Tumor Cell-Derived Nitric Oxide Is Involved in the Immune-Rejection of an Immunogenic Murine Lymphoma

Hu, De‐En; Dyke, Stephanie O.M.; Moore, Alistair M.; Thomsen, Lindy L.; Brindle, Kevin M.

doi:10.1158/0008-5472.can-03-1807

Cited by 23 publications

(26 citation statements)

References 46 publications

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“…NOS are isoenzymes that catalyze the synthesis of nitric oxide (NO), a free radical whose role in tumor biology is still controversial (37). On the one hand, NO can favor tumor growth and development by stimulating angiogenesis (38) and cause immunosuppression (39, 40); on the other hand, NO could play a role in tumor regression through its ability to induce apoptosis (41) and facilitate an immune response/rejection of the tumor (42). Studies have showed that certain antioxidants in vegetables and fruits regulate NOS expression and NO production.…”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms in Nitric Oxide Synthase Genes Modify the Relationship between Vegetable and Fruit Intake and Risk of Non-Hodgkin Lymphoma

Han

Zheng

Lan

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Oxidative damage caused by reactive oxygen species and other free radicals is involved in carcinogenesis. It has been suggested that high vegetable and fruit intake may reduce the risk of non-Hodgkin lymphoma (NHL) as vegetables and fruit are rich in antioxidants. The aim of this study is to evaluate the interaction of vegetable and fruit intake with genetic polymorphisms in oxidative stress pathway genes and NHL risk. This hypothesis was investigated in a population-based case-control study of NHL and NHL histologic subtypes in women from Connecticut, including 513 histologically confirmed incident cases and 591 randomly selected controls. Gene-vegetable/fruit joint effects were estimated using unconditional logistic regression model. The false discovery rate method was applied to adjust for multiple comparisons. Significant interactions with vegetable and fruit intake were mainly found for genetic polymorphisms on nitric oxide synthase (NOS) genes among those with diffuse large B-cell lymphoma and follicular lymphoma. Two single nucleotide polymorphisms in the NOS1 gene were found to significantly modify the association between total vegetable and fruit intake and risk of NHL overall, as well as the risk of follicular lymphoma. When vegetables, bean vegetables, cruciferous vegetables, green leafy vegetables, red vegetables, yellow/orange vegetables, fruit, and citrus fruits were examined separately, strong interaction effects were narrowed to vegetable intake among patients with diffuse large B-cell lymphoma. Our results suggest that genetic polymorphisms in oxidative stress pathway genes, especially in the NOS genes, modify the association between vegetable and fruit intake and risk

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Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms in Nitric Oxide Synthase Genes Modify the Relationship between Vegetable and Fruit Intake and Risk of Non-Hodgkin Lymphoma

Han

Zheng

Lan

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…NO plays many different biological roles including stimulation of cell growth, apoptosis, and angiogenesis, and inhibits blood clotting (22,(35)(36)(37)). Brindle's group (38) recently reported that tumor-derived NO was an important mechanism for rejection of their EG7 cell line, and that other reactive oxygen species including peroxynitrite can be generated and might be involved. Our EG7 cell line does not produce NO in the presence of 1000 U of IFN-␥ and 25 ng of TNF-␣ (Fig.…”

Section: Discussionmentioning

confidence: 99%

IFN-γ Regulates Donor CD8 T Cell Expansion, Migration, and Leads to Apoptosis of Cells of a Solid Tumor

Hollenbaugh

Dutton

2006

The Journal of Immunology

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We previously reported that IFN-γ secreted by donor cytotoxic T cell 1 (Tc1) cells was the most important factor in promoting EG7 (an OVA transfection the EL4 thymoma) rejection in mice. In this study, we show that the ability of the host to respond to Tc1-secreted IFN-γ is critical for promoting acute tumor rejection, while host production of IFN-γ is not important. CFSE-labeled wild-type and IFN-γ-deficient Tc1 cells divide rapidly in secondary lymphoid organs, indicating no defect in rate of cell division. However, wild-type Tc1 cells accumulate to significantly greater numbers in the tumor than deficient Tc1 cells. Hosts injected with wild-type Tc1 effectors had more T cells within the tumor at day 4, had higher levels of MCP-1, IFN-γ-inducible protein-10, MIP-1α, and MIP-1β mRNA transcripts, had greater numbers of CD11b+ and Gr-1+ cells within the tumor, and had massive regions of tumor cell apoptosis as compared with IFN-γ knockout Tc1 cell-treated hosts. NO has a cytostatic effect on EG7 growth in vitro, and NO is important for tumor eradication by day 22. These observations are compatible with a model in which the donor CD8 Tc1 effectors expand rapidly in the host, migrate to the tumor site, and induce the secretion of a number of chemokines that in turn recruit host cells that then attack the tumor.

