Mouse Genome Informatics
cn1
    Krastm4Tyj/Kras+
Trp53tm1Brn/Trp53tm1Brn
Tg(Scgb1a1-rtTA)1Jaw/0

involves: 129S4/SvJae
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• infiltrating inflammatory cells recruited to tumors in which NF-kB has been inhibited
• tumorigenesis is initiated by infection with lentiviruses expressing Cre and Nfkbia lentiviruses
• doxycycline (Dox)-mediated induction of Nfkbia expression specifically in the tumor cells starting at 16 weeks after tumor initiation results in a significantly diminished tumour growth rate
• tumorigenesis is initiated by infection with lentiviruses expressing Cre and Nfkbia lentiviruses
• doxycycline (Dox)-mediated induction of Nfkbia expression specifically in the tumor cells leads to a significant impairment of tumour development
• tumorigenesis is initiated by infection with lentiviruses expressing Cre and Nfkbia lentiviruses


Mouse Genome Informatics
cn2
    Col1a1tm5(tetO-GFP/RNAi:Cdkn2a)Slowe/Col1a1+
Gt(ROSA)26Sortm1(Luc)Kael/Gt(ROSA)26Sortm1(rtTA*M2)Jae
Krastm4Tyj/Kras+
Tg(Scgb1a1-rtTA)1Jaw/0

involves: 129S4/SvJae * 129S6/SvEvTac * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice treated with a cre-expressing adenovirus and treated with doxycycline exhibit reduced survival compared with control mice

tumorigenesis
• mice treated with a cre-expressing adenovirus and treated with doxycycline exhibit increased tumor incidence (size and number) in the lungs with rare noninvasive lung adenomas compared with control mice
• however, mice treated with a cre-expressing adenovirus and treated with doxycycline exhibit tumor regression after doxycycline removal
• in mice treated with a cre-expressing adenovirus and treated with doxycycline

respiratory system
• rapid shallow breathing in mice treated with a cre-expressing adenovirus and treated with doxycycline

growth/size/body
• in mice treated with a cre-expressing adenovirus and treated with doxycycline


Mouse Genome Informatics
cn3
    Foxa2tm1Khk/Foxa2tm1Khk
Tg(Scgb1a1-rtTA)1Jaw/0
Tg(tetO-cre)1Jaw/0

Not Specified
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
N
• no increase in the number of neutrophils or macrophages in mice treated with doxycycline from E0 through P16 (J:88601)

respiratory system
• goblet cell hyperplasia, associated with the accumulation of both neutral and acidic mucins, in the larger airways of mice treated with doxycycline from E0 through P16
• neither airspace nor alveolar morphological abnormalities were detected
• increased in mice treated with doxycycline
• decreased in mice treated with doxycycline


Mouse Genome Informatics
cx4
    Tg(Scgb1a1-rtTA)1Jaw/0
Tg(tetO-MYC)36Bop/0

involves: 129 * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice fed a diet supplemented with DOX to stimulate transactivating function of the rtTA protein and induce MYC expression exhibit reduced lifespan

tumorigenesis
• 16.7% of DOX treated mice exhibit metastases
• 100% of tumors show activating Kras mutations
• mice treated with DOX develop papillary adenomas
• 23.8% penetrance of adenocarcionomas in untreated mice and 56.7% penetrance in DOX treated mice


Mouse Genome Informatics
cx5
    Tg(Scgb1a1-rtTA)1Jaw/0
Tg(tetO-IL1B)KBry/0

involves: 129 * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• about 50% of newborns from females provided with doxycycline during pregnancy and lactation die before 7 days of age

growth/size/body
• pups from females provided with doxycycline during pregnancy and lactation weight about 36% less than controls
• postnatal growth of newborns from females provided with doxycycline during pregnancy and lactation is decreased

