Expression of Inducible Nitric Oxide Synthase in Colorectal Cancer and Its Association with Prognosis

Ropponen, Kirsi; Kellokoski, Jari; Lipponen, P; Eskelinen, Matti; Alanne, Leena; Alhava, Esko; Kosma, Veli‐Matti

doi:10.1080/003655200750056709

Cited by 29 publications

(5 citation statements)

References 33 publications

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“…For this reason we expanded our retrospective analysis with 12 TAM-associated genes and found a correlation between the M1-associated factor iNOS and prolonged survival as well as between an increased expression of M2-associated genes ( CD163 , FN1 and IRF4 ) and reduced survival. iNOS has previously been correlated with increased survival in colorectal cancer patients 45 . Furthermore, a correlation between CD163 and reduced survival has been recently observed in different types of cancer, including ccRCC 46 , 47 .…”

Section: Discussionmentioning

confidence: 88%

Tumor-associated macrophages subvert T-cell function and correlate with reduced survival in clear cell renal cell carcinoma

et al. 2013

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Although malignant cells can be recognized and controlled by the immune system, in patients with clinically apparent cancer immunosurveillance has failed. To better understand local immunoregulatory processes that impact on cancer progression, we correlated intratumoral immunological profiles with the survival of patients affected by primary clear cell renal cell carcinoma (ccRCC). A retrospective analysis of 54 primary ccRCC samples for 31 different immune response-related transcripts, revealed a negative correlation of CD68 (a marker of tumor-associated macrophages, TAMs) and FOXP3 (a marker of regulatory T cells, Tregs) with survival. The subsequent analysis of 12 TAM-related transcripts revealed an association between the genes coding for CD163, interferon regulatory factor 4 (IRF4) and fibronectin 1 (FN1), all of which have been linked to the M2 TAM phenotype, with reduced survival and increased tumor stage, whereas the opposite was the case for the M1-associated gene coding for inducible nitric oxide synthetase (iNOS). The M2 signature of (CD68+) TAMs was found to correlate with CD163 expression, as determined in prospectively collected fresh ccRCC tissue samples. Upon co-culture with autologous tumor cells, CD11b+ cells isolated from paired blood samples expressed CD163 and other M2-associated proteins, suggesting that the malignant cells promote the accumulation of M2 TAMs. Furthermore, the tumor-associated milieu as well as isolated TAMs induced the skewing of autologous, blood-derived CD4+ T cells toward a more immunosuppressive phenotype, as shown by decreased production of effector cytokines, increased production of interleukin-10 (IL-10) and enhanced expression of the co-inhibitory molecules programmed death 1 (PD-1) and T-cell immunoglobulin mucin 3 (TIM-3). Taken together, our data suggest that ccRCC progressively attracts macrophages and induces their skewing into M2 TAMs, in turn subverting tumor-infiltrating T cells such that immunoregulatory functions are increased at the expense of effector functions.

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Section: Discussionmentioning

confidence: 88%

Tumor-associated macrophages subvert T-cell function and correlate with reduced survival in clear cell renal cell carcinoma

et al. 2013

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“…Ropponen et al . suggest that high iNOS staining intensity and percentage distribution in tumor epithelium may have a protective role against colorectal cancer progression in humans [83]. They reported that iNOS expression correlated positively with cell cycle regulators p21 and AP-2.…”

Section: Anti-tumorigenic Properties Of Nomentioning

confidence: 99%

iNOS-Selective Inhibitors For Cancer Prevention: Promise And Progress

Janakiram

Rao

2012

Future Med. Chem.

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Nitric oxide (NO) is involved in various physiological functions and its role in tumorigenesis has been well studied. A large majority of human and experimental tumors appear to progress owing to NO resulting from iNOS, further stimulated by proinflammatory cytokines. Conversely, in some cases, NO is associated with induction of apoptosis and tumor regression. This dichotomy of NO is largely explained by the complexity of signaling pathways in tumor cells, which respond to NO very differently depending on its concentration. In addition, NO alters many signaling pathways through chemical modifications, such as the addition of S-nitrosothiols and nitrosotyrosine to target proteins altering various biological pathways. Hence, iNOS inhibitors are designed and developed to inhibit various organ site cancers including the colon. Here, we review iNOS expression, generation of NO, involvement of NO in altering signaling pathways, and iNOS select inhibitors and their possible use for the prevention and treatment of various cancers.

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“…Recently, accumulated evidence indicated that the elevated expression of iNOS was significantly associated with the angiogenesis, chemotherapeutic resistance, metastasis, and immune resistance in some malignant tumors, e.g., colorectal cancer, breast cancer, bladder cancer, gastric cancer, and melanoma [7–10]. In addition, several research studies also reported that iNOS expression had a correlation with unfavorable prognosis in human cancers [11–13], but there were still many controversies surrounding the prognostic value of iNOS in tumor [14, 15]. Due to the noncomprehensive analysis for survival data in a single study, we performed an integrated meta-analysis to investigate the prognostic value of iNOS by pooling the results of multiple studies and to support the role of the protein as a promising prognostic biomarker.…”

Section: Introductionmentioning

confidence: 99%

Prognostic Value of Inducible Nitric Oxide Synthase (iNOS) in Human Cancer: A Systematic Review and Meta-Analysis

Liao

Liu

2019

BioMed Research International

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Background. Inducible nitric oxide synthase (iNOS) is confirmed to regulate the production of nitric oxide (NO) when cells are exposed to external stimulus. Recent publications revealed that overexpression of iNOS predicted poor clinical outcomes for patients with malignant cancers, e.g., gastric, bladder, and colorectal cancers; however, several studies reported no obvious relationship between iNOS expression and prognosis of solid tumors. The aim of our study was to investigate the pooled effect of the prognostic value of iNOS expression. Materials and Methods. We performed a systematic search of PubMed, Web of Science, and Embase databases up to January 15, 2019. The concerned outcomes of interest included overall survival (OS), cancer-special survival (CSS), and recurrence-free survival (RFS). Results. Fourteen studies with 1,758 patients were included in this meta-analysis, and we reached the conclusion that increased iNOS expression was significantly associated with worse OS (HR: 1.89, 95% CI: 1.57 - 2.28, p ≤ 0.001), worse CSS (HR: 3.13, 95% CI: 1.88 - 5.20, p ≤ 0.001), and worse RFS (HR: 2.16, 95% CI: 1.29 - 3.62, p = 0.003) in solid tumors. Furthermore, the subgroup analysis identified the significant relationship of high iNOS expression with poor OS in gastric cancer. No obvious publication bias was detected by Begg’s tests. Conclusion. In summary, the results drawn in our meta-analysis demonstrated that elevated expression of iNOS had a significant association with poor survival in human cancer. iNOS might serve as a promising predictive biomarker of prognosis in cancer patients, and well-designed prospective studies are further needed to substantiate the prognostic value of iNOS.

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Expression of Inducible Nitric Oxide Synthase in Colorectal Cancer and Its Association with Prognosis

Abstract: These results suggest that iNOS has a protective role in colorectal carcinogenesis, but further studies are required to establish the clinical significance of iNOS in colorectal cancer.

Cited by 29 publications

References 33 publications

Tumor-associated macrophages subvert T-cell function and correlate with reduced survival in clear cell renal cell carcinoma

Tumor-associated macrophages subvert T-cell function and correlate with reduced survival in clear cell renal cell carcinoma

iNOS-Selective Inhibitors For Cancer Prevention: Promise And Progress

Prognostic Value of Inducible Nitric Oxide Synthase (iNOS) in Human Cancer: A Systematic Review and Meta-Analysis

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