The Oncogenic Potential of a Mutant TP53 Gene Explored in Two Spontaneous Lung Cancer Mice Models

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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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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Progress and applications of mouse models for human lung cancer

European Respiratory Journal ◽

10.1183/09031936.00124709 ◽

2010 ◽

Vol 35 (2) ◽

pp. 426-443 ◽

Cited By ~ 30

Author(s):

S. de Seranno ◽

R. Meuwissen

Keyword(s):

Lung Cancer ◽

Mouse Models ◽

Human Lung ◽

Human Lung Cancer

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Cell autonomous angiotensin II signaling controls the pleiotropic functions of oncogenic K-Ras

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015188 ◽

2020 ◽

pp. jbc.RA120.015188

Author(s):

Daniela Volonte ◽

Morgan Sedorovitz ◽

Victoria E. Cespedes ◽

Maria L. Beecher ◽

Ferruccio Galbiati

Keyword(s):

Lung Cancer ◽

Angiotensin Ii ◽

Cancer Cells ◽

Lung Tumor ◽

Tumor Formation ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Dependent Manner ◽

Ang Ii ◽

Normal Cells

Oncogenic K-Ras (K-RasG12V) promotes senescence in normal cells but fuels transformation of cancer cells after the senescence barrier is bypassed. The mechanisms regulating this pleiotropic function of K-Ras remain to be fully established and bear high pathological significance. We find that K-RasG12V activates the angiotensinogen (AGT) gene promoter and promotes AGT protein expression in a Kruppel Like Factor 6 (KLF6)-dependent manner in normal cells. We show that AGT is then converted to angiotensin II (Ang II) in a cell-autonomous manner by cellular proteases. We show that blockade of the Ang II receptor type 1 (AT1-R) in normal cells inhibits oncogene-induced senescence (OIS). We provide evidence that the oncogenic K-Ras-induced synthesis of Ang II and AT1-R activation promote senescence through caveolin-1-dependent and NOX2-mediated oxidative stress. Interestingly, we find that expression of AGT remains elevated in lung cancer cells but in a KLF6-independent and High Mobility Group AT-Hook 1 (HMGA1)-dependent manner. We show that Ang II-mediated activation of the AT1-R promotes cell proliferation and anchorage-independent growth of lung cancer cells through a STAT3-dependent pathway. Finally, we find that expression of AGT is elevated in lung tumors of K-RasLA2-G12D mice, a mouse model of lung cancer, and human lung cancer. Treatment with the AT1-R antagonist losartan inhibits lung tumor formation in K-RasLA2-G12D mice. Together, our data provide evidence of the existence of a novel cell-autonomous and pleiotropic Ang II-dependent signaling pathway through which oncogenic K-Ras promotes OIS in normal cells while fueling transformation in cancer cells.

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Overexpression of CXCR7 accelerates tumor growth and metastasis of lung cancer cells

Respiratory Research ◽

10.1186/s12931-020-01518-6 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Huan Liu ◽

Qian Cheng ◽

Dong-sheng Xu ◽

Wen Wang ◽

Zheng Fang ◽

...

Keyword(s):

