Classification of Proliferative Pulmonary Lesions of the Mouse

Nikitin, Alexander Yu.; Alcaraz, Ana; Anver, Miriam R.; Bronson, Roderick T.; Cardiff, Robert D.; Dixon, Darlene; Fraire, Armando E.; Gabrielson, Edward; Gunning, William T.; Haines, Diana C.; Kaufman, M. H.; Linnoila, R. Ilona; Maronpot, Robert R.; Rabson, Alan S.; Reddick, Robert L.; Rehm, Sabine; Rozengurt, Nora; Schüller, Hildegard M.; Shmidt, Elena N.; Travis, William D.; Ward, Jerrold M.; Jacks, Tyler

doi:10.1158/0008-5472.can-03-3376

Cited by 310 publications

(156 citation statements)

References 58 publications

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“…Within 6-8 weeks of doxycycline administration, Tet-op-EGFRvIII͞CCSP-rtTA bitransgenic mice developed atypical adenomatous hyperplasia (AAH) (Fig. 3 B and C) (22,23). Sustained doxycycline induction resulted in the growth of large lung adenomas after 12 weeks (Fig.…”

Section: Resultsmentioning

confidence: 98%

Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors

Zhao

Yuza

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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233

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The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIII) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvIII mutation was present in 5% (3͞56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0͞123). We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week. Similarly, Ba͞F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation.irreversible inhibitor ͉ lung cancer ͉ lung squamous cell carcinoma E pidermal growth factor receptor (EGFR) is commonly overexpressed and mutated in many human malignancies and is often associated with aggressive phenotypes (1-3). Before the recent discovery of the somatic mutations in the EGFR kinase domain (4-8) in non-small cell lung cancers (NSCLC), deletions of the extracellular domain were considered the most frequent EGFR mutations in the different tumor types (9-13). These deletions have an activating effect on the receptor, giving cells expressing these truncated receptors a proliferative advantage. The most common truncated receptor is the variant III EGFR deletion mutant (EGFRvIII, delta 801EGFR, del2-7 EGFR), containing an inframe deletion of exons 2-7 (801 bp) from the extracellular domain, initially characterized at the genomic level in glioblastoma.Studies using immunohistochemical assays with EGFRvIII mutant-specific antibodies suggest that this mutation is present in multiple other tumor types, including NSCLC (10,11,14). However, because of EGFR's large and complex genomic structure (28 exons spanning Ϸ190 kb) and its large intron 1 (123 kb) where genomic deletions frequently occur, it has been difficult to assess and verify the existence of the EGFRvIII mutations at the genomic level. EGFRvIII mutations have been well demonstrated in glioblastoma, where they are present in Ͼ50% of glioblastomas with amplification of EGFR gene locus (12, 15, 16), but no genomic evidence for the existence of EGFRvIII mutations has been reported in NSCLC. Furthermore, the role of EGFRvIII mutation in the potential pathogenesis of NSCLC is unclear.Here, we report that the EGFRvIII mut...

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Section: Resultsmentioning

confidence: 98%

Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors

Zhao

Yuza

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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233

175

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“…2). The diagnosis of pulmonary adenomas and adenocarcinomas was based on the criteria recommended by the Mouse Models of Human Cancers Consortium (23), and expression of prosurfactant protein C (SPC) and/or club cell 10-kDa protein (CC10) detected by immunohistochemistry (IHC) (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

Transposon Mutagenesis Screen Identifies Potential Lung Cancer Drivers and CUL3 as a Tumor Suppressor

