Expression of a Mutant p53 Results in an Age-Related Demographic Shift in Spontaneous Lung Tumor Formation in Transgenic Mice

Abstract BackgroundLung cancer is the number one cancer killer worldwide. A major impediment to progress in the lung cancer treatment field is the lack of realistic mouse models that replicate the complexity of human malignancy and immune contexture within the tumor microenvironment. Such models are urgently needed. Mutations of the tumor suppressor gene TP53 are among the most common alterations in human lung cancers.MethodsPreviously, we developed a line of lung cancer mouse model where mutant human TP53-273H is expressed in a lung specific manner in FVB/N background. To investigate whether the human TP53 mutant has a similar oncogenic potential when it is expressed in another strain of mouse, we crossed the FVB/N-SPC-TP53-273H mice to A/J strain and created A/J-SPC-TP53-273H transgenic mice. We then compared lung tumor formation between A/J-SPC-TP53-273H and FVB/N-SPC-TP53-273H.ResultsWe found the TP53-273H mutant gene has a similar oncogenic potential in lung tumor formation in both mice strains, although A/J strain mice have been found to be a highly susceptible strain in terms of carcinogen-induced lung cancer. Both transgenic lines survived more than 18 months and developed age related lung adenocarcinomas. With micro CT imaging, we found the FVB-SPC-TP53-273H mice survived more than 8 weeks after initial detection of lung cancer, providing a sufficient window for evaluating new anti-cancer agents.ConclusionsOncogenic potential of the most common genetic mutation, TP53-273H, in human lung cancer is unique when it is expressed in different strains of mice. Our mouse models are useful tools for testing novel immune check point inhibitors or other therapeutic strategies in treatment of lung cancer.

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The oncogenic potential of a mutant TP53 gene explored in two spontaneous lung cancer mice models

10.21203/rs.3.rs-22164/v2 ◽

2020 ◽

Author(s):

Julian Ramelow ◽

Christopher Brooks ◽

Li GaO ◽

Abeer A Almiman ◽

Terence M Williams ◽

...

Keyword(s):

Lung Cancer ◽

Mouse Models ◽

Human Lung ◽

Lung Tumor ◽

Mutant Gene ◽

Genetic Mutation ◽

Tumor Formation ◽

Human Lung Cancer ◽

Oncogenic Potential ◽

Age Related

Abstract Background: Lung cancer is the number one cancer killer worldwide. A major impediment to progress in the lung cancer treatment field is the lack of realistic mouse models that replicate the complexity of human malignancy and immune contexture within the tumor microenvironment. Such models are urgently needed. Mutations of the tumor suppressor gene TP53 are among the most common alterations in human lung cancers. Methods: Previously, we developed a line of lung cancer mouse model where mutant human TP53-273H is expressed in a lung specific manner in FVB/N background. To investigate whether the human TP53 mutant has a similar oncogenic potential when it is expressed in another strain of mouse, we crossed the FVB/N-SPC-TP53-273H mice to A/J strain and created A/J-SPC-TP53-273H transgenic mice. We then compared lung tumor formation between A/J-SPC-TP53-273H and FVB/N-SPC-TP53-273H. Results: We found the TP53-273H mutant gene has a similar oncogenic potential in lung tumor formation in both mice strains, although A/J strain mice have been found to be a highly susceptible strain in terms of carcinogen-induced lung cancer. Both transgenic lines survived more than 18 months and developed age related lung adenocarcinomas. With micro CT imaging, we found the FVB-SPC-TP53-273H mice survived more than 8 weeks after initial detection of lung cancer, providing a sufficient window for evaluating new anti-cancer agents. Conclusions: Oncogenic potential of the most common genetic mutation, TP53-273H, in human lung cancer is unique when it is expressed in different strains of mice. Our mouse models are useful tools for testing novel immune check point inhibitors or other therapeutic strategies in treatment of lung cancer.

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The oncogenic potential of a mutant TP53 gene explored in two spontaneous lung cancer mice models

10.21203/rs.3.rs-22164/v3 ◽

2020 ◽

Author(s):

Julian Ramelow ◽

Christopher Brooks ◽

Li GaO ◽

Abeer A Almiman ◽

Terence M Williams ◽

...