Lung Cancer ◽

Cell Migration ◽

Human Lung ◽

Lung Tumor ◽

Xenograft Model ◽

Cell Polarization ◽

Human Lung Cancer ◽

Migration And Invasion ◽

Mouse Xenograft ◽

Mouse Xenograft Model

Abstract Background Under physiological conditions, CXCL12 modulates cell proliferation, survival, angiogenesis, and migration mainly through CXCR4. Interestingly, the newly discovered receptor CXCR7 for CXCL12 is highly expressed in many tumor cells as well as tumor-associated blood vessels, although the level of CXCR7 in normal cells is low. Recently, many studies have suggested that CXCR7 promotes cell growth and metastasis in more than 20 human malignancies, among which lung cancer is the leading cause of cancer-associated deaths worldwide. Thus, the mechanism of CXCR7 in the progression of lung cancer is urgently needed. Methods First, we explored CXCR4 and CXCR7 expression in human lung cancer specimens and cell lines by immunohistochemistry, western blot and flow cytometry. Then, we chose the human lung adenocarcinoma cell line A549 that stably overexpressed CXCR7 through the way of lentivirus-mediated transduction. Next, “wound healing” assay and transwell assay were applied to compare the cell migration and invasion ability, and stripe assay was used to evaluate the cell polarization. Last, our team established a mouse xenograft model of human lung cancer and monitored tumor proliferation and metastasis by firefly luciferase bioluminescence imaging in SCID/Beige mice. Results In clinical lung cancer samples, CXCR7 expression was almost not detected in normal tissue but upregulated in lung tumor tissue, whereas, CXCR4 was highly expressed in both normal and tumor tissues. Furthermore, overexpression of CXCR7 enhanced A549 cell migration and polarization in vitro. Besides, mouse xenograft model of human lung cancer showed that CXCR7 promoted primary lung tumor’s growth and metastasis to the second organ, such as liver or bone marrow in SCID/Beige mice in vivo. Conclusions This study describes the multiple functions of CXCR7 in lung cancer. Thus, these results suggest that CXCR7 may be a malignancy marker and may provide a novel target for anticancer therapy.

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Jorunnamycin A Suppresses Stem-Like Phenotypes and Sensitizes Cisplatin-Induced Apoptosis in Cancer Stem-Like Cell-Enriched Spheroids of Human Lung Cancer Cells

Marine Drugs ◽

10.3390/md19050261 ◽

2021 ◽

Vol 19 (5) ◽

pp. 261

Author(s):

Somruethai Sumkhemthong ◽

Supakarn Chamni ◽

Gea U. Ecoy ◽

Pornchanok Taweecheep ◽

Khanit Suwanborirux ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Human Lung ◽

Suppressive Effect ◽

Tumor Formation ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Self Renewal ◽

Human Lung Cancer Cells ◽

Induced Apoptosis

It has been recognized that cancer stem-like cells (CSCs) in tumor tissue crucially contribute to therapeutic failure, resulting in a high mortality rate in lung cancer patients. Due to their stem-like features of self-renewal and tumor formation, CSCs can lead to drug resistance and tumor recurrence. Herein, the suppressive effect of jorunnamycin A, a bistetrahydroisoquinolinequinone isolated from Thai blue sponge Xestospongia sp., on cancer spheroid initiation and self-renewal in the CSCs of human lung cancer cells is revealed. The depletion of stemness transcription factors, including Nanog, Oct-4, and Sox2 in the lung CSC-enriched population treated with jorunnamycin A (0.5 μM), resulted from the activation of GSK-3β and the consequent downregulation of β-catenin. Interestingly, pretreatment with jorunnamycin A at 0.5 μM for 24 h considerably sensitized lung CSCs to cisplatin-induced apoptosis, as evidenced by upregulated p53 and decreased Bcl-2 in jorunnamycin A-pretreated CSC-enriched spheroids. Moreover, the combination treatment of jorunnamycin A (0.5 μM) and cisplatin (25 μM) also diminished CD133-overexpresssing cells presented in CSC-enriched spheroids. Thus, evidence on the regulatory functions of jorunnamycin A may facilitate the development of this marine-derived compound as a novel chemotherapy agent that targets CSCs in lung cancer treatment.

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Overexpression of CXCR7 Accelerates Tumor Growth and Metastasis of Lung Cancer Cells

10.21203/rs.3.rs-26764/v2 ◽

2020 ◽

Author(s):

Liu Huan ◽

Cheng Qian ◽

Xu Dong sheng ◽

Wang Wen ◽

Fang Zheng ◽

...