respiratory system
• pups from females provided with doxycycline during pregnancy and lactation exhibit abnormal vascular development of the lungs, showing capillaries of varying sizes scattered within the thick septa at P3 compared to control lungs that show capillaries lining the alveolar septa, and by P14, capillaries are dysmorphic
• lung fibrosis with extensive subepithelial fibrosis is seen in mutants administered doxycycline for 5 weeks, with lesions showing increased collagen deposition
• mutants administered doxycycline for 8 days show a 6- to 12-fold increase in the total number of inflammatory cells in bronchoalveolar lavage fluid, mainly due to an influx of neutrophils into the lung; most of the remaining cells are macrophages (J:107601)
• an increase in inflammatory cells is seen in the alveoli and parenchyma of lungs in mutants administered doxycycline for 5 weeks (J:107601)
• however, lung histology is normal in mutants not given doxycycline (J:107601)
• fetal and neonatal lungs in mutants from females provided with doxycycline during pregnancy and lactation exhibit neutrophil and macrophage infiltration in airways and airspaces (J:130523)
• number of neutrophils in the lungs increases rapidly from E18.5 to P0 and remains stable after that time, however the number of macrophages continues to increase during the first week of life (J:130523)
• newborns from females provided with doxycycline during pregnancy and lactation exhibit disrupted alveolar development, with absence of septation and thus thicker septa of distal airspaces and an increase in alveolar chord length compared to controls
• pups from females provided with doxycycline during pregnancy and lactation exhibit thickened epithelium and subepithelial smooth muscle in airway walls, indicating airway remodeling
• mean alveolar cord length is larger in mutants administered doxycycline for 5 weeks compared to controls
• airway mucus metaplasia in mutants administered doxycycline for 5 weeks
• newborns from females provided with doxycycline during pregnancy and lactation exhibit increased thickness of saccular/alveolar walls by 23% on P0 and by 38% on P7
• severe distal airspace enlargement is seen in mutants administered doxycycline for 5 weeks
• newborns from females provided with doxycycline during pregnancy and lactation exhibit thicker septa of distal airspaces
• mutants administered doxycycline for 5 weeks exhibit distal airspace enlargement consistent with emphysema
• elastin fibers are disrupted, frayed and short in the lungs of mutants administered doxycycline for 5 weeks compared to controls, indicating elastin degradation (J:107601)
• newborns from females provided with doxycycline during pregnancy and lactation exhibit abnormal elastin structure in the distal lung at P7, with poorly organized elastin fibers in the walls of airspaces and lack of elastin in septal crests, and by 3 weeks of age, elastin fibers are splayed and disorganized and are often perpendicular to the airspace wall, have inflammatory cells infiltrating the bundles, and distribution in the blunted secondary crests is abnormal (J:130523)
• bronchiolar thickening and peribronchiolar lymphocytic nodules are seen in mutants administered doxycycline for 5 weeks
• pups from females provided with doxycycline during pregnancy and lactation exhibit goblet cell hyperplasia
• lung volumes and lung volume/body weight ratios are increased after 5 weeks of doxycycline administration
• newborns from females provided with doxycycline during pregnancy and lactation (fetuses receive doxycycline transplacentally and newborns receive it from the mother's milk) develop respiratory insufficiency within several days after birth

immune system
• mutants administered doxycycline for 5 weeks exhibit increased production of CXC chemokines Cxcl1 (KC) and Cxcl2 (MIP-2) (J:107601)
• fetal and neonatal lungs in mutants from females provided with doxycycline during pregnancy and lactation exhibit increased production of chemokines, KC, MIP-2, MCP-1 and MCP-2 (J:130523)
• mutants administered doxycycline for 8 days show a 6- to 12-fold increase in the total number of inflammatory cells in bronchoalveolar lavage fluid, mainly due to an influx of neutrophils into the lung; most of the remaining cells are macrophages (J:107601)
• an increase in inflammatory cells is seen in the alveoli and parenchyma of lungs in mutants administered doxycycline for 5 weeks (J:107601)
• however, lung histology is normal in mutants not given doxycycline (J:107601)
• fetal and neonatal lungs in mutants from females provided with doxycycline during pregnancy and lactation exhibit neutrophil and macrophage infiltration in airways and airspaces (J:130523)
• number of neutrophils in the lungs increases rapidly from E18.5 to P0 and remains stable after that time, however the number of macrophages continues to increase during the first week of life (J:130523)

homeostasis/metabolism
• mutants administered doxycycline for 5 weeks exhibit increased production of CXC chemokines Cxcl1 (KC) and Cxcl2 (MIP-2) (J:107601)
• fetal and neonatal lungs in mutants from females provided with doxycycline during pregnancy and lactation exhibit increased production of chemokines, KC, MIP-2, MCP-1 and MCP-2 (J:130523)
• lung fibrosis with extensive subepithelial fibrosis is seen in mutants administered doxycycline for 5 weeks, with lesions showing increased collagen deposition

cardiovascular system
• pups from females provided with doxycycline during pregnancy and lactation exhibit abnormal vascular development of the lungs, showing capillaries of varying sizes scattered within the thick septa at P3 compared to control lungs that show capillaries lining the alveolar septa, and by P14, capillaries are dysmorphic


