S100P Human

What is S100P and what is its significance in human biology?

S100P is a calcium-binding protein that belongs to the S100 protein family. It plays crucial roles in both normal physiological processes and pathological conditions. In normal physiology, S100P has been identified in trophoblast cells during placentation, functioning as a regulator of cellular invasion and migration . In pathological contexts, S100P is overexpressed in various cancers where it correlates with metastasis and poor prognosis, making it a potential biomarker for cancer progression .

Methodologically, researchers should approach S100P as both an intracellular signaling molecule and an extracellular factor that can activate specific receptors. This dual functionality requires different experimental approaches depending on which aspect of S100P biology is being investigated.

How is S100P expressed in normal human tissues?

S100P shows a tissue-specific expression pattern in normal human tissues. Based on available research, S100P is predominantly expressed during early stages of placental formation with highest expression levels occurring during the first trimester of gestation, particularly in invading columns and anchoring villi . This temporal and spatial expression pattern suggests a physiological role in regulated trophoblast invasion during placentation.

For researchers studying normal S100P expression, it's recommended to examine tissue-specific expression using quantitative RT-PCR with appropriate housekeeping genes (such as YWHAZ, GAPD, and UBC) for normalization, as demonstrated in methodological approaches from published literature .

How does S100P contribute to cancer cell invasion and metastasis?

S100P promotes cancer progression through multiple mechanisms:

• Enhanced cell motility and invasion: S100P stimulates both cell motility and cellular invasion in cancer cells, with invasion capabilities being more dramatically affected than migration .

• Lymphatic invasion: In pancreatic cancer, S100P regulates collective invasion of cancer cell clusters into lymphatic vessels. This occurs through:

  • Induction of circular chemorepellent-induced defects (CCIDs) in lymphatic endothelial cell monolayers

  • Promotion of centrifugal migration of lymphatic endothelial cells (LECs) beneath cancer spheroids

  • Facilitation of cancer cell cluster penetration through lymphatic vessel walls

• RAGE signaling activation: Extracellular S100P activates the Receptor for Advanced Glycation End products (RAGE), leading to increased proliferation, invasion, and migration of cancer cells .

For researchers investigating these mechanisms, spheroid-based invasion assays and CCID formation assays represent valuable methodological approaches to quantitatively assess S100P's role in collective invasion processes.

What is the prognostic value of S100P expression in different cancer types?

The prognostic significance of S100P varies by cancer type:

For researchers evaluating S100P as a prognostic marker, sample size, population demographics, and detection methods significantly influence results. Immunohistochemistry (IHC) and RT-PCR methods have shown more consistent prognostic value than Western blot approaches .

What detection methods are most effective for S100P assessment in clinical samples?

Multiple methodologies have been employed for S100P detection, each with distinct advantages:

• Immunohistochemistry (IHC): Most commonly used for clinical samples, showing significant prognostic value (HR=1.57, 95% CI=1.13-2.18, P=0.007) . For optimal results, researchers should consider:

  • Cut-off values: Stained grade 2+ (HR=2.04, 95% CI=1.06-3.93) and stained cells 1% (HR=1.84, 95% CI=1.27-2.67) have shown significant prognostic associations

  • Appropriate antibodies: Monoclonal antibodies like 18-9 have been successfully used in research settings

• Quantitative RT-PCR: Provides quantitative assessment of S100P mRNA levels (HR=1.80, 95% CI=1.02-3.19, P=0.044) . For reliable results:

  • Design primers spanning different exons (e.g., forward: 5'-TCAAGGTGCTGATGGAGAA-3', reverse: 5'-ACACGATGAACTCACTGAA-3')

  • Use multiple housekeeping genes (YWHAZ, GAPD, UBC) for normalization

• Western Blot: Has shown less consistent prognostic value (HR=0.55, 95% CI=0.13-2.30, P=0.413) , but remains useful for protein expression analysis in experimental settings.

Researchers should select detection methods based on their specific research questions, available sample types, and required quantitative precision.

How can researchers effectively model S100P function in experimental systems?

