Inflammasome-driven IL-1ß and IL-18 cytokine signaling between macrophages and cancer cells within the breast tumor microenvironment

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Suryaprakash, D. (2018). Inflammasome-driven IL-1ß and IL-18 cytokine signaling between macrophages and cancer cells within the breast tumor microenvironment. Unc Charlotte Electronic Theses And Dissertations.
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Abstract

Breast cancer especially triple-negative breast cancer remains deadly, despite detection, monitoring and therapeutic advances. Indeed, aggressive breast cancers metastasize to tissues including the brain, bones, and lungs. Metastasis is favored by a pro-inflammatory tumor microenvironment regulated in part by tumor-associated macrophages. Macrophages especially secrete the pro-inflammatory cytokines IL-1ß and IL-18 mainly following the activation of inflammasomes. The role of the inflammasome-driven pro-inflammatory IL-1ß and IL-18 cytokines in the cross-talk between macrophages and tumor cells within the breast tumor microenvironment remains to be elucidated. Here, we used in vitro models to assess the role of inflammasome in the production of IL-1ß, IL-18 and the subsequent effects of IL-1ß and IL-18 on both 4T1 mammary tumor growth and J774, RAW and bone marrow derived macrophages. Our in vitro results demonstrate that (1) inflammasome proteins are expressed and co-localized in 4T1 tumor cells and in J774 macrophages; (2) conditioned media from inflammasome-activated 4T1 cells promoted macrophage secretions of inflammasome-related cytokines, (3) conditioned media from inflammasome-activated macrophages promoted 4T1 cell growth. Furthermore, (4) recombinant IL-18 reduced J774 cell growth and, dose-dependently, 4T1 cell growth. Finally, IL-18BP abrogated IL-18-driven J774 growth inhibition. Taken together, these data suggest that inflammasome modulation, especially through the disruption of the IL-18/IL-18BP signaling, may have potential therapeutic benefit for breast cancer patients.

Details
Author

Suryaprakash, Deepika

Title

Inflammasome-driven IL-1ß and IL-18 cytokine signaling between macrophages and cancer cells within the breast tumor microenvironment

Physical Description

1 online resource (45 pages) : PDF

Date

2018

Degree Granting Institution

University of North Carolina at Charlotte

Abstract

Breast cancer especially triple-negative breast cancer remains deadly, despite detection, monitoring and therapeutic advances. Indeed, aggressive breast cancers metastasize to tissues including the brain, bones, and lungs. Metastasis is favored by a pro-inflammatory tumor microenvironment regulated in part by tumor-associated macrophages. Macrophages especially secrete the pro-inflammatory cytokines IL-1ß and IL-18 mainly following the activation of inflammasomes. The role of the inflammasome-driven pro-inflammatory IL-1ß and IL-18 cytokines in the cross-talk between macrophages and tumor cells within the breast tumor microenvironment remains to be elucidated. Here, we used in vitro models to assess the role of inflammasome in the production of IL-1ß, IL-18 and the subsequent effects of IL-1ß and IL-18 on both 4T1 mammary tumor growth and J774, RAW and bone marrow derived macrophages. Our in vitro results demonstrate that (1) inflammasome proteins are expressed and co-localized in 4T1 tumor cells and in J774 macrophages; (2) conditioned media from inflammasome-activated 4T1 cells promoted macrophage secretions of inflammasome-related cytokines, (3) conditioned media from inflammasome-activated macrophages promoted 4T1 cell growth. Furthermore, (4) recombinant IL-18 reduced J774 cell growth and, dose-dependently, 4T1 cell growth. Finally, IL-18BP abrogated IL-18-driven J774 growth inhibition. Taken together, these data suggest that inflammasome modulation, especially through the disruption of the IL-18/IL-18BP signaling, may have potential therapeutic benefit for breast cancer patients.

Genre

masters theses

Subjects--Topics

Molecular biology
Oncology

Degree

M.S.

Keywords

Breast Cancer
Cytokine
Inflammasome
Inflammation
Macrophage
Microenvironment

Subject Area

Biology

Advisor(s)

Dréau, Didier

Committee Members

Reitzel, Adam
Truman, Andrew

Degree Note

Thesis (M.S.)--University of North Carolina at Charlotte, 2018.

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Rights Holder Information

Copyright is held by the author unless otherwise indicated.

Identifier

Suryaprakash_uncc_0694N_11956

Permalink

http://hdl.handle.net/20.500.13093/etd:965