Keyword(s):

Lung Cancer ◽

Cell Migration ◽

Human Lung ◽

Lung Tumor ◽

Xenograft Model ◽

Cell Polarization ◽

Human Lung Cancer ◽

Migration And Invasion ◽

Mouse Xenograft ◽

Mouse Xenograft Model

Abstract Background: Under physiological conditions, CXCL12 modulates cell proliferation, survival, angiogenesis, and migration mainly through CXCR4. Interestingly, the newly discovered receptor CXCR7 for CXCL12 is highly expressed in many tumor cells as well as tumor-associated blood vessels, although the level of CXCR7 in normal cells is low. Recently, many studies have suggested that CXCR7 promotes cell growth and metastasis in more than 20 human malignancies, among which lung cancer is the leading cause of cancer-associated deaths worldwide. Thus, the mechanism of CXCR7 in the progression of lung cancer is urgently needed.Methods: First, we explored CXCR4 and CXCR7 expression in human lung cancer specimens and cell lines by immunohistochemistry, western blot and flow cytometry. Then, we chose the human lung adenocarcinoma cell line A549 that stably overexpressed CXCR7 through the way of lentivirus-mediated transduction. Next, “wound healing” assay and transwell assay were applied to compare the cell migration and invasion ability, and stripe assay was used to evaluate the cell polarization. Last, our team established a mouse xenograft model of human lung cancer and monitored tumor proliferation and metastasis by firefly luciferase bioluminescence imaging in SCID/Beige mice. Results: In clinical lung cancer samples, CXCR7 expression was almost not detected in normal tissue but upregulated in lung tumor tissue, whereas, CXCR4 was highly expressed in both normal and tumor tissues. Furthermore, overexpression of CXCR7 enhanced A549 cell migration and polarization in vitro. Besides, mouse xenograft model of human lung cancer showed that CXCR7 promoted primary lung tumor’s growth and metastasis to the second organ, such as liver or bone marrow in SCID/Beige mice in vivo.Conclusions: This study describes the multiple functions of CXCR7 in lung cancer. Thus, these results suggest that CXCR7 may be a malignancy marker and may provide a novel target for anticancer therapy.

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Metatranscriptomic Analysis of Human Lung Metagenomes from Patients with Lung Cancer

Genes ◽

10.3390/genes12091458 ◽

2021 ◽

Vol 12 (9) ◽

pp. 1458

Author(s):

Ya-Sian Chang ◽

Ming-Hung Hsu ◽

Siang-Jyun Tu ◽

Ju-Chen Yen ◽

Ya-Ting Lee ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

Cancer Patients ◽

Human Lung ◽

Lung Tumor ◽

Receptor Gene ◽

Growth Factor Receptor ◽

Good Prognosis ◽

Human Lung Cancer ◽

Immune Receptor

This study was designed to characterize the microbiomes of the lung tissues of lung cancer patients. RNA-sequencing was performed on lung tumor samples from 49 patients with lung cancer. Metatranscriptomics data were analyzed using SAMSA2 and Kraken2 software. 16S rRNA sequencing was also performed. The heterogeneous cellular landscape and immune repertoires of the lung samples were examined using xCell and TRUST4, respectively. We found that nine bacteria were significantly enriched in the lung tissues of cancer patients, and associated with reduced overall survival (OS). We also found that subjects with mutations in the epidermal growth factor receptor gene were less likely to experience the presence of Pseudomonas. aeruginosa. We found that the presence of CD8+ T-cells, CD4+ naive T-cells, dendritic cells, and CD4+ central memory T cells were associated with a good prognosis, while the presence of pro B-cells was associated with a poor prognosis. Furthermore, high clone numbers were associated with a high ImmuneScore for all immune receptor repertoires. Clone numbers and diversity were significantly higher in unpresented subjects compared to presented subjects. Our results provide insight into the microbiota of human lung cancer, and how its composition is linked to the tumor immune microenvironment, immune receptor repertoires, and OS.

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