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Application of Proteomics in Cancer Study. By: Z.Hatefi . MSc Student In Biotechnology Isfahan University Of Medical Sciences Supervisor: Dr.M.sharifi. I ndex. Introduction The Proteomics Importance of proteomics Biomarker Biomarker discovery in cancer diagnosis
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Application of Proteomics in Cancer Study By: Z.Hatefi . MSc Student In Biotechnology Isfahan University Of Medical Sciences Supervisor: Dr.M.sharifi
Index • Introduction • The Proteomics • Importance of proteomics • Biomarker • Biomarker discovery in cancer diagnosis • Personalized Therapy v • Cancer Classification • Toxico proteomics • Patient Monitoring
The cancer • The numbers of deaths from cancer worldwide are gradually rising, with an estimated 12 million deaths in 2030 . • More tools that are sensitive are required for early detection of cancer. • Proteomics is using to biomarker discovery.
The Proteomics • The proteome represents the array of proteins that are expressed in a biological compartment (cell, tissue, or organ) at a particular time, under a particular set of conditions. • Large-scale, comparative analysis of proteins is the objective of proteome science (proteomics).
Cy3 for Sample 1 Cy5 for Sample 2 Cy2normalization Samples 1 and 2 2012;5:477 CircCardiovasc Genet.
Overview of proteomic analysis by MS/MS. Mol Cell Proteomics. 1, 376-86.
Importance of proteomics • Proteomes are also dynamic due to proteins’ varying localization, half-lives, and response to stimuli such as disease and treatment. • Protein functions are regulated by a complex system of intracellular and intercellular communication with other cells and microenvironment.
Importance of proteomics • Although the human genome contains 20,000–25,000 protein-coding genes it is estimated that the human proteome comprises >500,000 proteins. • Alternative splicing and post-translational modifications of proteins (e.g., phosphorylation, glycosylation, and proteolyticcleavage. further increase the diversity of a human proteome
Biomarker Biomarker: molecules that can reveals : • Physiological change • Progress of disease • Therapeutic effect .
Biomarker discovery in cancer diagnosis • The best strategies to reduce the mortality and morbidity of cancer patients are early diagnosis, provide effective therapy, and subsequently monitor treatment response. • Present screening tools for cancer detection, such as • (CEA) , (PSA) for prostate cancer • CA-125 for ovarian cancer • CA 19-9 for colorectal pancreatic cancer • which lack sufficient sensitivity and/or specificity for early detection.
Panel of Biomarkers • The cause and pathogenesis of cancer are heterogeneous, multiple dysregulated proteins and pathways are involved in the initiation and progression of cancer. • Improve the detection and clinical management of cancer patients. • Higher sensitivities and specificities.
Biological sample to study cancer • Cancer Cell Lines • Clinical Samples • Bio fluids
Clinical Samples • Resected tissues or biopsies, reflect the sheer number, complexity, and dynamics of biological events, and thus make them extremely valuable as sources for proteomics studies. • One important advantage of clinical samples is that ‘‘normal’’ tissue from the surrounding area of the tumor can be used for paired analysis.
Clinical Samples • Disadvantage • Small sample size of clinical samples • Heterogeneity of human tissues(Laser Capture Micro dissection(LCM) is a technique that reduces heterogeneity in tissues). • Most patients are admitted only at the moderate to late stage cancers so solid tumors offer prognostic information and less of predictive or therapeutic potential.
Bio fluids • Serum/Plasma • An ideal clinical cancer biomarker or biomarker panel should be tumor-type specific, produced at the earlier stages of cancer or in response to therapy, and measurable in easily accessible body fluids.
Bio fluids Advantage • Non- or less-invasive, larger quantities, human blood system perfuses. Disadvantage • It has been suggested that serum/ plasma contains over 10,000 protein species, and that such tumor tissue leakage factors are present in very low concentrations in the blood
Immunoaffinity columns Journal of Chromatography(2010) 103-121.
Sample preparation • Contamination. • Heat.
Personalized Therapy via Molecular Targeting Strategies • Effective ways of treating cancer has been a great focus of biomedical investigation for decades . • Cancer affects every patient and family in a different way. • The most therapeutic challenges is to design a specific drug for each individual .
Personalized Therapy • Drug targeting is a new developed way of treatment achieved by new molecular detection strategies such as proteomics. • These methods aid to the identification of protein biomarkers, their modification, and altered metabolic pathways by comparison of the proteomes of normal cell and cell from a patient that leads to drug designing.
Personalized Therapy • One of the good examples of these molecules is PTK (Protein tyrosine Kinases) and other kinases that represent the feature of many cancers. • These molecules placed in key positions in the signaling network; which are attractive targets for drug development such as inhibitors .
Cancer Classification • Proteomics is one of the choices for classification of tumor origin and states, based on their molecular source. • For cancer classification, the protein samples from cancer patients relative to normal or from different cancer stages analyze through MS appliance and the MS patterns uses to build a diagnostic classifier .
Cancer Classification • Good cancer classification models could eliminate the unclassifiable cancers as used in current classifications. • Future cancer treatments may be advanced by using an integrated model of cancer classification such as proteomics methods .
Toxico proteomics • A number of chemicals contaminations present in air, water, food and workplace are capable of inducing cancer. • Many studies have discovered the link of various types of environmental pollution with the development of cancer.
Toxico proteomics • Although many of them have been classified as carcinogens but their mechanism is still insufficient, and remained to identify . • Toxicoproteomicsallow the monitoring of the body’s response to a specific toxicant . • This advances supplies a means to identify and characterize mechanisms of action of toxicants in carcinogenesis.
Example • The liver carcinogen N-nitrosomorpholine (NNM) investigated in rats to identify potential early protein biomarker signatures indicative of the carcinogenic processes. • Analysis was performed 18 weeks following treatment revealed significant up regulation of stress proteins, including : • Caspase-8 precursor • Vimentin • Rho GDP dissociation inhibitor • Deregulates annexin A5 and fructose-1, 6-bisphosphatase.
Result • Determining toxic effects of anticancer drugs at an early stage is useful for developing safer cancer therapies • This finding may indicate their potential use as predictive biomarkers for early liver carcinogenicity .
Patient Monitoring • It is essential to know whether patients with malignant tumors are benefiting from the administered therapy or not. • Proteomic technologies, such as serum protein pattern profiling, combined with protein microarray technologies, constitute a new paradigm for detecting disease and monitoring disease response to therapy . • Protein biomarkers such as CEA, CA 153, AFP,PTKs and PSA are useful for therapy monitoring.
Reference • Emily I. Chen JRYI. Cancer proteomics by quantitative shotgun proteomics. molecular Oncology. 2007:144-159. • Blackstock WP WM. Proteomics: Quantitative and physical mapping of cellular protein. Trends Biotechnol. 1999, 17:121-127 • Zhang Z, Chan DW. Cancer proteomics: In pursuit of “true” biomarker discovery. Cancer Epidemiology Biomarkers & Prevention. 2005, 14:2283-2286. • Hanash S, Taguchi A. The grand challenge to decipher the cancer proteome. Nature reviews cancer. 2010, 10:652-660 • Mona Zamanian-Azodi1, Mostafa Rezaei-Tavirani1*, Application of Proteomics in Cancer Study,American Journal of Cancer Science.
