Cell Transformation Factors and Processes - Bond University PDF

ATTENDANCE Have you checked in? Please remember to check into the session via Osler! 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 1  Cell transformation factors and processes –...

ATTENDANCE Have you checked in? Please remember to check into the session via Osler! 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 1  Cell transformation factors and processes – The molecular basis of cancer Assistant Professor Joan Roehl 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 2  Acknowledgement of Country Bond University acknowledges the Kombumerri people, the traditional Owners and Custodians of the land on which the University now stands. We pay respect to Elders past, present and emerging. Copyright Warning. This material has been reproduced and communicated to you by or on behalf of Bond University in accordance with section 113P of the Copyright Act 1968 (Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 3  Week 6 Scenario Dr Tom Walker 52, anaesthetist, Townsville Hospital Avid fisherman, spends time in the sun Notices scaly area with red centre on back of his ear His GP is concerned that it might be a BCC, SCC or keratocanthoma – suspected cancerous lesion Biopsy sent for histopathology How do cells respond to injury? How is cell growth/replication normally regulated? How can disordered patterns of cell growth/replication arise and progress to form a cancer? 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 4  Week Learning outcomes Week 6 – Science and Scholarship During this session you will learn about  6. Outline the process of transformation of normal cells to neoplastic cells (Forum) 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 5  … is defined as a genetic disorder of cell growth that is triggered by acquired or less commonly inherited mutations affecting a single cell and its clonal progeny. 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 6  Session Learning outcomes During this session you will learn to  Briefly describe typical features of normal and abnormal cell growth  Briefly describe the processes of initiation, promotion and progression with respect to cancer development  Briefly describe the major functional classes of genes that can be “damaged” contributing to cancer development  Briefly describe how these “damaged” gene classes can contribute to cancer development  Define hyperplasia, hypertrophy, dysplasia, metaplasia 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 7  What is cancer? Cancer is an uncontrolled proliferation (growth and multiplication) of cells that can arise from any cell type in the body. Normally the cells of the body grow and divide to form new cells in an ordered manner as the body requires. Damaged or old cells are removed and replaced by new cells. In cancer, this ordered process becomes deranged. Abnormal or damaged cells survive and grow and divide at an uncontrolled rate, growing beyond normal tissue boundaries. Source: National Cancer Institute / Univ. of Pittsburgh Cancer Institute 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 8  What is cancer? 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 Source: Li, X., He, S. & Ma, B. Autophagy and autophagy-related proteins in cancer. 9 Mol Cancer 19, 12 (2020). https://doi.org/10.1186/s12943-020-1138-4  What is the process? Carcinogenesis Carcinogenesis is the process by which normal cells transform into malignant cells; it is not one single event that causes cancer to develop, but a series of events that cause cells to transform into cancerous cells: 1) Initiation – the initial event when the cell is exposed to an initiating factor 2) Promotion – secondary event when the cell is exposed to additional factors 3) Progression – the third stage when the cellular changes become irreversible and express malignant characteristics 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 10  What is the molecular basis of cancer? Genetic alterations Injury to a cell resulting in nonlethal genetic mutations is the definitive cause of cancer Damage may be caused by environmental exposures (viruses, chemicals, …), inherited, spontaneous/random Tumor is formed by clonal expansion of a single precursor cell that has incurred genetic damage (i.e., tumors are clonal). Caldas, C. Cancer sequencing unravels clonal evolution. Nat Biotechnol 30, 408–410 (2012). https://doi.org/10.1038/nbt.2213 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 11  Which genetic alterations? Normal Regulatory Genes are the Principal Targets of Cancer-Causing Mutations Growth promoting proto-oncogenes (“pro-cancer”) Growth inhibiting tumour-suppressor (“anti-cancer”) genes Genes central to DNA repair processes Genes central to regulation of cell death (apoptosis) Genes central to regulation of cell ageing (“lifespan”) Genetic damage resulting in combinations of gain of function and loss of function mutations leads to the development of cancer. 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 12  Carcinogenesis results from the accumulation of complementary mutations (Multi hit theory) Disordered regulation of cell growth results from accumulated damage to cellular DNA that is not repaired and does not result in cell death Damage resulting in dysregulated growth patterns can be the initiator of cancer formation (uncontrolled new growth) 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 13  Carcinogenesis results from the accumulation of complementary mutations (Multi hit theory) 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 Source: Robbins & Cotran Pathologic Basis of Disease. © 2021. 14  Carcinogenesis results from the accumulation of complementary mutations - example (2015). https://doi.org/10.1038/nrdp.2015.65 Kuipers, E., Grady, W., Lieberman, D. et al. Colorectal cancer. Nat Rev Dis Primers 1, 15065 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 15  Incr ea s ing Dis or der of Gr owt h is Es s ent ia l for t he “ S ucces s ful” P r ogr es s ion of a Tum or 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 16  Common biologic properties of cancer cells? Cellular and Molecular Hallmarks of Cancer 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 17  Comparing normal and abnormal growth Characteristics of Normal Growth growth factor-dependent growth anchorage-dependent growth contact inhibition limited lifespan facility to activate apoptotic cascades 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 18  Characteristics of Normal Growth: Gr owt h fa ct or - dependent gr owt h 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 19  Characteristics of Abnormal Growth: S elf- s ufficiency in gr owt h s igna ls (oncoge ne a ct iva t ion) 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 20  Characteristics of Abnormal Growth: S elf- s ufficiency in gr owt h s igna ls (oncoge ne a ct iva t ion) 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 21  Characteristics of Normal Growth: Growth factor- and anchorage-dependent growth 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 Robbins & Cotran Pathologic Basis of Disease 22  Characteristics of Abnormal Growth: Insensitivity to growth-inhibitory signals (tumour suppressor inactivation) 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 McCance & Huether, Pathophysiology, Mosby 23  Characteristics of Abnormal Growth: Tumour suppressor gene TP53 (p53 protein) 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 24  Characteristics of Abnormal Growth: Altered cellular metabolism (Warburg Effect) 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 25  Characteristics of Normal Growth: Regulated cell death 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 26  Characteristics of Abnormal Growth: Evasion of apoptosis 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 27  Characteristics of Normal Growth: Limited lifespan (number of cell divisions) 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 28  Characteristics of Abnormal Growth: Limitless replicative potential (immortality) Evasion of mitotic crisis 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 29  Carcinogenesis Carcinogenesis is the process by which normal cells transform into malignant cells; it is not one single event that causes cancer to develop, but a series of events that cause cells to transform into cancerous cells: 1) Initiation – the initial event when the cell is exposed to an initiating factor 2) Promotion – secondary event when the cell is exposed to additional factors 3) Progression – the third stage when the cellular changes become irreversible and express malignant characteristics 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 30  Characteristics of Abnormal Growth: Sustained angiogenesis 18/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 31  Characteristics of Abnormal Growth: Ability to invade and metastasise Source: Robbins & Cotran Pathologic Basis of Disease. © 2021. 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 32  bond.edu.au Assistant Professor Joan Roehl Faculty of Health Sciences and Medicine Bond University, Gold Coast, Australia 17/02/2024 CRICOS Provider Code: 00017B TEQSA: PRV12072 35