S100 proteins

Overview

S100 proteins are a family of low molecular weight (9–13 kDa) calcium-binding proteins found only in vertebrates. The name “S100” comes from their 100% solubility in ammonium sulfate at neutral pH. Structurally, they share similarities with calmodulin and troponin-C, containing two EF-hand calcium-binding motifs composed of α-helices separated by a loop.

These proteins usually form homo- or heterodimers and oligomeric assemblies, with exposed calcium-bound binding surfaces that regulate interactions with target proteins. They play crucial roles in cell proliferation, migration, invasion, apoptosis, immune response regulation, and axonal regeneration.

The S100 protein family has significant clinical relevance, particularly in the context of tumor biology, immune system disorders, and nervous system repair mechanisms. Immunohistochemistry, ELISA, and Western blotting are common methods used for their detection.

Symptoms

S100 proteins themselves do not cause symptoms, but their elevated serum levels or abnormal tissue expression are strongly associated with certain conditions, especially cancers and inflammatory diseases. Clinical manifestations vary depending on the underlying disease where S100 positivity is observed:

1. Cancer-related Symptoms:
   1. Unexplained weight loss
   2. Persistent fatigue
   3. Abnormal lumps or growths (skin or internal)
   4. Pigmented skin lesions in melanoma
   5. Neurological deficits in glial tumors
2. Neurological and Nerve-related Symptoms:
   1. Numbness or tingling (nerve sheath tumors)
   2. Pain or swelling in affected nerve regions
   3. Functional loss in advanced tumors
3. Inflammatory Conditions:
   1. Joint pain and swelling (seen in rheumatoid arthritis due to S100-mediated immune responses)
   2. Symptoms of atherosclerosis (chest pain, fatigue, circulatory issues)
   3. Signs of chronic infections or tissue inflammation

These symptoms typically lead to further diagnostic testing, including S100 protein immunohistochemistry or serum testing.

Causes

Abnormal S100 protein expression or elevated serum levels are caused by:

1. Tumorigenesis:
   1. Overexpression of S100 proteins is linked to multiple cancers including melanoma, breast, lung, ovarian cancer, clear cell sarcoma, and glial tumors.
   2. They influence tumor proliferation, migration, invasion, and apoptosis resistance.
2. Immune-mediated Mechanisms:
   1. Calgranulins, a subgroup of S100 proteins, modulate immune responses, contributing to inflammatory arthritis, atherosclerosis, and microbial infections.
3. Nervous System Injury:
   1. S100 proteins stimulate Schwann cell and macrophage recruitment to injury sites, releasing cytokines and trophic factors, promoting axonal regeneration.
4. Inflammatory Disorders:
   1. In conditions like rheumatoid arthritis, S100 proteins contribute to joint inflammation and cartilage degradation.

Risk Factors

Risk factors associated with abnormal S100 expression include:

1. Cancer Susceptibility:
   1. Individuals with genetic predisposition or family history of melanoma, nerve sheath tumors, or glial tumors are at higher risk.
2. Inflammatory and Autoimmune Disorders:
   1. Patients with rheumatoid arthritis, chronic infections, or systemic inflammatory conditions may have increased S100 protein activity.
3. Neurological Disorders:
   1. Those with prior nerve damage, traumatic injuries, or neurodegenerative conditions may show altered S100 protein expression.
4. Lifestyle and Environmental Exposures:
   1. Smoking, radiation, or exposure to carcinogens may influence tumorigenesis where S100 proteins play a role.
5. Age and Gender Factors:
   1. Certain tumors with S100 expression (e.g., glial tumors, sex cord stromal tumors) may be more prevalent in specific age groups or genders.

Prevention

S100 proteins themselves cannot be directly prevented, but conditions linked with abnormal S100 expression can be managed and detected early through:

1. Regular Screening and Monitoring:
   • Serum S100 protein levels (normally <0.2 µg/L) can be used to monitor melanoma progression and treatment response.
   • Immunohistochemistry is the gold standard for diagnosing melanoma, nerve sheath tumors, glial tumors, and myoepithelial tumors.
2. Accurate Diagnostic Practices:
   1. Use formalin-fixed tissue embedded in paraffin for reliable immunohistochemistry.
   2. Appendix tissue is recommended as a positive control for S100 staining, as Schwann cells and adipocytes strongly express it.
3. Cancer Prevention Strategies:
   1. Regular skin checks for suspicious pigmented lesions.
   2. Lifestyle modifications such as avoiding UV overexposure and carcinogenic exposures.
4. Managing Inflammatory Conditions:
   1. Early detection and treatment of rheumatoid arthritis or atherosclerosis reduce long-term complications linked to S100 proteins.
5. Neurological Care:
   1. Monitoring patients with nerve injuries to facilitate axonal regeneration with appropriate therapies.