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.
Highlights
The number of pancreatic cancer cases is predicted to reach 484,486 by 2020 [1]
We observed no liver metastases in KPC mice in our colony. We showed that this genetically engineered mouse model reproduces the hyperactivation of the DNA damage response (DDR) machinery observed in human PanINs and pancreatic ductal adenocarcinoma (PDAC), as measured by gH2AX immunostaining (Fig. 1), first reported by Koorstra et al [18], who themselves corroborated results from Bartkova et al, who showed DNA damage signaling hyperactivation in a large range of precursor lesions in other cancer sites [15]
We observed little or no gH2AX staining in normal acinar tissue, in the earlier precursor lesions (PanIN-1), or in areas of marked lymphocyte infiltration, and we observed little gH2AX staining in PanIN-2 lesions and in regions of PDAC
Summary
The number of pancreatic cancer cases is predicted to reach 484,486 by 2020 [1]. Diagnosis of pancreatic cancer usually depends on anatomic imaging techniques such as CT, endoscopic retrograde cholangiopancreatography, endoscopic ultrasound, laparoscopy, and MRI [5]. This information is used in conjunction with analysis of serum biomarkers (such as CA19-9 [6]) and biopsied tissue to confirm the diagnosis and the stage of disease [5]. The most widely utilized PET imaging agent, 18F-FDG, has been found to be ineffective for improving early detection of PDAC [7,8] Failure of this agent—which reveals abnormal glucose metabolism—is largely due to its inability to distinguish PDAC from chronic inflammation associated with focal mass-forming pancreatitis [8]. Similar results were previously obtained by Bartkova et al, showing DDR activation in bladder, breast, and colon cancer precursor lesions [15]
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