Prognostic significance of tumor iNOS and COX-2 in stage III malignant cutaneous melanoma

Johansson, C. Christian; Egyházi, Suzanne; Masucci, Giuseppe; Harlin, Helena; Mougiakakos, Dimitrios; Poschke, Isabel; Nilsson, Bo; Garberg, Liss; Tuominen, Rainer; Lindén, Diana; Stolt, Marianne Frostvik; Hansson, Johan; Kiessling, Rolf

doi:10.1007/s00262-008-0631-1

Cited by 45 publications

(48 citation statements)

References 37 publications

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“…This is in accordance with previous observations that COX-2 and its direct product PGE 2 are expressed at high levels in malignant melanomas and often correlate with poor prognosis (18,19). Interruption of the COX-2/PGE 2 pathway has been shown to be effective in blocking MDSCs induced by a mixture of cytokines in vitro (17,20).…”

Section: Introductionsupporting

confidence: 79%

Melanoma-Educated CD14+ Cells Acquire a Myeloid-Derived Suppressor Cell Phenotype through COX-2–Dependent Mechanisms

et al. 2013

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Tumors can suppress the host immune system by employing a variety of cellular immune modulators, such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells (MDSC). In the peripheral blood of patients with advanced stage melanoma, there is an accumulation of CD14 þ HLA-DR lo/À MDSC that suppress autologous T cells ex vivo in a STAT-3-dependent manner. However, a precise mechanistic basis underlying this effect is unclear, particularly with regard to whether the MDSC induction mechanism relies on cell-cell contact of melanoma cells with CD14 þ cells. Here, we show that early-passage human melanoma cells induce phenotypic changes in CD14 þ monocytes, leading them to resemble MDSCs characterized in patients with advanced stage melanoma. These MDSC-like cells potently suppress autologous T-cell proliferation and IFN-g production. Notably, induction of myeloid-suppressive functions requires contact or close proximity between monocytes and tumor cells. Further, this induction is largely dependent on production of cyclooxygenase-2 (COX-2) because its inhibition in these MDSC-like cells limits their ability to suppress T-cell function. We confirmed our findings with CD14 þ cells isolated from patients with advanced stage melanoma, which inhibited autologous T cells in a manner relying up prostaglandin E2 (PGE 2 ), STAT-3, and superoxide. Indeed, PGE 2 was sufficient to confer to monocytes the ability to suppress proliferation and IFN-g production by autologous T cells ex vivo. In summary, our results reveal how immune suppression by MDSC can be initiated in the tumor microenvironment of human melanoma. Cancer Res; 73(13); 3877-87. Ó2013 AACR.

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Section: Introductionsupporting

confidence: 79%

Melanoma-Educated CD14+ Cells Acquire a Myeloid-Derived Suppressor Cell Phenotype through COX-2–Dependent Mechanisms

et al. 2013

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“…In 2002, Cohen et al reported constitutive ERK-phosphorylation in >20% of benign nevi and >80% of primary melanoma (14), and hence confirmed activation of MAPK-signaling as an early event in human melanoma development. Pre-clinical studies developed over the following 15 years have underscored the importance of the BRAF-MAPK pathway in a multitude of processes involved in melanoma development and progression and BRAFV600E has been established as central for the control of melanoma cell proliferation and cell cycle progression, apoptosis, migration, invasion, glucose metabolism, adaptation to hypoxia or angiogenesis (3,(15)(16)(17)(18)(19)(20)(21)(22). Indeed it has now become well accepted that melanomas harboring BRAF mutations are addicted to the MAPK-pathway, as BRAFV600E cells show significant sensibility towards either genetic or chemical inhibition of this pathway.…”

Section: Introductionmentioning

confidence: 99%

Overcoming resistance to BRAF inhibitors

2017

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Abstract:The discovery of activating mutations in the serine/threonine (S/T) kinase BRAF followed by a wave of follow-up research manifested that the MAPK-pathway plays a critical role in melanoma initiation and progression. BRAF and MEK inhibitors produce an unparalleled response rate in melanoma, but it is now clear that most responses are transient, and while some patients show long lasting responses the majority progress within 1 year. In accordance with the key role played by the MAPK-pathway in BRAF mutant melanomas, disease progression is mostly due to the appearance of drug-resistance mechanisms leading to restoration of MAPK-pathway activity. In the present article we will review the development, application and clinical effects of BRAF and MEK inhibitors both, as single agent and in combination in the context of targeted therapy in melanoma. We will then describe the most prominent mechanisms of resistance found in patients progressed on these targeted therapies. Finally we will discuss strategies for further optimizing the use of MAPK inhibitors and will describe the potential of alternative combination therapies to either delay the onset of resistance to MAPK inhibitors or directly target specific mechanisms of resistance to BRAF/ MEK inhibitors.

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“…This is consistent with the emerging pathogenic role of endogenous NO in the development and clinical course of melanoma. In fact, con stitutive expression of inducible form of iNOS correlates with poor survival (14)(15)(16). NO seems to initiate progression of human melanoma via a feedback loop mediated by apurinic/apyrimidinic endonuclease-1/ redox factor-1 (17).…”

Section: Introductionmentioning

confidence: 99%

Unique antineoplastic profile of Saquinavir-NO, a novel NO-derivative of the protease inhibitor Saquinavir, on the in vitro and in vivo tumor formation of A375 human melanoma cells

Donia¹,

Mangano²,

Fagone³

et al. 2012

Oncology Reports

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Abstract.We have recently shown that covalent attachment of the nitric oxide (NO) moiety to the HIV protease inhibitor Saquinavir (Saq) produced a qualitatively new chemical entity, named Saquinavir-NO (Saq-NO), with enhanced anticancer properties and reduced toxicity both in vitro and in vivo. The aim of this study was to address several unanswered questions both on the pharmacological profile of Saq-NO as well as on the in vivo role of NO in the oncogenesis of A375 human melanoma cells. To this end, we have evaluated here the impact of single and combined effects of Saq-NO, Saq, the NO-donor DETA NONOate and the iNOS inhibitor L-NAME on the in vitro as well as in vivo growth of the iNOS positive A375 cells. Our data confirm clear-cut evidence for a strong and powerful anti-melanoma action of Saq-NO that is not duplicable by the combined use of Saq and DETA NONOate. Surprisingly, but also in agreement with the complex and multifaceted role of endogenous NO in A375 cells, both DETA NONOate and L-NAME significantly suppressed the in vivo growth of xenotransplants.

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Prognostic significance of tumor iNOS and COX-2 in stage III malignant cutaneous melanoma

Abstract: Our data show that iNOS is an independent and stronger prognostic factor for OS in stage III malignant cutaneous melanoma than COX-2.

Cited by 45 publications

References 37 publications

Melanoma-Educated CD14+ Cells Acquire a Myeloid-Derived Suppressor Cell Phenotype through COX-2–Dependent Mechanisms

Melanoma-Educated CD14+ Cells Acquire a Myeloid-Derived Suppressor Cell Phenotype through COX-2–Dependent Mechanisms

Overcoming resistance to BRAF inhibitors

Unique antineoplastic profile of Saquinavir-NO, a novel NO-derivative of the protease inhibitor Saquinavir, on the in vitro and in vivo tumor formation of A375 human melanoma cells

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