Mouse Genome Informatics
cx6
    Col1a1tm1(tetO-EML4/ALK)Kkw/Col1a1+
Tg(Scgb1a1-rtTA)1Jaw/0

involves: 129 * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• doxycycline-treated mice exhibit a median survival of 7 to 8 weeks

tumorigenesis
• withdrawal of doxycycline leads to complete tumor regression
• ALK kinase inhibitor is a more effective therapy than chemotherapy in doxycycline-treated mice
• doxycycline-treated mice develop lung tumorigenesis with a latency of less than 10 days
• however, withdrawal of doxycycline leads to complete tumor regression
• adenocarcinomas predominantly bronchioloalveolar carcinoma with occasional pleural space and airway invasion by an acinar component in doxycycline-treated mice

growth/size/body
• in tumor-bearing, doxycycline-treated mice in the first 4 weeks

respiratory system
N
• untreated mice exhibit normal lung histology (J:166724)

Mouse Models of Human Disease
OMIM IDRef(s)
Lung Cancer 211980 J:166724


Mouse Genome Informatics
cx7
    Tg(Scgb1a1-rtTA)1Jaw/0
Tg(tetO-Aimp1)29872Mcla/0

involves: 129 * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cellular
• 3 fold increase in caspase 3 activity in lung alveolar cells is measured as early as 4 weeks after doxycycline (dox) induction

hematopoietic system
• 28 weeks of doxycycline induction results in an increase in the number of alveolar macrophages in bronchoalveolar lavage fluid (BALF) and lung parenchyma from lung lysates

immune system
• 28 weeks of doxycycline induction results in an increase in the number of alveolar macrophages in bronchoalveolar lavage fluid (BALF) and lung parenchyma from lung lysates

respiratory system
• 3 fold increase in caspase 3 activity in lung alveolar cells is measured as early as 4 weeks after doxycycline (dox) induction
• increase in diameters of acinar airspaces (comprising alveolar ducts and alveoli) following dox treatment as compared to controls
• following doxycycline induction
• following doxycycline induction
• following doxycycline induction


Mouse Genome Informatics
cx8
    Tg(Scgb1a1-rtTA)1Jaw/0
Tg(tetO-CTGF)#Swu/0

involves: 129 * C57BL/6 * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• pups nursing on dams administered doxycycline from P1 to P14 exhibit decreased capillary formation in alveolar septa
• pups nursing on dams administered doxycycline from P1 to P14 exhibit thickening in the peribronchial/peribronchiolar and perivascular regions of the lungs and increased collagen deposition in these regions, indicating fibrosis
• pups nursing on dams administered doxycycline from P1 to P14 exhibit disrupted alveolarization, showing a 27% and 31% decrease in the mean alveolar airspace area and mean cord length, respectively
• pups nursing on dams administered doxycycline from P1 to P14 exhibit disorganized elastic fiber deposition on alveolar surfaces and in septa
• pups nursing on dams administered doxycycline from P1 to P14 exhibit a 34% decrease in secondary septa
• marker analysis indicates that pups nursing on dams administered doxycycline from P1 to P14 exhibit increased myofibroblast differentiation in alveolar septa
• pups nursing on dams administered doxycycline from P1 to P14 exhibit a 48% increase in the proliferating cell index in alveolar septa
• pups nursing on dams administered doxycycline from P1 to P14 exhibit decreased capillary formation in alveolar septa

cardiovascular system
• pups nursing on dams administered doxycycline from P1 to P14 exhibit decreased capillary formation in alveolar septa

homeostasis/metabolism
• pups nursing on dams administered doxycycline from P1 to P14 exhibit thickening in the peribronchial/peribronchiolar and perivascular regions of the lungs and increased collagen deposition in these regions, indicating fibrosis


Mouse Genome Informatics
cx9
    Tg(Scgb1a1-rtTA)1Jaw/0
Tg(tetO-PIK3CA*H1047R)13Lca/0

involves: 129 * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• at 12 weeks following doxycycline treatment, mice develop lung adenocarcinomas
• however, withdrawal of doxycycline or treatment with NVP-BEZ235 leads to tumor regression

Mouse Models of Human Disease
OMIM IDRef(s)
Lung Cancer 211980 J:142254


Mouse Genome Informatics
cx10
    Tg(Scgb1a1-rtTA)1Jaw/0
Tg(tetO-Spdef)1Jaw/0

involves: 129 * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• doxycycline-treated mice exhibit goblet cell differentiation without proliferation unlike similarly treated wild-type mice
• doxycycline-treated mice exhibit hyperplasia of lung goblet cells compared with similarly treated wild-type mice


