Epigenetic remodelling of gene expression profiles of neoplastic and normal tissues: immunotherapeutic implications

• Published in: British journal of cancer Vol. 107; no. 7; pp. 1116 - 1124
• Main Authors: Coral, S, Covre, A, JMG Nicolay, H, Parisi, G, Rizzo, A, Colizzi, F, Dalla Santa, S, Fonsatti, E, Fratta, E, Sigalotti, L, Maio, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25-09-2012; Nature Publishing Group
• Subjects: 5-aza-2'-deoxycytidine; 631/1647/2217/2018; 631/67/1059/2325; 692/420/2489/2487/2486; Animal models; Animals; Antigens; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Benign; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma; Cell Line, Tumor; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - immunology; Decitabine; DNA; DNA Methylation; DNA microarrays; Drug Resistance; Epidemiology; Epigenesis, Genetic; Epigenetics; Epigenomics - methods; Female; G protein-coupled receptors; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Immunology; Immunotherapy; Immunotherapy - methods; Mammary gland; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - therapy; Medical research; Medical sciences; Mice; Mice, Inbred BALB C; Molecular Medicine; Oncology; Promoter Regions, Genetic; Protein transport; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - immunology; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - immunology; Spermatogenesis; Translational Therapeutics; Tumors; Italy; cancer; gene expression profiling; DNA hypomethylation; immunotherapy; 5-aza-2′-deoxycytidine; Antineoplastic agent; Decitabine; Malignant tumor; Remodeling; Gene expression profile; Azanucleoside; Cancerology; Treatment; DNA; Immunotherapy; Epigenetics; Nucleoside analog; Methylation; Pyrimidine nucleoside; Cancer; 5-aza-2'-deoxycytidine
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2012.361

Background:
Epigenetic remodelling of cancer cells is an attractive therapeutic strategy and distinct DNA hypomethylating agents (DHA) are being actively evaluated in patients with hemopoietic or solid tumours. However, no studies have investigated the modulation of gene expression profiles (GEP) induced by DHA in transformed and benign tissues. Such information is mandatory to clarify the fine molecular mechanism(s) underlying the clinical efficacy of DHA, to identify appropriate therapeutic combinations, and to address safety issues related to their demethylating potential in normal tissues. Thus, utilising a syngeneic mouse model, we investigated the remodelling of GEP of neoplastic and normal tissues induced by systemic administration of DHA.
Methods:
The murine mammary carcinoma cells TS/A were injected s.c. into female BALB/c mice that were treated i.p. with four cycles of the DHA 5-aza-2′-deoxycytidine (5-AZA-CdR) at a fractioned daily dose of 0.75 mg kg
−1
(q8 h × 3 days, every week). Whole mouse transcriptomes were analysed by microarrays in neoplastic and normal tissues from control and treated mice. Results were processed by bioinformatic analyses.
Results:
In all, 332 genes were significantly (
P
⩽0.05; FC⩾4) modulated (294 up and 38 downregulated) in neoplastic tissues from 5-AZA-CdR-treated mice compared with controls. In decreasing order of magnitude, changes in GEP significantly (
P
⩽0.05) affected immunologic, transport, signal transduction, spermatogenesis, and G–protein–coupled receptor protein signalling pathways. Epigenetic remodelling was essentially restricted to tumour tissues, leaving substantially unaltered normal ones.
Conclusion:
The ability of 5-AZA-CdR to selectively target tumour GEP and its major impact on immune-related genes, strongly support the clinical use of DHA alone or combined with immunotherapeutic agents.