S100 protein tumormarker

S100 Protein Overview

S100 proteins are a family of low-molecular-weight, calcium-binding proteins first isolated from bovine brain tissue by B. Moore in 1965. The name "S100" derives from their solubility in a 100% saturated ammonium sulfate solution.

These proteins are highly concentrated in the nervous system, particularly in glial cells (astrocytes and Schwann cells), where their levels are vastly higher than in other tissues. However, different S100 family members are also expressed in various other cell types, including melanoma cells, chondrocytes, adipocytes, and muscle cells.

Clinically, measuring certain S100 proteins (primarily S100B) in the blood or cerebrospinal fluid (CSF) has become valuable as a biomarker for brain injury and as a tumor marker for malignant melanoma.

Biochemistry of S100 Proteins

S100 proteins typically exist as dimers, formed by two subunits, each having a molecular mass of about 10.5 kDa, resulting in a dimer molecular mass of approximately 21 kDa. These subunits belong to the EF-hand superfamily of calcium-binding proteins, meaning their activity is often regulated by intracellular calcium levels.

There are at least 25 known members of the S100 protein family in humans (e.g., S100A1–S100A18, S100B, S100G, S100P, etc.). They can form homodimers (two identical subunits) or heterodimers (two different subunits).

The most clinically relevant forms, particularly for blood testing, are dimers involving the B subunit:

• S100B (ββ dimer): Predominantly found in glial cells (astrocytes in the CNS, Schwann cells in the PNS) and melanocytes. This is the primary form measured in serum as a biomarker for brain injury and melanoma.
• S100A1B (αβ heterodimer): Also found in glial cells.
• S100A1 (αα homodimer): Found mainly in muscle (heart, skeletal) and other tissues.

Within cells, S100 proteins are located mainly in the cytoplasm but can also be found associated with membranes or the nucleus, interacting with various target proteins.

Functions of S100 Proteins

S100 proteins are multifunctional intracellular calcium sensors that regulate a wide array of cellular processes by interacting with different target proteins in a calcium-dependent manner. Their functions include involvement in:

• Cell growth, differentiation, and proliferation
• Cell cycle progression
• Energy metabolism (e.g., interaction with glycolytic enzymes)
• Intracellular signal transduction pathways
• Regulation of cytoskeletal organization and cell motility
• Calcium homeostasis
• Transcription regulation
• Protection against oxidative stress
• Phosphorylation events
• Inflammation and immune responses
• Apoptosis (programmed cell death) regulation

In the nervous system, S100 proteins (especially S100B) play roles in neuronal development, synaptic plasticity, learning, memory, and glial cell function. S100B exhibits both neurotrophic (supportive) effects at physiological concentrations and potentially neurotoxic effects at high concentrations (e.g., after injury).

Clinical Significance of S100 Testing

Measuring S100 protein levels (primarily S100B in serum) is clinically relevant in two main areas: brain injury assessment and melanoma monitoring.

Pathological conditions where S100 testing may be useful include:

1. Neurological Conditions (Brain Injury):
   • Traumatic Brain Injury (TBI) - especially mild TBI / concussion
   • Ischemic Stroke
   • Intracerebral or Subarachnoid Hemorrhage
   • Hypoxic Brain Damage (e.g., after cardiac arrest)
   • Monitoring during cardiac surgery (cardiopulmonary bypass)
   • Neurodegenerative diseases (e.g., Alzheimer's disease - research context)
   • Multiple Sclerosis (less common)
   • Perinatal hypoxic CNS lesions in newborns
2. Oncology (Tumor Marker):
   • Malignant Melanoma: Monitoring disease progression, assessing treatment efficacy, detecting recurrence/metastasis.
   • Other tumors expressing S100 (less common use as serum marker): Some gliomas, neuroblastomas, chondrosarcomas, certain other cancers.
3. Inflammatory Conditions: Levels might be elevated but generally not used diagnostically for these.

S100B as a Brain Injury Biomarker

When brain tissue, particularly astrocytes, is damaged due to trauma, ischemia, or other insults, S100B protein is released into the cerebrospinal fluid (CSF) and subsequently leaks across the disrupted blood-brain barrier (BBB) into the systemic circulation. Elevated serum S100B levels can therefore indicate CNS injury.

• Traumatic Brain Injury (TBI): Serum S100B measurement within the first few hours (ideally < 6 hours) after mild TBI (concussion) has high sensitivity and negative predictive value. A normal S100B level (typically < 0.10 µg/L or < 100 pg/mL, depending on assay) can help rule out significant intracranial injury (like bleeding or contusion) and potentially avoid the need for a head CT scan in low-risk patients according to specific clinical guidelines (e.g., Scandinavian Neurotrauma Committee guidelines). Persistently high or rising levels after moderate/severe TBI correlate with injury severity and poorer prognosis.
• Stroke and Hemorrhage: Serum S100B levels rise after ischemic stroke and intracerebral or subarachnoid hemorrhage. The magnitude of the increase generally correlates with the volume of brain tissue damage and can have prognostic value. High levels after SAH (> 0.3 µg/L) may predict unfavorable outcomes. Monitoring levels might help detect secondary injury or complications.
• Cardiac Arrest / Hypoxic Injury: Elevated S100B after cardiac arrest indicates hypoxic brain damage and predicts neurological outcome. Levels should normally return to baseline within ~24 hours after brief circulatory arrest; persistent elevation suggests significant injury.
• Cardiac Surgery: Transient increases occur during cardiopulmonary bypass; significant or prolonged elevations may indicate neurological complications.