Dorr

Janik

Weg

et al. 2015

Molecular Cancer Research

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Non-small cell lung cancers (NSCLCs) harbor thousands of passenger events that hide genetic drivers. Even highly recurrent events in NSCLC, such as mutations in PTEN, EGFR, KRAS, and ALK, are only detected in, at most, 30% of patients. Thus, many unidentified low-penetrant events are causing a significant portion of lung cancers. To detect low-penetrance drivers of NSCLC a forward genetic screen was performed in mice using the Sleeping Beauty (SB) DNA transposon as a random mutagen to generate lung tumors in a Pten deficient background. SB mutations coupled with Pten deficiency were sufficient to produce lung tumors in 29% of mice. Pten deficiency alone, without SB mutations, resulted in lung tumors in 11% of mice, while the rate in control mice was ~3%. In addition, thyroid cancer and other carcinomas as well as the presence of bronchiolar and alveolar epithelialization in mice deficient for Pten were also identified. Analysis of common transposon insertion sites identified 76 candidate cancer driver genes. These genes are frequently dysregulated in human lung cancers and implicate several signaling pathways. Cullin3 (Cul3), a member of an ubiquitin ligase complex that plays a role in the oxidative stress response pathway, was identified in the screen and evidence demonstrates that Cul3 functions as a tumor suppressor.

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“…Most NSCLC GEMMs arise peripherally and are characterized by intense hyperplastic lesions and adenoma formation, with foci of true invasive carcinoma and metastases occurring occasionally and relatively late in the disease process. 42, 43 By contrast, the GEMMs for NE carcinomas have relatively long latent periods, with the exception of the SV40 driven constitutive model from Linnoila laboratory, arise from the central compartment, hyperplastic foci are rare, adenomas are not seen, and invasive carcinomas and metastatic lesions are frequent. 42-44 …”

Section: Discussionmentioning

confidence: 99%

The Comparative Pathology of Genetically Engineered Mouse Models for Neuroendocrine Carcinomas of the Lung

Gazdar

Savage

Johnson

et al. 2015

Journal of Thoracic Oncology

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Introduction Because small cell lung carcinomas (SCLC) are seldom resected, human materials for study are limited. Thus, genetically engineered mouse models (GEMMs) for SCLC and other high-grade lung neuroendocrine (NE) carcinomas are crucial for translational research. Methods The pathologies of five GEMMs were studied in detail and consensus diagnoses reached by four lung cancer pathology experts. Hematoxylin and Eosin and immunostained slides of over 100 mice were obtained from the originating and other laboratories and digitalized. The GEMMs included the original Rb/p53 double knockout (Berns laboratory) and triple knockouts from the Sage, MacPherson and Jacks laboratories (double knockout model plus loss of p130 (Sage laboratory) or loss of Pten (MacPherson and Jacks laboratories). In addition, a GEMM with constitutive co-expression of SV40 large T antigen (Tag) and Ascl1 under the Scgb1a1 promoter from the Linnoila laboratory was included. Results The lung tumors in all of the models had common as well as distinct pathological features. All three conditional knockout models resulted in multiple pulmonary tumors arising mainly from the central compartment (large bronchi) with foci of in situ carcinoma and NE cell hyperplasia. They consisted of inter- and intra-tumor mixtures of SCLC and large cell NE cell carcinoma (LCNEC) in varying proportions. Occasional adeno- or large cell carcinomas were also seen. Extensive vascular and lymphatic invasion and metastases to the mediastinum and liver were noted, mainly of SCLC histology. In the Rb/p53/Pten triple knockout model from the MacPherson and Jacks laboratories and in the constitutive SV40/Tag model many peripherally arising NSCLC tumors having varying degrees of NE marker expression were present (NSCLC-NE tumors). The resultant histological phenotypes were influenced by the introduction of specific genetic alterations, by inactivation of one or both alleles of specific genes, by time from Cre activation and by targeting of lung cells or NE cell subpopulations. Conclusion The five GEMM models studied are representative for the entire spectrum of human high-grade NE carcinomas and are also useful for the study of multistage pathogenesis and the metastatic properties of these tumors. They represent one of the most advanced forms of currently available GEMM models for the study of human cancer.

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Classification of Proliferative Pulmonary Lesions of the Mouse

Cited by 310 publications

References 58 publications

Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors

Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors

Transposon Mutagenesis Screen Identifies Potential Lung Cancer Drivers and CUL3 as a Tumor Suppressor

The Comparative Pathology of Genetically Engineered Mouse Models for Neuroendocrine Carcinomas of the Lung

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