Keyword(s):

Lung Cancer ◽

Mouse Models ◽

Human Lung ◽

Lung Tumor ◽

Checkpoint Inhibitors ◽

Tumor Formation ◽

Human Lung Cancer ◽

Major Drawback ◽

Oncogenic Potential ◽

Age Related

Abstract Background: Lung cancer is the number one cancer killer worldwide. A major drawback in the lung cancer treatment field is the lack of realistic mouse models that replicate the complexity of human malignancy and immune contexture within the tumor microenvironment. Such models are urgently needed. Mutations of the tumor protein p53 are among the most common alterations in human lung cancers. Methods: Previously, we developed a line of lung cancer mouse model where mutant human TP53-273H is expressed in a lung specific manner in FVB/N background. To investigate whether the human TP53 mutant has a similar oncogenic potential when it is expressed in another strain of mouse, we crossed the FVB/N-SPC-TP53-273H mice to A/J strain and created A/J-SPC-TP53-273H transgenic mice. We then compared lung tumor formation between A/J-SPC-TP53-273H and FVB/N-SPC-TP53-273H. Results: We found the TP53-273H mutant gene has a similar oncogenic potential in lung tumor formation in both mice strains, although A/J strain mice have been found to be a highly susceptible strain in terms of carcinogen-induced lung cancer. Both transgenic lines survived more than 18 months and developed age related lung adenocarcinomas. With micro CT imaging, we found the FVB-SPC-TP53-273H mice survived more than 8 weeks after initial detection of lung cancer, providing a sufficient window for evaluating new anti-cancer agents. Conclusions: Oncogenic potential of the most common genetic mutation, TP53-273H, in human lung cancer is unique when it is expressed in different strains of mice. Our mouse models are useful tools for testing novel immune checkpoint inhibitors or other therapeutic strategies in the treatment of lung cancer.

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Cellular Werner Phenotypes in Mice Expressing a Putative Dominant-Negative Human WRN Gene

Genetics ◽

10.1093/genetics/154.1.357 ◽

2000 ◽

Vol 154 (1) ◽

pp. 357-362

Author(s):

Lan Wang ◽

Charles E Ogburn ◽

Carol B Ware ◽

Warren C Ladiges ◽

Hagop Youssoufian ◽

...

Keyword(s):

Mouse Model ◽

Transgenic Mice ◽

Werner Syndrome ◽

Dominant Negative ◽

Dominant Negative Mutation ◽

Fibroblast Cultures ◽

Age Related

Abstract Mutations at the Werner helicase locus (WRN) are responsible for the Werner syndrome (WS). WS patients prematurely develop an aged appearance and various age-related disorders. We have generated transgenic mice expressing human WRN with a putative dominant-negative mutation (K577M-WRN). Primary tail fibroblast cultures from K577M-WRN mice showed three characteristics of WS cells: hypersensitivity to 4-nitroquinoline-1-oxide (4NQO), reduced replicative potential, and reduced expression of the endogenous WRN protein. These data suggest that K577M-WRN mice may provide a novel mouse model for the WS.

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Blood Pressure Profiles and Cognitive Function from Adulthood to Old Age: Chasing a Golden Middle Way?

Journal of Clinical Medicine ◽

10.3390/jcm10153243 ◽

2021 ◽

Vol 10 (15) ◽

pp. 3243

Author(s):

Rita Del Pinto ◽

Davide Grassi ◽

Raffaella Bocale ◽

Francesco Carubbi ◽

Claudio Ferri ◽

...

Keyword(s):

Cognitive Impairment ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Demographic Shift ◽

Antihypertensive Medications ◽

Microvascular Damage ◽

Middle Way ◽

Alzheimer Type Dementia ◽

Age Related ◽

Pressure Profiles

With the demographic shift toward advanced ages, it is imperative to understand the biological mechanisms behind common, disabling age-related diseases such as cognitive impairment in its mild form to overt dementia. Hypertension, a major cardiovascular risk factor, is epidemiologically linked to vascular and Alzheimer-type dementia, with possible mechanisms being atherosclerotic macro- and microvascular damage leading to neuronal cell death, as well as proinflammatory events responsible for neurodegeneration. Nevertheless, there is currently a knowledge gap as to which population to target, what the diagnostics test, and how to manage early pathogenic events in order to prevent such a dramatic and disabling condition. While clinical trials data support the benefit of active BP control with antihypertensive medications on the risk of future cognitive impairment, hypotension appears to be related to accelerated cognitive decline in both the fit and the cognitively frail elderly. Dedicated, technologically advanced studies assessing the relation of BP with dementia are needed to clarify the pathophysiological mechanisms in the association before a tailored preventive, diagnostic, and therapeutic approach to one of the most widespread modern medical challenges becomes a reality.

