Table 1.

Summary of inflammatory markers, associated techniques, and tissue requirements with corresponding advantages and disadvantages of their application

Inflammatory markerExplanationTechniquesaAdvantagesDisadvantagesTissue requirementbCurrent evidence of cancer associationc
Cytokines and chemokines
Cytokines/chemokinesSmall 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 assaysSimultaneous measurement of several cytokines possibleNo strong evidence to predict progression or survival.Serum/plasma/tissue/cell culture supernatantDirect 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 countA measure of the total white blood content, generally indicative of infection (neutrophils and monocytes—bacteria, lymphocytes—viral, eosinophils—parasitic).FACSRoutinely 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.SerumAssociated with lung cancer risk in prospectively collected data.
Stable over time when frozen.Portable kits available that need only 10 μLAssociated with cancer-related mortality in prospective studies.
Blood neutrophilia and thrombocytosis established as indicators of systemic inflammatory response.
mGPSA 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.SerumNot related to risk of cancer development.
Standardized scoreEvidence suggests use as a prognostic score independent of tumor stage and treatment.
NLRThe ratio of neutrophils to lymphocytes, where higher values reflect states of dramatic inflammation.Same as WBC countPotential as a simple, cost effective, and readily available test.Different cutoff levels reported across studies.SerumShown 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
PLRThe ratio of platelets to lymphocytes, where higher values reflect states of dramatic inflammation.Same as WBC countRoutinely 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.SerumPredicts outcomes in colorectal cancer.
Potential as a simple, cost-effective, and readily available test.Not well studied with risk of disease.
Th17 lymphocytesRecently discovered inflammatory T-cell subset with associations to autoimmune diseases and potential role in cancer risk and progression.IHC, FACSAll 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
CRPAn 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, ELISAQuantitative and sensitive measurementNonspecific marker of inflammationSerum or plasmaLarge meta-analysis indicates poor evidence to support use as a diagnostic marker; may be useful in colorectal and lung cancers.
Easily measuredLevels 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).
SAASimilar to CRP an acute-phase protein, but levels may be even more responsive to inflammation.Fluorescencepolarization-immunoassay, nephelometry, ELISAEasily measuredLimited evidence for use to predict treatment response.Serum or plasmaStrongly associated with worse long-term survival from breast cancer.
Rather novel marker
ROS and RNS
ROS and RNSChemically 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 dateTissueDirect 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.SerumAssociation with expression/enzyme activity of ROS/RNS producers shown in various cancers.
Levels affected by lifestyle factors, i.e., nutritional statusWeak evidence of variants in ROS/RNS production genes and cancer risk.
Oxidatively/nitrosatively modified DNA, or proteinsThe product of excess ROS/RNS in tissue
3-NitrotyrosineThe product of nitrosylated proteinsHPLCNot well standardizedHealthy or tumor tissueHigher level observed in the tumors of never smoking lung cancer cases suggesting a marker for inflammation-related carcinogenesis.
8-oxodg or 8-OHdG8-oxodG is a sensitive surrogate biomarker for in vivo oxidative stress.ELISA, HPLC methodsProvides a measure of DNA damage due to ROS.Not tissue specificPlasma, urineElevated levels observed in several cancers included esophageal, colon, and breast
8-Iso-PGF2_αLPO product.ELISA, HPLC methodsProvides a measure of DNA damage due to ROS.Not tissue specificPlasma, urineRelated to breast and colon cancer risk
MDALPO product.ELISA, HPLC methodsProvides a measure of DNA damage due to ROS.Not tissue specificPlasma, urineAssociated with lung and colon cancer risk
HNELPO product.ELISA, HPLC methodsProvides a measure of DNA damage due to ROS.Not tissue specificPlasma, urineNot as well studied as other peroxidation products
Prostaglandins, COX, lipoxygenases, and related factors
Prostaglandin levelsLipid 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 stimulationELISALevels may be tissue-specific difficult to measure.Saliva, urine, serum, EDTA and heparin plasma
Liquid chromatography/tandem mass spectrometryAffected by several pharmacologic interventions which could complicate association modeling.
Some prostaglandins are rapidly degraded
COX2 expressionEnzymes integral to prostaglandin synthesis.IHCInterest as target for chemopreventionLevels may be tissue-specific difficult to measure.Tissue culture mediaCOX2 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 activationA transcription factor that functions in inflammatory pathways by inducing the expression of inflammatory cytokines, adhesion molecules, COX, NOS, and angiogenic factors.ELISACan measure quantity, activation, translocation and transcriptional potential.Clinical evaluation of NF-κB requires cell culture.Serum, plasma, peripheral blood lymphocytesPredictive of outcomes in breast cancer and colorectal cancer.
RT-PCR to measure mRNA
STAT3 activationA transcription factor activated in response to various factors, including inflammatory cytokines. Mediates the expression of several key cell growth and apoptosis genes.ELISAAlso regulated by other non-inflammatory growth factors.Serum or plasmaLess well studied than NF-κB.
  • aMost commonly cited techniques although others may exist.

  • bQuantity of sample will depend on quality of material extraction, processing, and type.

  • cFor additional details see text.