancreas. The humoral response to these antigens were validated by 2-DE WB in a set of 122 (14 of which resectable) PDAC patients and 143 controls (38 healthy subjects, 50 non-PDAC tumor patients, 43 chronic pancreatitis and 12 autoimmune diseases patients) sera. The presence of autoantibodies against at least two out of the seven antigens is able to discriminate PDAC patients from controls in a statistically significant way. Conclusions: Our results indicate that GEM models of PDAC, in combination with SERological Proteome Analysis, provide a useful strategy to identify proteins able to induce an early autoantibody response in PDAC. To confirm their diagnostic value, these antigens will be validated by an handy assay in a large cohort of resectable PDAC patients..
A Mouse To Human Autoantibody Signature in Pancreatic Ductal Adenocarcinoma
CAPELLO, Michela;CAPPELLO, Paola;NOVELLI, Francesco
2010-01-01
Abstract
Background: Pancreatic Ductal Adenocarcinoma (PDAC) is an highly aggressive malignancy characterized by rapid progression, invasiveness and resistance to treatments. Biomarkers for its early detection are lacking. Refined genetically engineered mouse (GEM) models of human cancer have been shown to faithfully recapitulate the molecular, biological and clinical features of human disease. Aim: In this study we have used two well-characterized GEM models of PDAC to identify antigens that elicit an early humoral response in PDAC. Methods and Results: Proteins from mouse PDAC cell line were separed by two-dimensional electrophoresis (2-DE) and the serum reactivity of 39 GEM mice at early and advanced stages of tumor development was tested by Western blot (WB) analysis and compared to matched controls. Spots specifically recognized by PDAC sera were identified by mass spectrometry and corresponded to three nuclear and four cytoskeletal proteins. Autoantibodies against these proteins were present already at the earliest stages of tumor development. According to microarray data, the mRNA of some on these proteins is over-expressed in PDAC compared to normal pancreas. The humoral response to these antigens were validated by 2-DE WB in a set of 122 (14 of which resectable) PDAC patients and 143 controls (38 healthy subjects, 50 non-PDAC tumor patients, 43 chronic pancreatitis and 12 autoimmune diseases patients) sera. The presence of autoantibodies against at least two out of the seven antigens is able to discriminate PDAC patients from controls in a statistically significant way. Conclusions: Our results indicate that GEM models of PDAC, in combination with SERological Proteome Analysis, provide a useful strategy to identify proteins able to induce an early autoantibody response in PDAC. To confirm their diagnostic value, these antigens will be validated by an handy assay in a large cohort of resectable PDAC patients..
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