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Inhibition of myc-dependent breast tumor formation in transgenic mice

Breast Cancer Research and Treatment ◽

10.1023/a:1013334013065 ◽

2002 ◽

Vol 71 (1) ◽

pp. 9-20 ◽

Cited By ~ 1

Author(s):

Wei Cui ◽

Barry A. Gusterson ◽

A. John Clark

Keyword(s):

Transgenic Mice ◽

Breast Tumor ◽

Tumor Formation

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DBL Expression Driven by the Neuron Specific Enolase Promoter Induces Tumor Formation in Transgenic Mice with a P53(±) Genetic Background

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1995.2687 ◽

1995 ◽

Vol 216 (3) ◽

pp. 762-770 ◽

Cited By ~ 9

Author(s):

G.L. Coluccidamato ◽

G. Santelli ◽

A. Dalessio ◽

G. Chiappetta ◽

A. Mineo ◽

...

Keyword(s):

Transgenic Mice ◽

Genetic Background ◽

Neuron Specific Enolase ◽

Tumor Formation

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P1-031: Age-related cerebral changes of brain-derived neurotrophic factor in a model of Alzheimer's disease in APP23 transgenic mice

Alzheimer s & Dementia ◽

10.1016/j.jalz.2006.05.406 ◽

2006 ◽

Vol 2 ◽

pp. S103-S103

Author(s):

Olaf Schulte-Herbrüggen ◽

Uwe Deicke ◽

Uwe Otten ◽

Dorothee Abramowski ◽

Matthias Staufenbiel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Neurotrophic Factor ◽

Brain Derived Neurotrophic Factor ◽

Model Of Alzheimer’S Disease ◽

Age Related

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Development of humanized complement factor H transgenic mice to interrogate the effect of age-related macular degeneration risk associated variants in vivo

Immunobiology ◽

10.1016/j.imbio.2012.08.101 ◽

2012 ◽

Vol 217 (11) ◽

pp. 1164

Author(s):

Una Kelly ◽

Jin-dong Ding ◽

Michael Landowski ◽

Marybeth Groelle ◽

Haixiang Jiang ◽

...

Keyword(s):

Transgenic Mice ◽

Macular Degeneration ◽

Factor H ◽

Age Related Macular Degeneration ◽

Complement Factor H ◽

Complement Factor ◽

Age Related ◽

Effect Of Age

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Leukotriene B4 receptor-2 contributes to KRAS-driven lung tumor formation by promoting interleukin-6-mediated inflammation

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00682-z ◽

2021 ◽

Author(s):

Jae-Hyun Jang ◽

Donghwan Park ◽

Guen-soo Park ◽

Dong-Wook Kwak ◽

JaeIn Park ◽

...

Keyword(s):

Lung Cancer ◽

Interleukin 6 ◽

Double Mutant ◽

Lung Tumor ◽

Leukotriene B4 ◽

Tumor Formation ◽

Human Lung Cancer ◽

Specific Expression ◽

Tissue Samples ◽

Attractive Therapeutic Target

AbstractAlthough lung cancer is the leading cause of cancer-related deaths worldwide and KRAS is the most frequently mutated oncogene in lung cancer cases, the mechanism by which KRAS mutation drives lung cancer has not been fully elucidated. Here, we report that the expression levels of leukotriene B4 receptor-2 (BLT2) and its ligand-producing enzymes (5-LOX, 12-LOX) were highly increased by mutant KRAS and that BLT2 or 5-/12-LOX blockade attenuated KRAS-driven lung cell proliferation and production of interleukin-6 (IL-6), a principal proinflammatory mediator of lung cancer development. Next, we explored the roles of BLT2 and 5-/12-LOX in transgenic mice with lung-specific expression of mutant KRAS (KrasG12D) and observed that BLT2 or 5-/12-LOX inhibition decreased IL-6 production and tumor formation. To further determine whether BLT2 is involved in KRAS-driven lung tumor formation, we established a KrasG12D/BLT2-KO double-mutant mouse model. In the double-mutant mice, we observed significantly suppressed IL-6 production and lung tumor formation. Additionally, we observed high BLT2 expression in tissue samples from patients with KrasG12D-expressing lung adenocarcinoma, supporting the contributory role of BLT2 in KRAS-driven human lung cancer. Collectively, our results suggest that BLT2 is a potential contributor to KRAS-driven lung cancer and identify an attractive therapeutic target for KRAS-driven lung cancer.

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