Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes.

By G. Fisher, Shari L. Wellen, D. Klimstra, Joi M. Lenczowski, J. Tichelaar, M. Lizak, Jeffrey A. Whitsett, A. Koretsky, H. Varmus. Genes & Development, 2001

618 citations recorded by the source corpus.

To investigate the role of an activated K-Ras gene in the initiation and maintenance of lung adenocarcinomas, we developed transgenic mice that express murine K-Ras4b(G12D) under the control of doxycycline in type II pneumocytes. Focal proliferative lesions of alveolar type II pneumocytes were observed as early as seven days after induction with doxycycline; after two months of induction, the lungs contained adenomas and adenocarcinomas, with focal invasion of the pleura at later stages. Removal of doxycycline caused a rapid fall in levels of mutant K-Ras RNA and concomitant apoptotic regression of both the early proliferative lesions and the tumors. Tumor burden was dramatically decreased by three days after withdrawal, and tumors were undetectable after one month. When similar experiments were performed with animals deficient in either the p53 gene or the Ink4A/Arf locus, tumors arose more quickly (within one month of exposure to doxycycline) and displayed more obvious histological features of malignancy; nevertheless, these tumors also regressed rapidly when the inducer was removed, implying that continued production of mutant K-Ras is necessary to maintain the viability of tumor cells in the absence as well as the presence of tumor suppressor genes. We also show that the appearance and regression of these pulmonary tumors can be readily monitored in anesthetized transgenic animals by magnetic resonance imaging.

Subfields: Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/a11d7a49a0c8bda439470df4a821b4225b130564

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Oncology

In Pulmonary and Respiratory Medicine

Citations in the corpus

Genetics and biology of pancreatic ductal adenocarcinoma. (2006, background): “Cooperation between activated RAS alleles and the loss of INK4A has been observed in animal models, including PDAC (Chin et al. 1997; Fisher et al. 2001; Aguirre et al. 2003).”
MYC activation is a hallmark of cancer initiation and maintenance. (2014, background): “Identical results have been observed for several other oncogenes (Table 1) (Chin et al. 1999; Felsher and Bishop 1999a; Huettner et al. 2000; D’Cruz et al. 2001; Fisher et al. 2001; Jain et al. 2002; Marinkovic et al. 2004; Shachaf et al. 2004; Lawlor et al. 2006; Ji et al. 2007; Li et al. 2007; Cha”
Dragging ras back in the ring. (2014, background): “Ablation of K-Ras in mouse models of lung adenocarcinoma (Fisher et al., 2001) or pancreas cancer (Ying et al., 2012) led to dramatic tumor regression, just as ablation of H-Ras leads to tumor regression in mouse models of melanoma (Chin et al., 1999).”
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).”
Pancreatic cancer biology and genetics (2002, result): “Although loss of INK4A probably facilitates the oncogenicity of activated RAS alleles, as shown in animal model”
Small-molecule antagonists of the oncogenic Tcf/β-catenin protein complex (2004, background): “Recent studies reveal that tumors rely throughout their natural history on dysregulation imposed by early molecular lesions (Chin et al., 1999; Felsher and Bishop, 1999; Fisher et al., 2001), and interference with CRT can revert transformed phenotypes in colon cancer.”
RAS oncogenes: weaving a tumorigenic web (2011, background): “Additionally, withdrawal of doxycycline-inducible oncogenic KRAS G12D expression from type II pneumocytes causes apoptosis and regression of both early proliferative lesions and lung cancer”
Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. (2003, methodology): “…tumor models that recapitulate more closely those events responsible for theRas proteins, both alone and associated with some of their downstream effectors, has been resolved, thus opening new human disease (Fisher et al., 2001; Jackson et al., 2001; John- son et al., 2001; Meuwissen et al., 2001).”
KRAS and YAP1 converge to regulate EMT and tumor survival (2014, background): “We focused on the largest category, transcription factors involved in the immediate early gene response, which are regulated by both growth factor stimulation and Ras signaling (O’Donnell et al., 2012).”
The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis (2004, background): “In lung cancer, Fisher et al (2001) has demonstrated that RAS mutation is necessary for induction and maintenance of lung cancer.”