Neoplastic transformation is a multistage process and distinct gene products of specific cell regulatory pathways are involved at each stage. Identification of genes overexpressed at a specific stage provides an unprecedented opportunity to address the immune system against antigens with a driving role in tumor progression (oncoantigens). The ERBB2 oncogene is a prototype of deregulated oncogenic protein kinase membrane receptors. Mice transgenic for rat ERBB2 (BALB-neuT mice) were used in this study to identify an additional set of oncoantigens expressed at defined stages by most breast carcinomas to be used as alternatives to ERBB2-driven vaccination. To address this question, we integrated the transcription data generated by comparing preneoplastic lesions and neoplasia in BALB-neuT mice with a meta-analysis on transcription profiles generated from normal and breast tumor human specimens. Forty-six putative oncoantigens identified and prioritized according to their expression on the cell membrane or in the extra cellular space, cytoplasm and nucleus were chosen for preclinical investigation as vaccination targets.
"To address this point, we performed a transcription profile analysis of BALB-neuT preneoplastic and invasive lesions, integrated with a meta-analysis of data obtained from healthy human and neoplastic specimens. Of the 46 putative OAs identified , B7-H4 , Claudin 3 , Hepsin , CD52 , and Desmoglein 2  are Class I OAs, expressed on the plasma membrane of cancer and TME cells and therefore constitute promising targets for vaccination. Class II OAs are another group of identified OAs and includes cytokines and chemokines copiously released in the TME. "
[Show abstract][Hide abstract] ABSTRACT: The tyrosine kinase human epidermal growth factor receptor 2 (HER2) gene is amplified in approximately 20% of human breast cancers and is associated with an aggressive clinical course and the early development of metastasis. Its crucial role in tumor growth and progression makes HER2 a prototypic oncoantigen, the targeting of which may be critical for the development of effective anticancer therapies. The setup of anti-HER2 targeting strategies has revolutionized the clinical outcome of HER2(+) breast cancer. However, their initial success has been overshadowed by the onset of pharmacological resistance that renders them ineffective. Since the tumor microenvironment (TME) plays a crucial role in drug resistance, the design of more effective anticancer therapies should depend on the targeting of both cancer cells and their TME as a whole. In this review, starting from the successful know-how obtained with a HER2(+) mouse model of mammary carcinogenesis, the BALB-neuT mice, we discuss the role of TME in mammary tumor development. Indeed, a deeper knowledge of antigens critical for cancer outbreak and progression and of the mechanisms that regulate the interplay between cancer and stromal cell populations could advise promising ways for the development of the best anticancer strategy.
BioMed Research International 06/2014; 2014(4785):534969. DOI:10.1155/2014/534969 · 3.17 Impact Factor
"In this study, we sought to identify new candidate biomarkers and/or potential oncoantigens involved in both initiation of lung cancer and/or its progression to an aggressive cancer phenotype. To this aim, we adapted to the lung cancer disease our consolidated pipeline for oncoantigen detection [8,10]. Thanks to the RNA-seq technology we also extended our pipeline to the detection of tumor specific transcript isoforms and fusion proteins . "
[Show abstract][Hide abstract] ABSTRACT: Background
Non-small cell lung cancer (NSCLC) accounts for 81% of all cases of lung cancer and they are often fatal because 60% of the patients are diagnosed at an advanced stage. Besides the need for earlier diagnosis, there is a high need for additional effective therapies. In this work, we investigated the feasibility of a lung cancer progression mouse model, mimicking features of human aggressive NSCLC, as biological reservoir for potential therapeutic targets and biomarkers.
We performed RNA-seq profiling on total RNA extracted from lungs of a 30 week-old K-rasLA1/p53R172HΔg and wild type (WT) mice to detect fusion genes and gene/exon-level differential expression associated to the increase of tumor mass. Fusion events were not detected in K-rasLA1/p53R172HΔg tumors. Differential expression at exon-level detected 33 genes with differential exon usage. Among them nine, i.e. those secreted or expressed on the plasma membrane, were used for a meta-analysis of more than 500 NSCLC RNA-seq transcriptomes. None of the genes showed a significant correlation between exon-level expression and disease prognosis. Differential expression at gene-level allowed the identification of 1513 genes with a significant increase in expression associated to tumor mass increase. 74 genes, i.e. those secreted or expressed on the plasma membrane, were used for a meta-analysis of two transcriptomics datasets of human NSCLC samples, encompassing more than 900 samples. SPP1 was the only molecule whose over-expression resulted statistically related to poor outcome regarding both survival and metastasis formation. Two other molecules showed over-expression associated to poor outcome due to metastasis formation: GM-CSF and ADORA3. GM-CSF is a secreted protein, and we confirmed its expression in the supernatant of a cell line derived by a K-rasLA1/p53R172HΔg mouse tumor. ADORA3 is instead involved in the induction of p53-mediated apoptosis in lung cancer cell lines. Since in our model p53 is inactivated, ADORA3 does not negatively affect tumor growth but remains expressed on tumor cells. Thus, it could represent an interesting target for the development of antibody-targeted therapy on a subset of NSCLC, which are p53 null and ADORA3 positive.
Our study provided a complete transcription overview of the K-rasLA1/p53R172HΔg mouse NSCLC model. This approach allowed the detection of ADORA3 as a potential target for antibody-based therapy in p53 mutated tumors.
"ErbB-2,55 (blue Y), Epsin, (brown E), Claudin,53 (green C) and CSPG4,56 (purple f) are class II oncoantigens expressed on tumor cell membrane (middle panel). The protein product of the NPM-ALK translocation,57 (ALK, purple ♒) and BIRC5,53 (orange b) are class III oncoantigens present in the cytoplasm and nucleus of carcinomas and lymphomas (right panel). Several additional molecule endowed with the properties of oncoantigens have been validated in immunization assay by other laboratories.58 "
[Show abstract][Hide abstract] ABSTRACT: The emerging evidence that DNA vaccines elicit a protective immune response in rodents, dogs and cancer patients, coupled with the US Food and Drug Administration (FDA) approval of an initial DNA vaccine to treat canine tumors is beginning to close the gap between the optimistic experimental data and their difficult application in a clinical setting. Here we review a series of conceptual and biotechnological advances that are working together to make DNA vaccines targeting molecules that play important roles during cancer progression (oncoantigens) a promise with near-term clinical impact.
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