To investigate S100P function, researchers can employ several experimental approaches:

• Gain/loss of function studies:

  • Overexpression systems using vectors like pSG5C-S100P

  • siRNA-mediated knockdown to silence S100P expression

  • Recombinant S100P protein treatment to study extracellular effects

• Specialized invasion assays:

  • CCID assays using cancer cell spheroids on lymphatic endothelial monolayers to quantify invasion

  • Migration assays to assess cell motility after S100P manipulation

• Pathway inhibition experiments:

  • RAGE antagonist peptide to block S100P-RAGE signaling

  • Assessment of downstream signaling molecules

For investigating collective invasion specifically, spheroid-based assays more accurately recapitulate the pathological situation compared to single-cell invasion assays .

What is known about S100P's role in lymphatic invasion specifically?

S100P plays a critical role in lymphatic invasion, particularly in pancreatic cancer:

• Lymphatic endothelial expression: S100P is expressed in lymphatic endothelial cells (LECs) in lymphatic vessels surrounding primary pancreatic tumors, as demonstrated by both immunohistochemistry and immunofluorescence staining .

• Induction by cancer secretions: LECs increase S100P expression when exposed to:

  • Culture supernatant from pancreatic cancer cells

  • Interleukin-6 (IL-6), which is highly expressed by pancreatic cancer cells

• Mechanism of collective invasion:

  • S100P promotes formation of circular chemorepellent-induced defects (CCIDs) in LEC monolayers

  • These CCIDs enable entire tumor clusters to penetrate lymphatic vessels

  • Higher CCID formation is observed with cancer spheroids compared to fibroblast spheroids, and in LECs compared to HUVECs

• S100P/RAGE signaling axis: Extracellular S100P activates RAGE on LECs, increasing their migration and CCID formation, which can be suppressed using RAGE antagonist peptides .

For researchers studying lymphatic invasion, the CCID assay represents a valuable tool to quantitatively investigate the cluster-specific mechanisms of lymph vessel invasion and elucidate underlying molecular mechanisms.

How does S100P expression correlate with clinicopathological features in cancer?

S100P expression correlates with several aggressive tumor phenotypes:

• Distant metastasis: High S100P expression significantly correlates with distant metastasis (OR=3.58, 95% CI: 1.04-12.36, P=0.044) .

• Advanced clinical stage: S100P expression is associated with advanced disease stage (OR=2.03; 95% CI=1.03-4.01; P=0.041) .

• Tumor recurrence: Higher rates of recurrence are observed in tumors with elevated S100P expression (OR=1.66; 95% CI=1.15-2.38; P=0.007) .

• Lymphatic invasion: In pancreatic cancer, S100P expression is observed in clusters of cancer cells penetrating lymphatic vessel walls around primary tumors .

What are the key limitations in studying S100P in animal models?

Researchers face significant challenges when studying S100P in animal models:

• Lack of S100P expression in rodents: S100P is not expressed in rodents , making traditional mouse models problematic for studying S100P function in vivo.

• Alternative approaches:

  • Human xenograft models to study human S100P-expressing cells in immunocompromised mice

  • Humanized mouse models with tissue-specific S100P expression

  • Ex vivo organ culture systems to study human tissue responses

• Translational limitations: The absence of rodent S100P creates challenges in translating findings from preclinical models to human applications, necessitating careful experimental design and interpretation.

For researchers designing in vivo studies, these limitations must be carefully considered when selecting appropriate model systems and interpreting results in the context of human disease.

What are promising areas for future S100P research?

Based on current knowledge, several promising research directions emerge:

• Therapeutic targeting:

  • Developing S100P inhibitors or RAGE antagonists as potential cancer therapeutics, particularly for cancer types where S100P shows strong prognostic value

  • Investigating combination approaches targeting both S100P expression and downstream signaling pathways

• Biomarker development:

  • Standardizing S100P detection methods for clinical application

  • Exploring S100P as part of multi-marker panels for improved prognostication

  • Investigating S100P in liquid biopsies for non-invasive monitoring

• Physiological roles:

  • Further characterizing S100P's normal physiological functions in trophoblast invasion and placentation

  • Investigating potential links between dysregulated S100P in placentation and pregnancy complications

• Mechanistic studies:

  • Deeper investigation of S100P/RAGE signaling mechanisms

  • Exploration of S100P's role in programming the tumor microenvironment

  • Understanding cell-type specific responses to S100P

These research directions have potential to advance both basic understanding of S100P biology and clinical applications in cancer management.