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


CONCLUSIONS
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.
Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy.
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Coral
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Covre
H J M G
HJ
Nicolay
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G
Parisi
A
A
Rizzo
F
F
Colizzi
S
S
Dalla Santa
E
E
Fonsatti
E
E
Fratta
L
L
Sigalotti
M
M
Maio
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics* / Q000276:immunology; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D007167:Immunotherapy / Q000379:methods*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D000951:Antigens, Neoplasm; D043562:Receptors, G-Protein-Coupled; C076546:tumor rejection antigen P815A, mouse; D000077209:Decitabine; D001374:Azacitidine