Overall, serum S100B serves as a sensitive marker of astroglial damage and BBB disruption.

S100 as a Tumor Marker (Malignant Melanoma)

S100 proteins (including S100B, S100A1, S100A6) are expressed by melanocytes, the cells from which malignant melanoma arises. When melanoma cells proliferate and metastasize, they can release S100 proteins into the bloodstream.

• Monitoring Metastatic Melanoma: Serum S100B is the most established serological marker for monitoring patients with malignant melanoma, particularly those with Stage IIB, IIC, III, and IV disease.
• Correlation with Stage/Burden: Levels often correlate with tumor stage and burden of metastatic disease. Rising levels suggest disease progression or recurrence, while falling levels indicate response to therapy (e.g., immunotherapy, targeted therapy).
• Prognostic Value: Elevated S100B levels at diagnosis of metastatic disease or during follow-up are associated with a poorer prognosis.
• Early Detection of Recurrence: Serial monitoring can detect relapse earlier than clinical examination or imaging in some patients.
• Limitations: Sensitivity is limited for detecting primary melanoma or early-stage disease. Specificity is affected by potential release from non-melanoma sources (including brain injury or even vigorous exercise). Lactate Dehydrogenase (LDH) is another important prognostic serum marker often used alongside S100B in melanoma.

Interpretation of Results

Interpreting S100 protein levels requires knowing the specific isoform measured (usually S100B for serum tests), the assay method used, and the clinical context.

• Reference Values: Vary significantly between assays. A common cutoff for ruling out significant brain injury after mild TBI is < 0.10 - 0.105 µg/L (or 100-105 pg/mL) when measured within 6 hours of injury. For melanoma monitoring, the upper limit of normal is typically similar, but trends over time are more important than single values. Always use the reference range provided by the testing laboratory.
• Assay Comparison: Results obtained using different laboratory methods or kits cannot be directly compared. Serial monitoring should use the same method consistently.
• Conditions Causing Elevated S100:
  1. Neurological Disorders: As listed above (TBI, stroke, hemorrhage, etc.).
  2. Malignant Melanoma: Especially metastatic disease.
  3. Other Cancers (less common): Glioma, neuroblastoma, chondrosarcoma, some other malignancies.
  4. Inflammatory Conditions: Systemic inflammatory responses can potentially increase levels slightly.
  5. Renal Failure: Impaired clearance might cause slight elevation.
  6. Intense Physical Exercise: Can cause transient increases due to muscle or minor tissue damage.
  7. Benign Skin Conditions: Extensive inflammatory skin disease might theoretically increase levels.
  8. Sample Hemolysis: False elevation due to release from red blood cells (though less of an issue than for NSE).

The S100 Blood Test Procedure

• Sample Type: Blood serum (most common) or plasma. CSF can also be tested but is less routine.
• Preparation: No specific patient preparation like fasting is generally required.
• Collection: Standard venipuncture. Careful handling to avoid hemolysis is recommended.
• Processing & Analysis: Sample is centrifuged, and serum/plasma is analyzed using immunoassays (e.g., electrochemiluminescence - ECLIA, commonly used on automated platforms like Roche Elecsys).

References

1. Thelin, E. P., Nelson, D. W., & Bellander, B. M. (2017). A review of the clinical utility of serum S100B protein levels in the assessment of traumatic brain injury. *Acta Neurochirurgica*, 159(2), 209–225. https://doi.org/10.1007/s00701-016-3046-3
2. Undén, J., & Romner, B. (2010). Can low serum levels of S100B predict normal CT findings after minor head injury in adults?: an evidence-based review and meta-analysis. *Journal of Head Trauma Rehabilitation*, 25(4), 228–240. https://doi.org/10.1097/HTR.0b013e3181e57f62
3. Ghanem, G., Loir, B., Muller, M., Bouffioux, B., & Lejeune, F. (1999). Serum S100 protein: a useful marker in malignant melanoma. *Melanoma Research*, 9(1), 61–67.
4. National Cancer Institute (NCI). (n.d.). Tumor Markers. Retrieved from https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet
5. Donato, R., Cannon, B. R., Sorci, G., Riuzzi, F., Hsu, K., Weber, D. J., & Geczy, C. L. (2013). Functions of S100 proteins. *Current Molecular Medicine*, 13(1), 24–57. https://doi.org/10.2174/1566524011313010004
6. Lab Tests Online. (n.d.). S100. Retrieved from https://labtestsonline.org/tests/s100