Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras.

By E. Jackson, Nicholas A. Willis, Kim L. Mercer, R. Bronson, D. Crowley, Raymond Montoya, T. Jacks, D. Tuveson. Genes & Development, 2001

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Adenocarcinoma of the lung is the most common form of lung cancer, but the cell of origin and the stages of progression of this tumor type are not well understood. We have developed a new model of lung adenocarcinoma in mice harboring a conditionally activatable allele of oncogenic K-ras. Here we show that the use of a recombinant adenovirus expressing Cre recombinase (AdenoCre) to induce K-ras G12D expression in the lungs of mice allows control of the timing and multiplicity of tumor initiation. Through the ability to synchronize tumor initiation in these mice, we have been able to characterize the stages of tumor progression. Of particular significance, this system has led to the identification of a new cell type contributing to the development of pulmonary adenocarcinoma.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/55f12e31d294e3a4c0da4f31b5f1b2ce036454e8

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Recent insights into the function of autophagy in cancer (2016, background): “Spontaneous non-small-cell lung cancer (NSCLC) arises following Kras activation through a stepwise progression from hyperplasia to adenoma to adenocarcinoma, associated with spontaneous mutation in p53 (Jackson et al. 2001; Johnson et al. 2001).”
LKB1 modulates lung cancer differentiation and metastasis (2007, neutral): “Only point mutation or deletion 8 of 80 (10) 4 of 42 (10) 1 of 22 (5) 13 of 144 (9) Only single-copy loss by MLPA 11 of 80 (14) 2 of 42 (5) 1 of 22 (5) 14 of 144 (10) Homozygous mutation or deletion 8{ of 80 (10) 2 of 42 (5) 0 of 22 (0) 10 of 144 (7) Total 27 of 80 (34) 8 of 42 (19) 2 of 22 (9) 37 o”
Neutrophil Elastase-Mediated Degradation of IRS-1 Accelerates Lung Tumor Growth (2010, methodology): “To determine the role of neutrophil elastase (encoded by Elane ) on tumor progression, we used the loxP -Stop- loxP K-ras G12D (LSL–K-ras) model of mouse lung adenocarcinom”
Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH (2015, methodology): “Compound mutant mice were generated by crossing available Apc mice (14), LSLKras mice (15), and Lgr5-EGFP-creER (16) animals, enabling intestinal restricted alteration of Apc and Kras.”
Genetics and biology of pancreatic ductal adenocarcinoma. (2006, background): “…by studies in mouse cells in which an activated K-RAS allele, expressed at physiological levels, provokes immortalization of fibroblasts in vitro and preneoplastic hyperplasias of the lung and GI track when activated in vivo (Jackson et al. 2001; Guerra et al. 2003; Tuveson et al. 2004).”
Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia (2012, background): “Animal Models The LSL-Kras and p48-Cre strains have been described previously (Jackson et al., 2001; Kawaguchi et al., 2002).”
Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer (2010, methodology): “mouse strains have been previously described (8, 12, 20, 22, 29, 41, 42).”
Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. (2007, background): “In this model, an endogenous K-Ras oncogene (Jackson et al., 2001) is turned on during the early stages of embryonic pancreatic development by expressing a Cre recombinase under the control of the Pdx1 or P48 promoters (Kawaguchi et al.”
Stable suppression of tumorigenicity by virus-mediated RNA interference. (2002, background): “In mouse models of lung cancer, somatic activation of oncogenic K-ras was necessary for early onset of tumors, and its continued production for maintenance of tumor viability (Chin et al., 1999; Fisher et al., 2001; Jackson et al., 2001; Johnson et al., 2001).”
Disruption of differentiation in human cancer: AML shows the way (2003, methodology): “This could be applied either in treating bone marrow ex vivo with differentiation agents, followed by bone-marrow transplantation for re-introduction into the patient, or by local therapies, such as instillation into the lung by bronchoscop”
Identification of bronchioalveolar stem cells in normal lung and lung cancer. (2005, positive): “In fact, lesions present at early time points after oncogenic K-ras activation appeared to be continuations of bronchiolar hyperplasia and alveolar hyperplasia arising in terminal bronchioles (Jackson et al., 2001).”