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Peer-reviewedCC BY 4.0The Journal of Liquid Biopsy

Exploration of circulating proteins associated with tumor stromal content using matched serum and tissue samples from patients with colon cancer

  • F.(Floor) Heilijgers1
  • J.E.(Fien) van Went1
  • A.S.L.P.(Stijn) Crobach2
  • C.M.(Christa) Cobbaert3
  • K.C.M.J.(Koen) Peeters1
  • L.R.(Renee) Ruhaak3
  • B.J.M.(Bart) van Vlijmen4,5
  • Y.E.M.(Yuri) van der Burgt3
  • W.E.(Wilma) Mesker1
5 affiliations
  1. 1Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
  2. 2Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
  3. 3Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, the Netherlands
  4. 4Department of Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
  5. 5Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands
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Abstract

Introduction: Liquid biopsies provide a source of biomolecules that allow tumor characterization. Increasing evidence shows that the tumor microenvironment (TME) plays a central role in behavior of colon cancer. This study assessed which proteins in the circulation correlate with tumor stromal content through analysis of serum and corresponding tissue samples from patients with colon cancer. A broad set of circulating proteins is quantified, ranging from common apolipoproteins, transport and complement factors, to key factors from interconnected stromal pathways such as coagulation and acute phase inflammation.

Materials and methods: The cohort consisted of 97 patients with colon cancer and 50 control individuals who all underwent colonoscopy. Targeted mass spectrometry was applied to quantify 156 serum proteins via their surrogate peptides and corresponding internal standards. Matching solid tumor tissue slides from all 97 patients were used to determine the Tumor-Stroma Ratio (TSR). Serum protein levels were compared between stroma-high and stroma-low tumors, resulting in a subset of discriminating proteins. Composite protein scores were evaluated in multivariable Cox models.

Results: Four serum proteins differed significantly between stroma-high and stroma-low tumors, all showing elevated levels in stroma-high patients, including complement-related proteins (C2, factor B, and C1r subcomponent-like protein) and the coagulation-related vitamin K-dependent protein S. This resulted in a composite Stromal Protein Score that may capture TME-driven variations. The Stromal Protein Score was significantly different between stroma-high and stroma-low patients (adjusted p < 0.001).

Conclusion: Our data indicate that stroma-high tumors are associated with systemic alterations in complement and coagulation-related proteins. The results encourage further development of liquid biopsy–based protein profiling approaches, aiming for clinical implementation as a non-invasive strategy for TME-informed risk stratification and treatment monitoring in colon cancer.

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Cite

BibTeXRIS
BibTeX
@article{heilijgers2026exploration,
  title = {{Exploration of circulating proteins associated with tumor stromal content using matched serum and tissue samples from patients with colon cancer}},
  author = {F.(Floor) Heilijgers and J.E.(Fien) van Went and A.S.L.P.(Stijn) Crobach and C.M.(Christa) Cobbaert and K.C.M.J.(Koen) Peeters and L.R.(Renee) Ruhaak and B.J.M.(Bart) van Vlijmen and Y.E.M.(Yuri) van der Burgt and W.E.(Wilma) Mesker},
  journal = {The Journal of Liquid Biopsy},
  year = {2026},
  month = oct,
  doi = {10.1016/j.jlb.2026.100688},
  url = {https://doi.org/10.1016/j.jlb.2026.100688},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Exploration of circulating proteins associated with tumor stromal content using matched serum and tissue samples from patients with colon cancer
AU  - F.(Floor) Heilijgers
AU  - J.E.(Fien) van Went
AU  - A.S.L.P.(Stijn) Crobach
AU  - C.M.(Christa) Cobbaert
AU  - K.C.M.J.(Koen) Peeters
AU  - L.R.(Renee) Ruhaak
AU  - B.J.M.(Bart) van Vlijmen
AU  - Y.E.M.(Yuri) van der Burgt
AU  - W.E.(Wilma) Mesker
PY  - 2026
DA  - 2026/10/23
JO  - The Journal of Liquid Biopsy
DO  - 10.1016/j.jlb.2026.100688
UR  - https://doi.org/10.1016/j.jlb.2026.100688
AB  - Introduction: Liquid biopsies provide a source of biomolecules that allow tumor characterization. Increasing evidence shows that the tumor microenvironment (TME) plays a central role in behavior of colon cancer. This study assessed which proteins in the circulation correlate with tumor stromal content through analysis of serum and corresponding tissue samples from patients with colon cancer. A broad set of circulating proteins is quantified, ranging from common apolipoproteins, transport and complement factors, to key factors from interconnected stromal pathways such as coagulation and acute phase inflammation.  Materials and methods: The cohort consisted of 97 patients with colon cancer and 50 control individuals who all underwent colonoscopy. Targeted mass spectrometry was applied to quantify 156 serum proteins via their surrogate peptides and corresponding internal standards. Matching solid tumor tissue slides from all 97 patients were used to determine the Tumor-Stroma Ratio (TSR). Serum protein levels were compared between stroma-high and stroma-low tumors, resulting in a subset of discriminating proteins. Composite protein scores were evaluated in multivariable Cox models.  Results: Four serum proteins differed significantly between stroma-high and stroma-low tumors, all showing elevated levels in stroma-high patients, including complement-related proteins (C2, factor B, and C1r subcomponent-like protein) and the coagulation-related vitamin K-dependent protein S. This resulted in a composite Stromal Protein Score that may capture TME-driven variations. The Stromal Protein Score was significantly different between stroma-high and stroma-low patients (adjusted p < 0.001).  Conclusion: Our data indicate that stroma-high tumors are associated with systemic alterations in complement and coagulation-related proteins. The results encourage further development of liquid biopsy–based protein profiling approaches, aiming for clinical implementation as a non-invasive strategy for TME-informed risk stratification and treatment monitoring in colon cancer.
SN  - 2950-1954
ER  -