Article Figures & Data
Figures
- Figure 1.
The complex interactions involved in the role of inflammation in the cancer progression spectrum.
Tables
- Table 1.
Summary of inflammatory markers, associated techniques, and tissue requirements with corresponding advantages and disadvantages of their application
Inflammatory marker Explanation Techniquesa Advantages Disadvantages Tissue requirementb Current evidence of cancer associationc Cytokines and chemokines Cytokines/chemokines Small secreted proteins that mediate as well as regulate immunity, inflammation, and hematopoiesis. Cytokines generally act at very low concentrations over short distances and short time spans. ELISA, multiplex bead assays Simultaneous measurement of several cytokines possible No strong evidence to predict progression or survival. Serum/plasma/tissue/cell culture supernatant Direct measurement in several cancers with correlation with tumor stage and disease extent. Blood draw and processing conditions can affect levels. Degradation over time when samples stored improperly or over multiple freeze/thaw cycles. Depends on assay used (5–100 μL) Related to cancer risk in prospective collected data. Costly Tumors create an inflammatory milieu and can produce cytokines. Difficult to assess reverse causality without longitudinal data Lack of standardization of assays Function in multiple pathways (lack of specificity) Immune-related effectors WBC count A measure of the total white blood content, generally indicative of infection (neutrophils and monocytes—bacteria, lymphocytes—viral, eosinophils—parasitic). FACS Routinely measured and used in clinical practice (useful for prediction and maximization of currently available data and used clinical algorithms). Levels may be altered because of transient infection not-related to chronic inflammation. Serum Associated with lung cancer risk in prospectively collected data. Stable over time when frozen. Portable kits available that need only 10 μL Associated with cancer-related mortality in prospective studies. Blood neutrophilia and thrombocytosis established as indicators of systemic inflammatory response. mGPS A combination of albumin and CRP measurements into a 3-level predictive score. 2 when both CRP >10 mg/L and albumin <35 g/L. 1 if only one abnormality present. 0 if both not. Combined CRP and albumin tests. Inexpensive if CRP and albumin already measured. Levels may be altered because of transient infection not-related to chronic inflammation same issues for CRP. Serum Not related to risk of cancer development. Standardized score Evidence suggests use as a prognostic score independent of tumor stage and treatment. NLR The ratio of neutrophils to lymphocytes, where higher values reflect states of dramatic inflammation. Same as WBC count Potential as a simple, cost effective, and readily available test. Different cutoff levels reported across studies. Serum Shown to be related to survival in many cancer sites after diagnosis and various treatment modalities. Additional value obtained beyond normal white cell counts is of question PLR The ratio of platelets to lymphocytes, where higher values reflect states of dramatic inflammation. Same as WBC count Routinely measured and used in clinical practice (useful for prediction and maximization of currently available data and used clinical algorithms). Levels may be altered because of transient infection not-related to chronic inflammation. Serum Predicts outcomes in colorectal cancer. Potential as a simple, cost-effective, and readily available test. Not well studied with risk of disease. Th17 lymphocytes Recently discovered inflammatory T-cell subset with associations to autoimmune diseases and potential role in cancer risk and progression. IHC, FACS All three cell types give insight into the T-cell functional status, and thus immune responses. A combined analysis can potentially advance the current analysis focusing on one of the cell types. Heterogeneous results are assumable between cancer entities. Material acquisition might be problematic. Tissue (TMAs), peripheral blood cells (require fresh cells for flow cytometry) Not as of yet extensively studied with risk. Acute-phase proteins CRP An acute-phase protein produced by hepatocytes in response to proinflammatory cytokines. Produced in times of inflammation to age damaged cells for excretion by the liver. Fluorescence polarization-immunoassay, nephelometry, ELISA Quantitative and sensitive measurement Nonspecific marker of inflammation Serum or plasma Large meta-analysis indicates poor evidence