Early Detection in a Mouse Model of Pancreatic Cancer by Imaging DNA Damage Response Signaling.
J Nucl Med
; 61(7): 1006-1013, 2020 07.
Article
em En
| MEDLINE
| ID: mdl-31862800
ABSTRACT
Despite its widespread use in oncology, the PET radiotracer 18F-FDG is ineffective for improving early detection of pancreatic ductal adenocarcinoma (PDAC). An alternative strategy for early detection of pancreatic cancer involves visualization of high-grade pancreatic intraepithelial neoplasias (PanIN-3s), generally regarded as the noninvasive precursors of PDAC. The DNA damage response is known to be hyperactivated in late-stage PanINs. Therefore, we investigated whether the SPECT imaging agent 111In-anti-γH2AX-TAT allows visualization of the DNA damage repair marker γH2AX in PanIN-3s in an engineered mouse model of PDAC, to facilitate early detection of PDAC. Methods:
Genetically engineered KPC (KRasLSL.G12D/+; p53LSL.R172H/+; PdxCre) mice were imaged with 18F-FDG and 111In-anti-γH2AX-TAT. The presence of PanIN/PDAC as visualized by histologic examination was compared with autoradiography and immunofluorescence. Separately, the survival of KPC mice imaged with 111In-anti-γH2AX-TAT was evaluated.Results:
In KPC mouse pancreata, γH2AX expression was increased in high-grade PanINs but not in PDAC, corroborating earlier results obtained from human pancreas sections. Uptake of 111In-anti-γH2AX-TAT, but not 111In-IgG-TAT or 18F-FDG, within the pancreas correlated positively with the age of KPC mice, which correlated with the number of high-grade PanINs. 111In-anti-γH2AX-TAT localizes preferentially in high-grade PanIN lesions but not in established PDAC. Younger, non-tumor-bearing KPC mice that show uptake of 111In-anti-γH2AX-TAT in the pancreas survive for a significantly shorter time than mice with physiologic 111In-anti-γH2AX-TAT uptake.Conclusion:
111In-anti-γH2AX-TAT imaging allows noninvasive detection of DNA damage repair signaling upregulation in preinvasive PanIN lesions and is a promising new tool to aid in the early detection and staging of pancreatic cancer.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Dano ao DNA
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Transdução de Sinais
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Detecção Precoce de Câncer
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Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
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Screening_studies
Limite:
Animals
Idioma:
En
Revista:
J Nucl Med
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Reino Unido