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

The process of skin carcinogenesis is still not fully understood. Both experimental and epidemiological evidence indicate that chronic inflammation is one of the hallmarks of microenvironmental-agent-mediated skin cancers and contributes to its development. Maintaining an inflammatory microenvironment is a condition leading to tumor formation. Multiple studies focus on the molecular pathways activating tumorigenesis by inflammation and indicate several biomarkers and factors that can improve diagnostic and prognostic processes in oncology and dermatology. Reactive oxygen species produced by ultraviolet radiation, oxidizers, or metabolic processes can damage cells and initiate pro-inflammatory cascades. Considering the potential role of inflammation in cancer development and metastasis, the identification of early mechanisms involved in carcinogenesis is crucial for clinical practice and scientific research. Moreover, it could lead to the progress of advanced skin cancer therapies. We focus on a comprehensive analysis of available evidence and on understanding how chronic inflammation and ultraviolet radiation can result in skin carcinogenesis. We present the inflammatory environment as complex molecular networks triggering tumorigenesis and constituting therapeutic targets.

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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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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.

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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

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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

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Tumor Cell Associated Hyaluronan-CD44 Signaling Promotes Pro-Tumor Inflammation in Breast Cancer

Cancers ◽

10.3390/cancers12051325 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1325 ◽

Cited By ~ 1

Author(s):

Patrice M. Witschen ◽

Thomas S. Chaffee ◽

Nicholas J. Brady ◽

Danielle N. Huggins ◽

Todd P. Knutson ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Chronic Wound ◽

Gene Signature ◽

Tumor Formation ◽

Human Breast ◽

Inflammatory Microenvironment ◽

Tumor Types

Cancer has been conceptualized as a chronic wound with a predominance of tumor promoting inflammation. Given the accumulating evidence that the microenvironment supports tumor growth, we investigated hyaluronan (HA)-CD44 interactions within breast cancer cells, to determine whether this axis directly impacts the formation of an inflammatory microenvironment. Our results demonstrate that breast cancer cells synthesize and fragment HA and express CD44 on the cell surface. Using RNA sequencing approaches, we found that loss of CD44 in breast cancer cells altered the expression of cytokine-related genes. Specifically, we found that production of the chemokine CCL2 by breast cancer cells was significantly decreased after depletion of either CD44 or HA. In vivo, we found that CD44 deletion in breast cancer cells resulted in a delay in tumor formation and localized progression. This finding was accompanied by a decrease in infiltrating CD206+ macrophages, which are typically associated with tumor promoting functions. Importantly, our laboratory results were supported by human breast cancer patient data, where increased HAS2 expression was significantly associated with a tumor promoting inflammatory gene signature. Because high levels of HA deposition within many tumor types yields a poorer prognosis, our results emphasize that HA-CD44 interactions potentially have broad implications across multiple cancers.

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