to support use as a diagnostic marker; may be useful in colorectal and lung cancers. Easily measured Levels may be altered because of transient infection not related to chronic inflammation (CRP rises drastically in acute inflammation, such as infection, therefore several measurements over time are encouraged for a better characterization of chronic states). SAA Similar to CRP an acute-phase protein, but levels may be even more responsive to inflammation. Fluorescencepolarization-immunoassay, nephelometry, ELISA Easily measured Limited evidence for use to predict treatment response. Serum or plasma Strongly associated with worse long-term survival from breast cancer. Rather novel marker ROS and RNS ROS and RNS Chemically reactive molecules produced as byproducts of normal metabolic processes in all aerobic organisms. Characterized by the presence of unpaired electrons. Would provide a direct estimate of ROS burden and would be beneficial for prediction of risk and carcinogenicity of lifestyle patterns. No standardized methods to capture actual ROS levels in humans to date Tissue Direct evidence and measurement in prospective studies lacking Compounds have very short half-life in systems. Signaling pathways regulated by ROS in cancer models. Questionable quality due to the volatility of compounds. Serum Association with expression/enzyme activity of ROS/RNS producers shown in various cancers. Levels affected by lifestyle factors, i.e., nutritional status Weak evidence of variants in ROS/RNS production genes and cancer risk. Oxidatively/nitrosatively modified DNA, or proteins The product of excess ROS/RNS in tissue 3-Nitrotyrosine The product of nitrosylated proteins HPLC Not well standardized Healthy or tumor tissue Higher level observed in the tumors of never smoking lung cancer cases suggesting a marker for inflammation-related carcinogenesis. 8-oxodg or 8-OHdG 8-oxodG is a sensitive surrogate biomarker for in vivo oxidative stress. ELISA, HPLC methods Provides a measure of DNA damage due to ROS. Not tissue specific Plasma, urine Elevated levels observed in several cancers included esophageal, colon, and breast 8-Iso-PGF2_α LPO product. ELISA, HPLC methods Provides a measure of DNA damage due to ROS. Not tissue specific Plasma, urine Related to breast and colon cancer risk MDA LPO product. ELISA, HPLC methods Provides a measure of DNA damage due to ROS. Not tissue specific Plasma, urine Associated with lung and colon cancer risk HNE LPO product. ELISA, HPLC methods Provides a measure of DNA damage due to ROS. Not tissue specific Plasma, urine Not as well studied as other peroxidation products Prostaglandins, COX, lipoxygenases, and related factors Prostaglandin levels Lipid compounds containing 20 carbon ring including a 5-carbon group. Produced by the sequential oxidation of prostaglandin. By COX1 and COX2. COX1 is believed to control baseline levels of prostaglandins, whereas COX2 increases levels of PGE by response to stimulation ELISA Levels may be tissue-specific difficult to measure. Saliva, urine, serum, EDTA and heparin plasma Liquid chromatography/tandem mass spectrometry Affected by several pharmacologic interventions which could complicate association modeling. Some prostaglandins are rapidly degraded COX2 expression Enzymes integral to prostaglandin synthesis. IHC Interest as target for chemoprevention Levels may be tissue-specific difficult to measure. Tissue culture media COX2 expression observed in nearly every tumor type examined. Affected by several pharmacologic interventions that could complicate association modeling. TMA Transcription factors and growth factors NF-κB activation A transcription factor that functions in inflammatory pathways by inducing the expression of inflammatory cytokines, adhesion molecules, COX, NOS, and angiogenic factors. ELISA Can measure quantity, activation, translocation and transcriptional potential. Clinical evaluation of NF-κB requires cell culture. Serum, plasma, peripheral blood lymphocytes Predictive of outcomes in breast cancer and colorectal cancer. RT-PCR to measure mRNA STAT3 activation A transcription factor activated in response to various factors, including inflammatory cytokines. Mediates the expression of several key cell growth and apoptosis genes. ELISA Also regulated by other non-inflammatory growth factors. Serum or plasma Less well studied than NF-κB.
September 2014
Volume 23, Issue 9
Volume 23, Issue 9
A Review of the Application of Inflammatory Biomarkers in Epidemiologic Cancer Research
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