Mouse Genome Informatics
cx11
    Tg(Scgb1a1-rtTA)1Jaw/0
Tg(tetO-EGFR*L858R)56Hev/0

involves: C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• after only 4 days' induction with doxycycline, lung tissue from doubly transgenic mice contained nearly 2-fold the number of type II pneumocytes, identified by staining with antibody against surfactant protein C, than control tissue
• immunohistochemical analysis demonstrates that the tumors induced by doxycycline in these mice express the mutant human EGFR protein and that they are composed of cells that express surfactant protein C, characteristic of type II pneumocytes, but not Clara cell protein CC26
• as early as 2 weeks after initiation of doxycycline, lungs of bitransgenic mice exhibit scattered thickening of the alveolar walls due to proliferation of abnormal pneumocytes, with a lepidic growth pattern similar to human bronchioalveolar carcinoma (BAC), a subtype of lung adenocarcinoma; this wall thickening may be progressive, gradually compressing the air spaces

tumorigenesis
• as early as 2 weeks after initiation of doxycycline, lungs of bitransgenic mice exhibit scattered thickening of the alveolar walls due to proliferation of abnormal pneumocytes, with a lepidic growth pattern similar to human bronchioalveolar carcinoma (BAC), a subtype of lung adenocarcinoma; this wall thickening may be progressive, gradually compressing the air spaces
• after longer than 4 weeks on doxycycline, bitransgenic mice develop multifocal invasive adenocarcinoma of the lungs, with papilliform tumors of varying size embedded in the abnormal lung parenchyma; the adenocarcinoma cells have moderately pleomorphic nuclei with large nucleoli
• immunohistochemical analysis demonstrates that the tumors in these mice express the mutant human EGFR protein and that they are composed of cells that express surfactant protein C, characteristic of type II pneumocytes, but not Clara cell protein CC26
• discontinuation of doxycycline treatment in two mice after 122 and 180 days resulted in diminution of lung opacities on MRI at 9 and 2 days afterward; histologic examination of the second mouse immediately after MRI found tumors present, whereas examination of the first mouse 31 days after deinduction revealed that the tumors had regressed completely, leaving scar tissue
• treatment of tumor-bearing mice with the tyrosine kinase inhibitor erlotinib, while the mice continued receiving doxycycline, resulted in partial to complete disappearance of opacities on MRI in all mice on at least 12.5 mg kg-1 d-1 erlotinib and, in mice examined after at least 4 days on erlotinib, complete or nearly complete (i.e., some residual tumor cells remained) histological regression of the tumors


Mouse Genome Informatics
cx12
    Tg(Scgb1a1-rtTA)1Jaw/0
Tg(tetO-EGFR*L858R)57Hev/0

involves: C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• after only 4 days' induction with doxycycline, lung tissue from doubly transgenic mice contained nearly 2-fold the number of type II pneumocytes, identified by staining with antibody against surfactant protein C, than control tissue
• immunohistochemical analysis demonstrates that the tumors induced by doxycycline in these mice express the mutant human EGFR protein and that they are composed of cells that express surfactant protein C, characteristic of type II pneumocytes, but not Clara cell protein CC26

tumorigenesis
• as early as 2 weeks after initiation of doxycycline, lungs of bitransgenic mice exhibit scattered thickening of the alveolar walls due to proliferation of abnormal pneumocytes, with a lepidic growth pattern similar to human bronchioalveolar carcinoma (BAC), a subtype of lung adenocarcinoma; this wall thickening may be progressive, gradually compressing the air spaces
• after longer than 4 weeks on doxycycline, bitransgenic mice develop multifocal invasive adenocarcinoma of the lungs, with papilliform tumors of varying size embedded in the abnormal lung parenchyma; the adenocarcinoma cells have moderately pleomorphic nuclei with large nucleoli
• immunohistochemical analysis demonstrates that the tumors in these mice express the mutant human EGFR protein and that they are composed of cells that express surfactant protein C, characteristic of type II pneumocytes, but not Clara cell protein CC26
• discontinuation of doxycycline treatment in two mice after 43 and 55 days resulted in complete disappearance of lung opacities on MRI within a week; histologic examination at 32 and 169 days after deinduction revealed that the tumors had regressed completely, in one case leaving scar tissue
• treatment of tumor-bearing mice with the tyrosine kinase inhibitor erlotinib, while the mice continued receiving doxycycline, resulted in partial to complete disappearance of opacities on MRI in 2-8 days and, in mice examined after at least 4 days on erlotinib, complete or nearly complete (i.e., some residual tumor cells remained) histological regression of the tumors


