Lung tumor formation in guinea pigs by intraperitoneal administration of choline

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.

Download Full-text

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

10.21203/rs.3.rs-22164/v1 ◽

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 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.

Download Full-text

Inhibition of 7,12-dimethylbenz[a]anthracene- and urethan-induced lung tumor formation in A/J mice by long-term treatment with dehydroepiandrosterone

Carcinogenesis ◽

10.1093/carcin/2.12.1335 ◽

1981 ◽

Vol 2 (12) ◽

pp. 1335-1337 ◽

Cited By ~ 83

Author(s):

A. G. Schwartz ◽

R. H. Tannen

Keyword(s):

Lung Tumor ◽

Term Treatment ◽

Tumor Formation ◽

Long Term Treatment

Download Full-text

Abstract 313: K-ras- and EGFR-mediated lung tumor formation require epithelial NF-κB signaling to modulate the inflammatory microenvironment

10.1158/1538-7445.am2012-313 ◽

2012 ◽

Author(s):

Jamie A. Ausborn ◽

Taylor Sherrill ◽

Rinat Zaynagetdinov ◽

Vasiliy Polosukhin ◽

Frank McMahon ◽

...

Keyword(s):

Lung Tumor ◽

Tumor Formation ◽

Inflammatory Microenvironment

Download Full-text

STUDIES ON THE EFFECTS OF PHAGOCYTIC STIMULATION ON MICROBIAL DISEASE: V. STIMULATION OF PHAGOCYTIC ACTIVITY OF MONOCYTES AGAINST TUBERCLE BACILLI, STRAIN BCG

Canadian Journal of Biochemistry and Physiology ◽

10.1139/y56-062 ◽

1956 ◽

Vol 34 (1) ◽

pp. 571-579

Author(s):

Béla Gözsy ◽

László Kátó

Keyword(s):

Phagocytic Activity ◽

Guinea Pigs ◽

Saline Solution ◽

Defense Mechanism ◽

Direct Action ◽

Intraperitoneal Administration ◽

Cellular Defense ◽

Appropriate Treatment ◽

Stimulation Of

Monocytes were obtained by the washing of the peritoneal cavity of guinea pigs with Hanks' solution six days after intraperitoneal administration of a saline solution containing glycogen. Phagocytosis of tubercle bacilli (BCG strain) was studied after a one hour incubation at 37 °C. under the influence of histamine and 1,4-dimethyl-7-isopropyl-bicyclo-decapentane, which latter substance had shown a beneficial influence on the outcome of experimental tuberculosis. Histamine increased the phagocytic activity of monocytes, within the limits of 1 μgm. to 10 μgm per ml. This stimulation was inhibited in vitro by a synthetic antihistamine substance. Fifty and 100 μgm. per ml. histamine decreased the phagocytosis of tubercle bacilli (BCG) by the monocytes. Monocytes withdrawn from histamine treated guinea pigs showed no stimulated activity. From 0.5 to 100 μgm. per ml. of 1,4-dimethyl-7-isopropylbicyclo-decapentane stimulated the phagocytic activity of monocytes against tubercle bacilli (BCG) in vitro and monocytes withdrawn from animals treated with the same substance showed equally a stimulated activity. This increased phagocytosis was equally inhibited in vitro by the antihistamine, but to a lesser degree than the inhibition of the histamine stimulated phagocytosis. The above observations suggest that the stimulating action of the 1,4-dimethyl-7-isopropyl-bicyclo-decapentane is a direct action on the monocytes rather than an indirect one caused by activation of latent histamine. Experiments also show the possibility of stimulation of the cellular defense mechanism, by appropriate treatment.

Download Full-text

EpCAM Targeted 3WJ RNA Nanoparticle Harboring Delta-5-desaturase siRNA Inhibited Lung Tumor Formation via COX-2 Catalyzed Dihomo-γ-linolenic acid Peroxidation

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2019.10.194 ◽

2019 ◽

Vol 145 ◽

pp. S73

Keyword(s):

Linolenic Acid ◽

Lung Tumor ◽

Tumor Formation ◽

Cox 2 ◽

Delta 5 Desaturase

Download Full-text

Capsaicin challenge, reflex bronchoconstriction, and local action of substance P

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1988.254.5.r845 ◽

1988 ◽

Vol 254 (5) ◽

pp. R845-R852 ◽

Cited By ~ 5

Author(s):

D. R. Bergren

Keyword(s):

Substance P ◽

Guinea Pigs ◽

Airway Resistance ◽

Intraperitoneal Administration ◽

Whole Body ◽

Specific Airway Resistance ◽

Insufflation Pressure ◽

Substance P Receptor ◽

Bilateral Vagotomy ◽

Substance P Release

Capsaicin was administered as an aerosol to unanesthetized guinea pigs in a whole body plethysmograph and intravenously to anesthetized guinea pigs to investigate its mechanism of action. Capsaicin increased specific airway resistance in the unanesthetized guinea pigs and increased insufflation pressure in anesthetized guinea pigs. To investigate the possible reflex action of capsaicin, an atropine or lidocaine aerosol was administered before the capsaicin aerosol challenge in unanesthetized guinea pigs. Both lidocaine and atropine reduced the effect of capsaicin. However, neither intravenous atropine nor bilateral vagotomy antagonized the effect of injected capsaicin in the anesthetized guinea pigs. To investigate further the possible action of capsaicin, spantide (a substance P receptor antagonist) was administered before capsaicin challenge. Spantide injection in anesthetized guinea pigs attenuated the effects of the intravenous capsaicin challenge. In unanesthetized guinea pigs spantide pretreatment, as an aerosol, did not ameliorate the effects of a capsaicin aerosol challenge. However, intraperitoneal administration of spantide did reduce the effect of the capsaicin aerosol challenge as the specific airway resistance increased. Therefore, capsaicin produced its effects independent of vagal reflexes, although reflex actions of capsaicin could have occurred through other pathways. Reflex actions of capsaicin, however, were demonstrable only in the unanesthetized guinea pig. Because spantide attenuated the effect of capsaicin, increased insufflation pressure and specific airway resistance due to capsaicin challenge in both unanesthetized and anesthetized guinea pigs may be attributed, at least in part, to capsaicin's induction of substance P release or the release of other tachykinins.

Download Full-text