Multiplex analysis of serum cytokines in melanoma patients treated with interferon-α2b
ABSTRACT Interferon (IFN)-alpha2b is the only Food and Drug Administration-approved treatment for operable high-risk melanoma that has been shown to significantly and durably prolong relapse-free survival (RFS) of patients with stage IIB-III melanoma. Development of reliable serum assays may contribute to the development of methods for earlier detection of melanoma and the selection of patients who may be most susceptible to current available interventions with IFNalpha.
A powerful high-throughput xMAP multiplex immunobead assay technology (Luminex Corp., Austin, TX) was used to simultaneously test 29 cytokines, chemokines, angiogenic as well as growth factors, and soluble receptors in the sera of 179 patients with high-risk melanoma and 378 healthy individuals.
Serum concentrations of interleukin (IL)-1alpha, IL-1beta, IL-6, IL-8, IL-12p40, IL-13, granulocyte colony-stimulating factor, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, IFNalpha, tumor necrosis factor (TNF)-alpha, epidermal growth factor, vascular endothelial growth factor (VEGF), and TNF receptor II were found to be significantly higher in patients with resected high-risk melanoma compared with healthy controls. Bayesian Network algorithm classification of the data offered 90% sensitivity at 98% specificity with 96.5% of melanoma patients distinguished from healthy individuals. IFN-alpha2b therapy resulted in a significant decrease of serum levels of immunosuppressive and tumor angiogenic/growth stimulatory factors (VEGF, epidermal growth factor, and hepatocyte growth factor) and increased levels of antiangiogenic IFN-gamma inducible protein 10 (IP-10) and IFN-alpha. Pretreatment levels of proinflammatory cytokines IL-1beta, IL-1alpha, IL-6, TNF-alpha, and chemokines MIP-1alpha and MIP-1beta were found to be significantly higher in the serum of patients with longer RFS values of 1 to 5 and >5 years when compared with patients with shorter RFS of <1 year.
These data show that multiplexed analysis of serum biomarkers is useful for the evaluation of prognostic markers of clinical outcome and potential predictive markers of response to IFN-alpha2b in patients with high-risk operable melanoma.
- SourceAvailable from: Jeong-Hun Kang
Breakthroughs in Melanoma Research, 06/2011; , ISBN: 978-953-307-291-3
- "Survival or proliferation-associated factor Moretti et al., 2001; Yurkovetsky et al., 2007 Soluble IL-2 receptor "
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- "However, most metastatic melanoma cell lines were relatively resistant to death ligands, FasL, and TRAIL. Numerous observations demonstrated expression and secretion of proinflammatory cytokines by cancer cells, including malignant melanoma cells in culture and in vivo [Mattei et al., 1994; Yurkovetsky et al., 2007]. We wondered whether cytokine-mediated inflammatory signaling, which could perform many functions in cell–cell communications, might also be involved in anti-apoptotic protection of melanoma cells. "
ABSTRACT: Melanoma is the most lethal form of human skin cancer. However, only limited chemotherapy is currently available for the metastatic stage of the disease. Since chemotherapy, radiation and sodium arsenite treatment operate mainly through induction of the intrinsic mitochondrial pathway, a strongly decreased mitochondrial function in metastatic melanoma cells, could be responsible for low efficacy of the conventional therapy of melanoma. Another feature of metastatic melanoma cells is their proinflammatory phenotype, linked to endogenous expression of the inflammatory cytokines, such as TNFα IL6 and IL8, their receptors, and constitutive NF-κB- and STAT3-dependent gene expression, including cyclooxygenase-2 (PTGS2/COX2). In the present study, we treated melanoma cells with immunological (monoclonal antibody against TNFα or IL6), pharmacological (small molecular inhibitors of IKKβ-NF-κB and JAK2-STAT3) or genetic (specific RNAi for COX-2) agents that suppressed the inflammatory response in combination with induction of apoptosis via TRAIL. As a result of these combined treatments, exogenous TRAIL via interactions with TRAIL-R2/R1 strongly increased levels of apoptosis in resistant melanoma cells. The present study provides new understanding of the regulation of TRAIL-mediated apoptosis in melanoma and will serve as the foundation for the potential development of a novel approach for a therapy of resistant melanomas.Journal of Cellular Biochemistry 02/2011; 112(2):463-75. DOI:10.1002/jcb.22934 · 3.37 Impact Factor
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- "A neoadjuvant study with high-dose IFN-alpha2b implicated that immunogic mechanisms are more strongly correlated than other potential mechanisms for the clinical benefit of this modality [Moschos, S. J. et al., 2006]. Therefore, the effects of IFN-alpha2b therapy on a panel of serum proteins were evaluated in two prospective cooperative group trials [Yurkovetsky, Z. R. et al., 2007]. The screening included the sera of 179 patients with high-risk melanoma and 378 healthy individuals and a broad collection of 29 serum proteins for cytokines and other proimflammatory and proangiogenic proteins considered to represent the downstream intermediates relevant to the host response of patient with melanoma. "
ABSTRACT: Cutaneous malignant melanoma represents one of the most aggressive human cancers with high metastatic po-tential. Differences in the response and toxicity to current melanoma therapies among individuals are observed in nearly all-available treatment regimens. The first step toward personalized medicine is identifying a panel of biomarkers that al-low classification of melanoma patients for appropriate treatment and prediction of probable response to therapy. The tra-ditional approach to biomarker detection relied on studying a few candidate markers suspected of affecting clinical out-come. However, these studies have yielded contradictory results because of the small number of molecular determinants examined. This has been a major limitation of translational studies in malignant melanoma. Recent studies using high-throughput technologies, such as gene expression profiling and serum proteomic fingerprinting, have explored the utility of molecular markers to discriminate between clinical stages and predict disease progression in melanoma patients. This expert review highlights key approaches for the discovery and validation of biomarkers at the levels of DNA, RNA and protein. It also summarizes biomarker work performed by less invasive approaches, i.e., RT-PCR in detection of circulat-ing melanoma cells and serum markers that may be used to monitor early response to treatment and guide the therapeutic strategy. We anticipate that pharmacogenomics will play an integral role in disease assessment, patient selection and treatment response in melanoma clinical management with the ultimate goal of individualizing treatment and improving overall survival for patients.Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) 12/2008; 6(4). DOI:10.2174/187569208786733866