Mouse Genome Informatics
cx13
    Tg(Scgb1a1-rtTA)1Jaw/0
Tg(tetO-EGFR*delta19)11Hev/0

involves: C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• a bitransgenic mouse examined histologically 8 days after initiation of doxycycline exhibited proliferative lung lesions characteristic of early atypical adenomatous hyperplasia (AHH) at the lung periphery
• immunohistochemical analysis demonstrates that the tumors induced in these mice express the mutant human EGFR protein and that they are composed of cells that express surfactant protein C, characteristic of type II pneumocytes, but not Clara cell protein CC26
• bitransgenic mice on doxycycline 28 days or longer exhibit multifocal, frondiform tumors arising and radiating from bronchioalveolar duct junctions (BADJ) into the surrounding, BAC-free parenchyma; more advanced tumors form compact papilliform masses

tumorigenesis
• a bitransgenic mouse examined after 13 days on doxycycline exhibited scattered thickening of the alveolar walls due to proliferation of abnormal pneumocytes, with a lepidic growth pattern similar to human bronchioalveolar carcinoma (BAC); animals examined after 28 days or longer on doxycycline exhibited BAC-like lesions at the lung periphery
• mice on doxycycline 28 days or longer exhibit multifocal, frondiform tumors radiating from bronchioalveolar duct junctions (BADJ) into the surrounding, BAC-free parenchyma; more advanced tumors form compact papilliform masses
• discontinuation of doxycycline treatment in two mice after 99 and 168 days resulted in partial remission of lung opacities on MRI at 6 and 4 days, respectively; histologic examination 4 days after deinduction found tumors still present, but at 31 days revealed that the tumors had regressed completely, leaving scar tissue
• treatment of two tumor-bearing bitransgenic mice (the second heterozygous for a Trp53-inactivating mutation) with the tyrosine kinase inhibitor erlotinib, while the mice continued receiving doxycycline, resulted in partial disappearance of opacities on MRI at 4 and 14 days and, after 4 days and 4 weeks on erlotinib, respectively, nearly complete histological regression of the tumors (i.e., some residual tumor cells remained)


Mouse Genome Informatics
cx14
    Tg(tetO-Plau)1Ths/0
Tg(Scgb1a1-rtTA)1Jaw/0

involves: C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice exhibit decreased mortality rate following bleomycin-induced lung injury

homeostasis/metabolism
• mice exhibit decreased mortality rate following bleomycin-induced lung injury


Mouse Genome Informatics
cx15
    Tg(tetO-Vegfa)90Ala/?
Tg(Scgb1a1-rtTA)1Jaw/?

involves: FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• administration of doxycycline to pregnant mother and consequent VEGF-A164 expression in conducting airway epithelial cells of E10.5 to E16.5 embryo caused irregular evagination of epithelium into the lumen of bronchi and bronchioli


Mouse Genome Informatics
cx16
    Tg(Scgb1a1-rtTA)1Jaw/0
Tg(tetO/CMV-KRAS*G12C)9.1Msmi/0

involves: FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
respiratory system
• after 12 days of doxycycline (DOX) treatement, small, hyperplastic lung foci are detected; untreated mice have normal lungs
• after 5 weeks of DOX treatment, extensive epithelial hyperplasia of alveolar region of lung is observed; untreated mice have normal lungs

tumorigenesis
• after 3 months treatment, visible macroscopic lesions are found; tumor incidence at 3 months is 55%, with multiplicity of 3.5 tumors/mouse
• lesions are <1mm in size
• early hyperplastic lesions are of bronchiolar origin
• at 6 and 9 months DOX treatment, visible lesions increase in number; multiplicity is 28.8 and 34 tumors/mouse after 9 and 12 months, higher than SFTPC/KRAS bitransgenic mice; treated monotransgenic mice show no tumor incidence
• when DOX treatment was stopped after 9 months, within 2 weeks only 4 tumors are visible on lung surface; these remain after 1 months; minimal hyperplastic foci microscopically are detectable, showing no proliferation (or apoptosis)
• single adenoma was detected at 3 months; at 6, 9, and 12 months of treatment, incidence increases; mice develop higher incidence of proliferative changes with lower latency than SFTPC/KRAS mice
• at 12 months of treatment, 2 adenomas have progressed to low grade carcinomas