Early detection in a mouse model of pancreatic cancer by imaging DNA damage response signalling
<p><strong>Rationale:</strong> Despite its widespread use in oncology, the PET radiotracer 18F-FDG is ineffectivefor improving early detection of pancreatic ductal adenocarcinoma (PDAC). An alternative strategy for early detection of pancreatic cancer involves visualisation of high...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
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Society of Nuclear Medicine
2019
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| _version_ | 1797058375712768000 |
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| author | Cornelissen, B Knight, J Baguna Torres, J Goldin, R Mosley, M Dias, G Contreras Bravo, L Kersemans, V Allen, P Mukherjee, S Smart, S |
| author_facet | Cornelissen, B Knight, J Baguna Torres, J Goldin, R Mosley, M Dias, G Contreras Bravo, L Kersemans, V Allen, P Mukherjee, S Smart, S |
| author_sort | Cornelissen, B |
| collection | OXFORD |
| description | <p><strong>Rationale:</strong> Despite its widespread use in oncology, the PET radiotracer 18F-FDG is ineffectivefor improving early detection of pancreatic ductal adenocarcinoma (PDAC). An alternative strategy for early detection of pancreatic cancer involves visualisation of high-grade pancreatic intraepithelial neoplasias (PanIN-3), generally regarded as the non-invasive precursors of PDAC. The DNA damage response is known to be hyper-activated in late-stage PanINs. Therefore, we investigated whether the SPECT imaging agent, 111In-anti-γH2AX-TAT, allows visualisation of the DNA damage repair marker γH2AX in PanIN-3s in an engineered mouse model of PDAC, to facilitate early detection of PDAC.</p> <p><strong>Methods:</strong> Genetically engineered KPC mice (KRasLSL.G12D/+; p53LSL.R172H/+; PdxCre) were imaged with 18F-FDG and 111In-anti-γH2AX-TAT. PanIN/PDAC presence visualised by histology was compared with autoradiography and immunofluorescence. Separately, the survival of KPC mice imaged with 111In-anti-γH2AX-TAT was evaluated.</p> <p><strong>Results:</strong> 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 was positively correlated with the age of KPC mice, which was correlated with the number of highgrade PanINs. 111In-anti-γH2AX-TAT localises preferentially in high-grade PanIN lesions, but not in established PDAC. Younger, non-tumour-bearing KPC mice that show uptake of 111Inanti-γH2AX-TAT in the pancreas survive significantly shorter than mice with physiological 111In-anti-γH2AX-TAT uptake.</p> <p><strong>Conclusion:</strong> 111In-anti-γH2AX-TAT imaging allows non-invasive detection of DNA damage repair signalling upregulation in pre-invasive PanIN lesions and is a promising new tool to aid in the early detection and staging of pancreatic cancer.</p> |
| first_indexed | 2024-03-06T19:49:38Z |
| format | Journal article |
| id | oxford-uuid:23856588-9eef-478a-b3c1-95825f5756b7 |
| institution | University of Oxford |
| last_indexed | 2024-03-06T19:49:38Z |
| publishDate | 2019 |
| publisher | Society of Nuclear Medicine |
| record_format | dspace |
| spelling | oxford-uuid:23856588-9eef-478a-b3c1-95825f5756b72022-03-26T11:44:46ZEarly detection in a mouse model of pancreatic cancer by imaging DNA damage response signallingJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:23856588-9eef-478a-b3c1-95825f5756b7Symplectic Elements at OxfordSociety of Nuclear Medicine2019Cornelissen, BKnight, JBaguna Torres, JGoldin, RMosley, MDias, GContreras Bravo, LKersemans, VAllen, PMukherjee, SSmart, S<p><strong>Rationale:</strong> Despite its widespread use in oncology, the PET radiotracer 18F-FDG is ineffectivefor improving early detection of pancreatic ductal adenocarcinoma (PDAC). An alternative strategy for early detection of pancreatic cancer involves visualisation of high-grade pancreatic intraepithelial neoplasias (PanIN-3), generally regarded as the non-invasive precursors of PDAC. The DNA damage response is known to be hyper-activated in late-stage PanINs. Therefore, we investigated whether the SPECT imaging agent, 111In-anti-γH2AX-TAT, allows visualisation of the DNA damage repair marker γH2AX in PanIN-3s in an engineered mouse model of PDAC, to facilitate early detection of PDAC.</p> <p><strong>Methods:</strong> Genetically engineered KPC mice (KRasLSL.G12D/+; p53LSL.R172H/+; PdxCre) were imaged with 18F-FDG and 111In-anti-γH2AX-TAT. PanIN/PDAC presence visualised by histology was compared with autoradiography and immunofluorescence. Separately, the survival of KPC mice imaged with 111In-anti-γH2AX-TAT was evaluated.</p> <p><strong>Results:</strong> 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 was positively correlated with the age of KPC mice, which was correlated with the number of highgrade PanINs. 111In-anti-γH2AX-TAT localises preferentially in high-grade PanIN lesions, but not in established PDAC. Younger, non-tumour-bearing KPC mice that show uptake of 111Inanti-γH2AX-TAT in the pancreas survive significantly shorter than mice with physiological 111In-anti-γH2AX-TAT uptake.</p> <p><strong>Conclusion:</strong> 111In-anti-γH2AX-TAT imaging allows non-invasive detection of DNA damage repair signalling upregulation in pre-invasive PanIN lesions and is a promising new tool to aid in the early detection and staging of pancreatic cancer.</p> |
| spellingShingle | Cornelissen, B Knight, J Baguna Torres, J Goldin, R Mosley, M Dias, G Contreras Bravo, L Kersemans, V Allen, P Mukherjee, S Smart, S Early detection in a mouse model of pancreatic cancer by imaging DNA damage response signalling |
| title | Early detection in a mouse model of pancreatic cancer by imaging DNA damage response signalling |
| title_full | Early detection in a mouse model of pancreatic cancer by imaging DNA damage response signalling |
| title_fullStr | Early detection in a mouse model of pancreatic cancer by imaging DNA damage response signalling |
| title_full_unstemmed | Early detection in a mouse model of pancreatic cancer by imaging DNA damage response signalling |
| title_short | Early detection in a mouse model of pancreatic cancer by imaging DNA damage response signalling |
| title_sort | early detection in a mouse model of pancreatic cancer by imaging dna damage response signalling |
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