Oncoantigens as anti-tumor vaccination targets: the chance of a lucky strike?
ABSTRACT 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.
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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; 2014:534969. DOI:10.1155/2014/534969 · 2.71 Impact Factor
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ABSTRACT: Vaccines are one of the main arms of preventive medicine. Recently a large series of experiments with cancer-prone genetically engineered mice have shown that preventive vaccines are also extremely efficacious inhibitors of the progression of carcinogenesis. Early vaccination affords significant and persistent protection, whereas its efficacy fades when neoplastic lesions become more advanced. Our current attempts to use combination strategies and technological advances to make vaccines effective in cancer prevention able to cure more advanced stages of cancer lesions are based on the temporary and systemic T(reg) removal, the preparation of new bimodular plasmids for DNA vaccination, and the search for fresh target oncoantigens.American Journal of Cancer Research 01/2011; 1(2):255-264. · 3.97 Impact Factor
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ABSTRACT: The immune system effectively prevents cancer, whereas severe immunodepression increases its incidence. Cancer immunoprevention is a strategy based on the concept that enhancement of tumor immunity in healthy individuals reduces cancer risk. It can be viewed as a kind of chemoprevention. For cancer immunoprevention, the cancer universe can be neatly divided between tumors caused - directly or indirectly - by infectious agents and all other tumors. Immunoprevention of tumors caused by infectious agents is already implemented at the population level for hepatitis B virus (HBV)-related hepatocellular carcinoma and for tumors caused by human papillomaviruses (HPV), like cervical carcinoma. Now the challenge is to develop immunological strategies to prevent the bulk ( > 80%) of human tumor burden, unrelated to infections. Both vaccines against tumor antigens and immune modulators can prevent tumor onset in cancerprone mice. These studies outlined the target antigens and the molecular and cellular mechanisms of cancer immunoprevention: a) the best target antigens are surface molecules controlling tumor growth and progression (oncoantigens); b) combinations of potent vaccines and nonspecific stimuli (adjuvants) yield the strongest protection; c) immunoprevention must start early in the natural history of tumors, before key progression events like the onset of carcinoma in situ; d) lifetime protection requires repeated boosts, to maintain a strong and steady immune response; e) antibodies and helper, rather than cytotoxic, T cells mediate long-term protection from tumor onset; f) immunoprevention can be combined with chemoprevention. The development of agents like tamoxifen, which went from cancer therapy to chemoprevention, could be a model for the translation of cancer immunoprevention from mice to humans.Current drug targets 12/2010; 12(13):1957-73. DOI:10.2174/138945011798184146 · 3.60 Impact Factor