Molecular Basis of Cancer-1 PDF

Molecular Basis of Cancer-1 Dr. MM Khan Unit of Pathology  Topic Learning Outcomes Lecture 81: [PATH] Molecular basis of cancer – 1 Objectives: The objective of this lecture is to discuss the hallmarks of cancer and common oncogenes. Topic Outcomes: At the end of the le...

Molecular Basis of Cancer-1 Dr. MM Khan Unit of Pathology  Topic Learning Outcomes Lecture 81: [PATH] Molecular basis of cancer – 1 Objectives: The objective of this lecture is to discuss the hallmarks of cancer and common oncogenes. Topic Outcomes: At the end of the lecture, students should be able to: 81.1 List the fundamental changes in cell physiology, i.e., hallmarks of cancer and the simplified scheme of the molecular basis of cancer. 81.2 Classify the common oncogenes and tumour suppressor genes and their associated human tumours. 81.3 Describe the mode of activation and the role of MYC in malignant transformation. 81.4 List chromosomal abnormalities and its association with specific neoplasms.  What Causes CANCER? cell division Genetic (DNA) Mutation I gene from parents A. Inherited germ line mutations (5-10%) B. Environmental Carcinogens (15-20%) Chemicals Radiation Pathogens C. Spontaneous Somatic Mutation (70%) Tumour Growth and Progression  The Hallmarks of Cancer 1. Self-sufficiency in growth signals: Tumors have the capacity to proliferate without external stimuli, due to oncogene activation. 2. Insensitivity to growth-inhibitory signals: Tumors do not respond to growth inhibitory signals. 3. Evasion of apoptosis: Tumor cells become resistant to apoptosis due to inactivation of p53 or activation of anti-apoptotic genes. 4. Limitless replicative potential: Tumor cells regain unlimited proliferative capacity, avoiding cellular senescence. 5. Sustained angiogenesis: Tumor cells, like normal cells, need nutrients and oxygen for sustained growth. Hence, tumors must induce angiogenesis. 6. Ability to invade and metastasize: Tumor metastases are the cause of the vast majority of cancer deaths and depend on processes that are intrinsic to the cell or are initiated by signals from the tissue environment. 7. Evasion of immune surveillance: Tumor cells evades the host immune surveillance mechanism by altering the host immunity 8. Defects in DNA repair: In tumor cells, DNA damage caused by carcinogens is impaired, leading to genomic instability and mutations in proto-oncogenes and tumor suppressor genes The Hallmarks of Cancer  Self-Sufficiency in Cell Growth Signals The self-sufficiency in cell growth stems from gain-of-function mutations that convert proto-oncogenes to oncogenes The cell cycle is regulated by activators and inhibitors Activators: Cyclins and CDK Inhibitors: CDK Inhibitors CDK Inhibitors Cyclins/CDK Proto-oncogenes: normal cellular genes whose products promote cell proliferation Oncogenes: mutant or overexpressed versions of proto-oncogenes that function autonomously without a requirement for normal growth-promoting signals  Insensitivity to growth-inhibitory signals Oncogenes promote cell growth, while tumor suppressor genes apply brakes to stop cell growth and proliferation. Inactivation of tumor suppressor genes due to mutations renders cells refractory to growth inhibition and mimics the growth-promoting effects of oncogenes. Tumor suppressor genes Oncogenes Evasion of Cell Death Limitless Replicative Potential (Immortality)  Sustained Angiogenesis Vascularization of tumors is essential for their growth and is controlled by the balance between angiogenic and antiangiogenic factors that are produced by tumor and stromal cells. Hypoxia triggers angiogenesis through the actions of HIF-1α on the transcription of the proangiogenic factor VEGF. Invasion and Metastasis Evasion of Immune Surveillance 1. Selective outgrowth of antigen-negative variants: 2. Loss or reduced expression of MHC molecules: 3. Lack of co-stimulation: 4. Immunosuppression: 5. Antigen masking: 6. Tumor antigens treated as self-antigen: 7. Degradation of tumor antigens: 8. Apoptosis of cytotoxic T cells:  What Causes CANCER? Genetic (DNA) Mutation A. Inherited germ line mutations (5-10%) B. Environmental Carcinogens (15-20%) Chemicals Radiation Pathogens C. Spontaneous Somatic Mutation (70%) Flow chart of molecular basis of cancer  Oncogenes Oncogenes are generally dominant gain-of- function mutations of normal cellular genes known as protooncogenes Tumor suppressor genes Oncogenes Oncogenes are created by mutations in proto-oncogenes which promote cell growth in the absence of growth-promoting signals Protooncogene-Oncogene  Types of Oncogenes Growth Cytoplasmic Nuclear Cell Growth Factors Factors Signal Signal Cycle Receptors Transducer Transducer Regulator Common Oncogenes and Their Associated Tumors  Tumor Suppressor Genes Tumor suppressor genes are normal genes that slow down cell division, repair DNA defects and promote apoptosis oncogenes promote cell growth, while tumor suppressor genes apply brakes to stop cell proliferation. In 1997, Kinzler and Bert Vogelstein grouped these genes into two classes: "caretakers" and "gatekeepers"  Mode of activation of MYC  Role of MYC in Malignant Transformation Myc activate expression of many pro-proliferative genes. Myc has a direct role in the control of DNA replication. Myc is activated upon various mitogenic signals such as serum stimulation or by Wnt and EGF. By modifying the expression of its target genes, Myc activates many biological process. It also plays a very important role in regulating cell growth, apoptosis, differentiation and stem cell self- renewal. Chromosomal Abnormality  Chromosomal Abnormality 1. Numerical A. Aneuploidy: abnormal numbers of individual chromosomes monosomy or trisomy karyotype 45X. Ullrich-Turner syndrome Trisomy21: Down syndrome B. Polyploidy: entire set of chromosomes are affected, for e.g., each chromosome occurs 3 times (triploidy) or more  Chromosomal Abnormality 2. Structural A. Deletions: Part of chromosome is removed or deleted. B. Duplications: Part of chromosome is duplicated, resulting in extra genetic material. C. Inversions: A chromosome breaks in two places and the region between the break rotates 180° before rejoining with the two end fragments D. Insertions: Part of chromosome has been deleted from its normal place and inserted into another chromosome. E. Translocations: Part of chromosome has been transferred to another chromosome.  Oncogenic Activation Due to Chromosomal abnormality  Chromosomal Translocations Chromosomal translocation is a type of rearrangement between two chromosomes that involves breakage of each chromosome followed by fusion of the fragments generated by the break Chromosomal Abnormality & Associated Cancers Chromosomal Translocations & Associated Cancers Thanks for your attention