Biophysical reasons for the variability in detecting cancer biomarkers: the overlooked role of protein–lipid interactions
Beatrice Barletti, Isabelle Vilgrain, Marco Maccarini, Donald K. MartinAbstract
Background
Circulating protein biomarkers are central to oncology diagnostics. They exist in plasma as heterogeneous molecular populations, and immunoassays measure an analytically accessible fraction of a target biomarker rather than necessarily its total abundance. This accessibility can depend on chemical modification, conformation, and intermolecular association. Post-translational modifications such as glycosylation and glycation can remodel protein surfaces and influence their interactions with the surrounding environment. The plasma environment itself contains diverse lipid-rich particles that differ in composition and biological origin. These features may therefore shape interactions between circulating biomarkers and lipid-rich interfaces, but their potential contribution to biomarker measurement has rarely been considered together.
Purpose and scope
This perspective examines the biological and biophysical basis of a potential link between post-translational modification, lipid-particle association, and biomarker detectability, with emphasis on the molecular interactions underlying this relationship. It evaluates the evidence supporting this potential link and considers complementary approaches needed to determine whether such interactions contribute to variability in biomarker measurement.
Synthesis
Post-translational modifications, including glycosylation and glycation, can remodel protein surfaces and alter their physicochemical and recognition properties, potentially influencing interactions with lipid-rich interfaces. The dynamic and heterogeneous plasma environment provides lipid-rich interfaces whose composition can vary with physiological and pathological states, including nutritional status and tumour-associated metabolic remodelling. These variations are distinct from the well-established analytical effects of lipemia. Evidence from soluble tumour-associated and other plasma proteins indicates that protein–lipid association can occur, while simplified biophysical systems provide controlled models of these interactions. Such associations could reduce the analytical accessibility of circulating biomarkers by partially masking them from antibody recognition.
Conclusion
Existing biological and biophysical evidence is sufficient to justify testing whether protein–lipid interactions contribute to what is measured by immunoassays. Addressing this question requires complementary investigation across controlled biophysical systems, native biological samples, and immunological measurements.