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Nitric Oxide and Cancer: Pathogenesis and Therapy pp 159–175Cite as

Nitric Oxide: Immune Modulation of Tumor Growth

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Abstract

Nitric oxide (NO) plays a pivotal role in the physiology of diverse tissues including cells of the immune system. It is well established that the levels of nitric oxide must be regulated carefully to maintain homeostasis. Dysregulation or overproduction of nitric oxide has been implicated in the pathogenesis of many disorders including atherosclerosis, neurodegenerative diseases, autoimmune diseases, and cancer. Tumor-associated generation of NO, predominately via inducible nitric oxide synthase (iNOS), can be produced by the immune-system (dendritic cells, NK cells, mast cells, monocytes, macrophages, Kupffer cells) as well as by other cells involved in tumor growth. Depending upon the levels of NO generated, the potential exists for it to behave like a “double-edged” biological sword. In tumorigenesis assays, both protective and toxic effects of NO generated from immune cells frequently are seen in parallel. Thus, there is no simple, uniform picture of the function of NO in the immune modulation of tumor growth. The striking inter- and intracellular signaling between tumor cells and immune system cells makes it extremely difficult to predict the effect of NOS inhibitors and NO donors. This complexity has delayed evaluation of NO regulatory drugs as frontline therapies for cancer.

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Abbreviations

NO:

Nitric oxide

iNOS (NOS-II):

Inducible nitric oxide synthase

nNOS (NOS-I):

Neuronal nitric oxide synthase

eNOS (NOS-II):

Endothelial nitric oxide synthase

NK:

Natural killer cells

DC:

Dendritic cells

T reg:

T regulatory cells

IL4:

Interleukin 4

LPS:

Lipopolysaccharide

IFN-γ:

Interferon-γ

IL-10:

Interleukin 10

TGF-β:

Transforming growth factor-β

Bid:

BH3 interacting domain

DnIKK2:

Kinase-defective dominant negative form of IKK2

MCP-1:

Monocyte chemo attractant protein 1

IBD:

Inflammatory bowel disease

UC:

Ulcerative colitis

PNT:

Peroxynitrite radical

PGE2 :

Prostaglandin E2

TNF-α:

Tumor necrosis factor-α

COX-1:

Cyclo-oxygenase-1

COX-2:

Cyclooxygenase-2

NF-kB:

Nuclear factor–κB

VEGF:

Vascular endothelial growth factor

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

NSAID:

NOn-steroidal anti-inflammatory drug

NO-NSAID:

NO-releasing NSAID

L-NAME:

L-nitro arginine methyl ester

L-NMA:

N-monomethyl-L-arginine

Apc:

Adenomatouspolyposis coli

CRC:

Colorectal cancer

IL8:

Interleukin 8

TILs:

Tumor-infiltrating lymphocytes

TcR:

T cell receptor

CTLs:

Cytotoxic T lymphocytes

MDSCs:

Myeloid-derived suppressor cells

AOM:

Azoxymethane

Se-PBIT:

Selenium [S,S’-1,4-phenylenebis(1,2-ethanediyl) bis-isothiourea]

GI:

Gastrointestinal

MIP:

Macrophage inflammatory protein

DMH:

Dimethyl hydrazine

MDFs:

Mucin depleted foci

DSS:

Dextran sulfate sodium

PGF2α:

Prostaglandin F2α

TxB2:

Thromboxane B2

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Acknowledgment

The authors thank Dr. Julie Sando for her critical reading of the chapter. The works cited were supported by in part by grant NIH-NCI R01 CA109247 and the Kerley-Cade Chair Endowment.

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  1. Center for Cancer Prevention and Cancer Drug Development, Department of Medicine, Hematology Oncology Section, PCS Cancer Center, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1203, OUHSC, 73104, Oklahoma City, OK, USA

    Naveena B. Janakiram Ph.D. & Chinthalapally V. Rao Ph.D.

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  1. Naveena B. Janakiram Ph.D.
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  2. Chinthalapally V. Rao Ph.D.
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Correspondence to Chinthalapally V. Rao Ph.D. .

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  1. Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California of Los Angeles, Los Angeles, California, USA

    Benjamin Bonavida

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Janakiram, N., Rao, C. (2015). Nitric Oxide: Immune Modulation of Tumor Growth. In: Bonavida, B. (eds) Nitric Oxide and Cancer: Pathogenesis and Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-13611-0_11

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