Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse.

By S. Hingorani, E. Petricoin, A. Maitra, V. Rajapakse, Catrina E. King, Michael A. Jacobetz, S. Ross, Thomas P. Conrads, Timothy D. Veenstra, B. Hitt and 10 more. Cancer Cell, 2003

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To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRAS(G12D) to progenitor cells of the mouse pancreas. We find that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients.

Subfields: Oncology, Surgery

View Paper: https://www.semanticscholar.org/paper/fef7e280eb0f46398d3b5b2bea0274264766b91f

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Citations in the corpus

Hyperactive Ras in developmental disorders and cancer (2007, background): “Use of tissue-specific Cre strains in the developing pancreas induced pancreatic cancer precursor lesions, and some animals developed invasive carcinomas with prolonged latency or in the presence of cooperating tumour-suppressor gene mutation”
Pancreatic cancers require autophagy for tumor growth. (2011, positive): “Our studies employed a similar Kras-driven genetically engineered mouse model (GEMM) of PDAC (Hingorani et al. 2003; Bardeesy et al. 2006).”
G-quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcription (2006, background): “(6) have investigated the role of oncogenic RAS mutations in the pancreatic tumorigenesis.”
Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia (2012, methodology): “To ascertain whether the immunologic reaction evoked by Kras-PDECs in the orthogenic system is physiologically relevant, we compared by flow cytometry analysis the overall abundance and subtype distribution of immune cells in pancreata containing GFP-Kras-PDEC grafts and pancreata from p48-Cre;LSL-K”
Genetics and biology of pancreatic ductal adenocarcinoma. (2006, background): “Cre-induced activation of LSL-KrasG12D leads to the rapid development of PanIN lesions in the first few weeks of life (Aguirre et al. 2003; Hingorani et al. 2003).”
Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. (2011, background): “Kras mouse lines express a constitutively active form of mutated K-Ras in the pancreas, thereby recapitulating the entire spectrum of pancreatic carcinogenesis that is observed in humans (Hingorani et al., 2003).”
Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis (2011, background): “Elevated protein expression of the Nrf2 target gene Nqo1 and decreased immunoreactivity for 8-oxo-dGuo were evident in K-Ras mutant murin”
Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy (2015, positive): “Without the addition of cooperating mutations, only one-third of Pdx1-Cre Kras G12D/+ mice develop PDAC by 500 days (Hingorani et al , 2003).”