Biological systems continually express and suppress the production of molecules in response to the environment or a biological state. Correlation of the up and down regulation of these molecules can be very useful in discerning various biological pathways. While biomarkers can be any molecule that indicates a biological state, generally in life science research, peptides and proteins are of greatest importance. These proteins can play many roles in the body. Hormones and their regulation can indicate metabolic states or disorders. Cytokines, chemokines, and growth factors indicate intercellular signaling, and phosphoproteins intracellular signaling. Cell signaling and metabolism refer to the mechanisms behind common disease states and the associated markers are useful in measuring and monitoring such things as disease progression and drug response. In this section we discuss the importance of biomarker discovery and the practical use of biomarkers in cancer and other disease research.
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One important goal of biomarker discovery is to screen new drugs for safety and efficacy at various stages of their development. The discovery of new biomarkers is best achieved by collaboration between life science, clinical diagnostics, pharmaceutical companies and academia. Some biomarkers are detected and measured to investigate specific physiological or pharmacological mechanisms and can be used to validate novel drug targets and predict drug response. Other biomarkers may be used to reveal drug targets and optimize selection of molecules that interact with these targets for further drug development. Many of these biomarkers are proteins and serve as critical indicators of specific biological states. Some examples of biomarkers include hormones, cytokines, chemokines, growth factors, and phosphoproteins.
Cytokines — small secreted proteins that mediate and regulate immunity, inflammation, and hematopoiesis. They are produced in response to an immune stimulus. They act by binding to specific membrane receptors, which then transmit the signal into the cell via secondary messengers. Responses to cytokines include increased or decreased expression of membrane proteins (including cytokine receptors), and proliferation and secretion of effector molecules.
Chemokines — a family of small cytokines secreted by cells to induce chemotaxis, which is critical in cellular movement and in multicellular organism development.
Growth factors — substances (usually proteins) that act as signaling molecules between cells, by interacting with receptor molecules on the surfaces of target cells.
All three of these types of molecules function as indicators of inflammation or disease and provide a means of manipulating cellular responses in vivo and in vitro.
The ability to detect these factors has become increasingly important to researchers and clinicians and can be used to study and diagnose disease. For example, in healthy individuals, cytokine levels are expected to be low or undetectable, whereas they are elevated in a number of disease states.
The production and release of cytokines are strictly regulated. A complex but transient pattern of cytokine expression is elicited following a stimulus such as a viral or bacterial infection. Complex regulatory feedback loops, involving other cytokines, are triggered to restore homeostasis. Uncontrolled, constitutive expression of cytokines can occur when cells have undergone malignant transformation. An increasing number of cytokines have been implicated in various cancers. Most of the studies on cytokines and cancer have involved in vitro studies of cell lines or in vivo studies in animals. Studies in cancer patients have often focused on a single cytokine; however elevation of multiple cytokines in blood, diseased tissues, pleural effusions, urine, and many other matrices has also been reported. The sizeable effort required to develop specific and sensitive assays to detect these biomarkers is illustrated by the multitude of published scientific studies of cytokine interaction networks associated with various disease studies.
The phosphorylation of proteins is a central paradigm of signal transduction. Phosphoproteins are an important family of biomolecules that play pivotal roles in the transduction of signals. Growth factor responses in phosphoprotein-driven signaling networks play a crucial role in cancer cell survival and pathology. Analysis of cancer cell signaling networks may be used to identify mechanisms by which cells interpret environmental cues for continued growth. Profiling these cellular signals requires a technology platform tailored for multiplex analysis, such as the Bio-Plex® suspension array system using phosphoprotein signal transduction assays. These bead-based assays can be used to detect the expression levels of phosphorylated proteins in lysates derived from cell culture or tissue samples. The results are used to investigate a wide variety of biological processes such as apoptosis, translation control, gene expression, cell cycle, cytoskeletal regulation, and neurological processes.
Dr Spinale, Professor of Cardiothoracic Surgery at Medical University of South Carolina, explains how the Bio-Plex system allowed him to tackle important questions in childhood disease research.