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“…However, NO also has stimulatory and inhibitory roles in anti-tumor immunity29. Inhibiting NOS delayed immune rejection of tumors30, and stromal cell production of NO suppressed growth31. Therefore, general inhibition of NOS may not be an effective strategy to control tumor growth.…”

Section: Angiogenic Factors Stimulate No Synthesismentioning

confidence: 99%

Regulation of nitric oxide signalling by thrombospondin 1: implications for anti-angiogenic therapies

et al. 2009

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In addition to long term regulation of angiogenesis, angiogenic growth factor signaling through nitric oxide (NO) acutely controls blood flow and hemostasis. Inhibition of this pathway may account for the hypertensive and prothrombotic side effects of vascular endothelial growth factor antagonists currently used for cancer treatment. The first identified endogenous angiogenesis inhibitor, thrombospondin-1, also controls tissue perfusion, hemostasis, and radiosensitivity by antagonizing NO signaling. We examine the role of these and other emerging activities of thrombospondin-1 in cancer. Clarifying how endogenous and therapeutic angiogenesis inhibitors regulate vascular NO signaling could facilitate development of more selective inhibitors.The insight that tumor growth requires angiogenesis led to the development and clinical use of angiogenesis inhibitors as cancer therapeutics. The drugs bevacizumab, sorafenib, and sunitinib, which are approved by the US Food and Drug Administration for the treatment of several cancers, act specifically or in part by blocking the angiogenic activity of the vascular endothelial growth factor (VEGF) pathway. These targeted drugs significantly extend survival of cancer patients but have cardiovascular side effects that include hypertension [G] and thrombosis [G] [1][2][3] . Although most attempts to define the etiology of their hypertensive activity have focused on long term changes in vessel architecture, VEGF signaling via nitric oxide (NO) also has acute effects on vessel tone [G] 4,5 , and hypertension induced by the experimental VEGF receptor kinase inhibitor cediranib was recently shown to be caused by acute disruption of NO synthesis in vascular endothelium 6 . Recent studies of the first identified endogenous angiogenesis inhibitor, thrombospondin-1 (TSP1), reveal that it also inhibits NO-mediated signaling to acutely control tissue perfusion [G] and hemostasis [G] 7,8 .Interestingly, the pioneering work of Folkman and colleagues showed that tumors can produce circulating angiogenesis inhibitors 9 , and circulating TSP1 levels are elevated in people and mice with certain cancers [10][11][12] . The benefit to the tumor of circulating angiogenesis inhibitors, which in some cases are produced by stromal rather than tumor cells, is unclear. We propose that elevated plasma TSP1 can enhance tumor perfusion through its hypertensive activity. This review synthesizes emerging evidence that hemostasis and tissue blood flow are acute targets of both endogenous and therapeutic angiogenesis inhibitors and explores ways that this insight can be used to improve anti-angiogenic therapy. Nitric oxidePhysiological activity of NO was first described by Davy in 1800 13 , but its production by mammalian tissues and role as a signaling molecule in vascular cells was not discovered until the 1980s 14 . The primary endogenous source of NO in endothelial cells is the endothelial isoform of nitric oxide synthase [G] (eNOS, also known as NOS3). eNOS is a highly regulated enzyme th...

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Tumor Cell-Derived Nitric Oxide Is Involved in the Immune-Rejection of an Immunogenic Murine Lymphoma

Cited by 23 publications

References 46 publications

Genetic Polymorphisms in Nitric Oxide Synthase Genes Modify the Relationship between Vegetable and Fruit Intake and Risk of Non-Hodgkin Lymphoma

Genetic Polymorphisms in Nitric Oxide Synthase Genes Modify the Relationship between Vegetable and Fruit Intake and Risk of Non-Hodgkin Lymphoma

IFN-γ Regulates Donor CD8 T Cell Expansion, Migration, and Leads to Apoptosis of Cells of a Solid Tumor

Regulation of nitric oxide signalling by thrombospondin 1: implications for anti-angiogenic therapies

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