Abstract
Tumor-derived, circulating proteins are potentially useful as biomarkers for detection of cancer, for monitoring of disease progression, regression and recurrence, and for assessment of therapeutic response. Here we interrogated how a protein's stability, cellular localization, and abundance affect its observability in blood by mass-spectrometry-based proteomics techniques. We performed proteomic profiling on tumors and plasma from two different xenograft mouse models. A statistical analysis of this data revealed protein properties indicative of the detection level in plasma. Though 20% of the proteins identified in plasma were tumor-derived, only 5% of the proteins observed in the tumor tissue were found in plasma. Both intracellular and extracellular tumor proteins were observed in plasma; however, after normalizing for tumor abundance, extracellular proteins were seven times more likely to be detected. Although proteins that were more abundant in the tumor were also more likely to be observed in plasma, the relationship was nonlinear: Doubling the spectral count increased detection rate by only 50%. Many secreted proteins, even those with relatively low spectral count, were observed in plasma, but few low abundance intracellular proteins were observed. Proteins predicted to be stable by dipeptide composition were significantly more likely to be identified in plasma than less stable proteins. The number of tryptic peptides in a protein was not significantly related to the chance of a protein being observed in plasma. Quantitative comparison of large versus small tumors revealed that the abundance of proteins in plasma as measured by spectral count was associated with the tumor size, but the relationship was not one-to-one; a 3-fold decrease in tumor size resulted in a 16-fold decrease in protein abundance in plasma. This study provides quantitative support for a tumor-derived marker prioritization strategy that favors secreted and stable proteins over all but the most abundant intracellular proteins.
Highlights
Blood-based protein biomarkers indicative of the presence, progression, and phenotype of a tumor are of significant clinical interest for diagnostics and prognostics [1,2,3,4]
A431 cells sensitive (A431s) or resistant (A431gr derived in vivo as described in Materials and Methods) to gefitinib were mixed with Matrigel and subcutaneously injected into the flanks of nude athymic BALB/c female mice
A total of 445 and 395 mousespecific proteins were identified in the A431s and A431gr experiments, respectively. This indicates that human-specific tumor proteins make up approximately 20% of all proteins identified in plasma based on our strict filtering criteria
Summary
Blood-based protein biomarkers indicative of the presence, progression, and phenotype of a tumor are of significant clinical interest for diagnostics and prognostics [1,2,3,4]. In principle one should select those tumor proteins that are most likely to find their way into peripheral blood at detectable levels. The attributes that allow cellular proteins to find their way into the plasma in detectable levels are poorly understood. In this study we sought to estimate the relative importance of each of these three factors in predicting which proteins derived from a tumor are observed in plasma and which are not
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