Single Vs Multiple Biomarkers of Cancer
Because cancer is a polygenic disease, most diagnostic assessments would probably rely on multiple biomarkers. Although few biomarkers may be needed for testing for predisposition, possibly more would be required for early detection, prognosis prediction, and determination of drug response. Such biomarkers might be qualitative for predisposition tests and early detection of lesions, but quantitative for determining differential gene expression (as may be required for determining prognosis and drug response). If gene expression is not confined to a single library, it should be at least eight times the level of expression in the other library to be statistically significant.
Cancer is a product of the tissue microenvironment. Therefore, interactions between the cancer cells, the surrounding epithelial and stromal cells, vascular channels, the extracellular matrix, and the immune system are the ultimate determinant of the final pathology. Cell-surface antigens and receptors, cell-anchored and secreted enzymes, cytokines, and extracellular matrix molecules are the mode of communication between disease cells and the surrounding microenvironment. The outcome is a complex cascade of molecules available for sampling by the ongoing vascular perfusion. Low molecular weight peptides in the blood may comprise a recording of events in the disease microenvironment. The peptidome signature shed from the microenvironment is a reflection of the microenvironment as a whole. In case of cancer biomarkers, cancer specificity is not derived from proteins secreted exclusively by tumor cells. MS profiling indicates that a higher level of both specificity and sensitivity might be achieved by measuring the combination of biomarkers emanating from both the diseased cells and the reactive cells in the microenvironment. In this way the peptidome can potentially supplant individual single biomarkers and transcend the issues of tumor and population heterogeneity. Therefore, trend in biomarker discovery is moving away from the ideal single, cancer-specific biomarker such as prostate specific antigen. Despite decades of effort, most single biomarkers have not reached the level of cancer specificity and sensitivity required for routine clinical use in early detection and screening purposes. A growing confluence of scientific data and results point to combinations of blood-borne markers using MS profiling techniques as well as tissue MS profiling strategies, and multiplexed immunoassay providing more superior results than single markers alone.
Genetic alterations in tumor cells often lead to the emergence of growth- stimulatory autocrine and paracrine signals, involving overexpression of secreted peptide growth factors, cytokines, and hormones. Increased levels of these soluble proteins may be exploited as markers for cancer diagnosis and management or as points of therapeutic intervention. The combination of annotation/protein sequence analysis, transcript profiling, immunohistochemistry, and immunoassay is a powerful approach for delineating candidate biomarkers with potential clinical significance.