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Explore the nature of cancer and how it arises, the pathways involved in cancer development, the cell cycle clock and its role in cancer, and the molecular targets of cancer. Learn about the different stages of tumor development, the principles of cancer development, and the importance of proto-oncogenes and tumor suppressor genes. Discover the pathways involved in cancer growth regulation, apoptosis, angiogenesis, cytoskeletal signaling, immune regulation, and cell cycle control. Finally, delve into the molecular targets, specifically kinases, that are crucial in cancer therapeutics.
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Advanced Bioinformatics Lecture 2: Cancer pathways and therapeutics ZHU FENG zhufeng@cqu.edu.cn http://idrb.cqu.edu.cn/ Innovative Drug Research Centre in CQU 创新药物研究与生物信息学实验室
Table of Content The nature of cancer How cancer arises Pathway involved in cancer Cell cycle clock and cancer Molecular target of cancer 2
The nature of cancer cells • Normal cells Reproduce only when instructed to do so by other cells in their vicinity. Such unceasing collaboration ensures that each tissue maintains a size and architecture appropriate to the body’s needs. • Cancer cells (in stark contrast) • become deaf to the usual controls on proliferation and follow their own internal agenda for reproduction. • possess an even more insidious ability: migrating and invading nearby tissues and forming masses at distant sites in the body. 6
Tumor Development Occurs in Stages 7 Migrate & Invade
Principles in cancer development • Common ancestor Cancer cells descend from a common ancestral cell, usually decades before a tumor initiates a program of inappropriate reproduction. • Accumulation of mutations The malignant transformation of a cell comes about through the accumulation of mutations in specific classes of the genes within it. • Genes playing major roles in triggering cancer Proto-oncogenes encourage growth, whereas tumor suppressor genes inhibit it. Collectively these two gene classes account for much of the uncontrolled cell proliferation seen in human cancers. 8
Proto-oncogene Mutations on proto-oncogene may cause the over-production of its encoded growth stimulatory protein or an overly active form of it. Mutated proto-oncogene becomes carcinogenic oncogene that drive excessive multiplication. From proto-oncogene to oncogene 9
Tumor suppressor gene Contribute to cancer when they are inactivated by mutations. The resulting loss of functional suppressor proteins deprives the cell of crucial brakes that prevent inappropriate growth. 11
p53 – tumor suppressor Inactivated by its negative regulator, mdm2 Many pathways lead to dissociation of p53-mdm2 complex Active form of p53 12
Pathways involved in cancer • Growth regulation (cell development, division and reproduction) • Regulation of apoptosis (process of programmed cell death) • Angiogenesis (new blood vessels form from pre-existing vessels) • Cytoskeletal signaling (cellular scaffold govern migration) • Immune regulation (defense sytem to avoid disease) • Cell cycle control (events leading to cell division and duplication) • Multiple regulation (collective effects reflect pathway complexity) 17
Growth regulation MAPK/Erk in Growth and Differentiation 18
Regulation of apoptosis Apoptosis regulation via mitochondria Apoptosis regulation via death receptor 19
Angiogenesis Endothelial cells, which form the innermost layer of blood vessel, encircle red blood cell. Pericytes characteristically lining the outer surface of endothelial cells 20
Cytoskeletal signaling, invasion and migration Regulation of Microtubule Dynamics Regulation of Actin Dynamics 21
Immune regulation B Cell Receptor Signaling T Cell Receptor Signaling 22
Cell cycle control G1/S Checkpoint G2/M DNA Damage Checkpoint 23
Multiple regulation PI3K / Akt Signaling 24
