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Neoplasia Molecular basis of Carcinogenesis PowerPoint Presentation

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Description : Neoplasia, Molecular basis of Carcinogenesis

Tags : fariha,neoplasia,molecular basis of carcinogenesis,carcinogenesis

Published on : Sep 29, 2023 | Views : 2135 | Downloads : 9

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Neoplasia, Molecular basis of Carcinogenesis Dr. Fariha Sahrish Consultant Histopathologist
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Learning objectives At the end of the session, students will be able to Enlist principal mutations causing cancer Enlist regulatory genes Describe the main events in carcinogenesis. Elaborate molecular hallmarks of cancer. Enlist oncogenes and proto-oncogenes. Describe mutations that develop the self sufficiency in carcinogenesis
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Neoplastic Alterations Nonlethal genetic damage Clonal expansion of single precursor cell that incurred genetic damage
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Cancer is a disease of the cell cycle
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Regulatory Genes
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Learning objectives At the end of the session, students will be able to Define proto-oncogene Describe its role in carcinogenesis
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Oncogenes Mutations convert proto oncogenes into oncogenes involved in tumor development
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Onco-Proteins Encoded by oncogenes Mutated proteins Promote cell growth in the absence of normal growth promoting signals Endow cells with self sufficiency in growth
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Growth Factors
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Enlisting of Growth factors
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Growth Factor Receptors Most important in cell signaling Tyrosine kinase receptor is most common mutated receptor Have two domains Intracellular and extracellular domain Extracellular domain is ligand binding site which bind to growth factors Intracellular domain is cytoplasmic tyrosine kinase with coverts to active dimeric state and cause rapid change in receptor conformation
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Enlisting of Growth Factor Receptors
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Mutated Receptors Constitutive dimerized and activated oncogenic receptors without binding to growth factor Following mutations commonly occurs Point mutation in ERBB1 that encodes epidermal growth factor receptor (EGFR) Gene amplification in ERBB2 encodes HER2 Gene rearrangement in EML4-ALK causes ALK mutation Used in targeted therapies
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Signal Transducing Proteins Mutations in signal-transducing proteins can lead to a continuous proliferating state and uncontrolled growth. Example: RAS mutation
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Signal Transduction Proteins Normally RAS protein is located at the inner leaflet of plasma membrane. It plays an important role in signaling cascade downstream the growth factor. These membrane-bound signal transducers receive signals from receptor related tyrosine kinase & transmit signal to nucleus by secondary messenger.
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RAS Oncogene (GTP-binding proteins) Mutation of RAS is most common oncogene encountered & is observed in 30% of all human tumors of various types (90% of pancreatic cancer, 50% of colon & 30% of lung carcinoma) Activated by point mutation Normally, there is orderly cycling of RAS between guanosine diphosphate (RAS -GDP, inactive form) & RAS -GTP (active form) * GAP (GTPase activating protein) causes hydrolysis of ras-GTP to its inactive form With mutation of RAS, GAP can not hydrolyse RAS -GTP which remains in active state & stimulate another downstream mitogenic signal pathways namely BRAF-1 & MAPK (mitogen activated protein kinase)
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Oncogenic activation of BRAF and PI3K Heterodimer proteins Composed of regulatory and catalytic subunit Activates serine/threonine kinases Which turns activates AKT AKT stimulates mTOR, BAD and FOXO which are involved in keeping cellular nutrient status , increased cell survival and negative regulation of apoptosis.
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Alterations in Non-Receptor kinases BCR-ABL oncogene fusion In chronic myeloid leukemia (CML), proto-oncogene (ABL) is translocated from its normal location on chromosome 9 to chromosome 22 where it fuses with BCR (break point cluster region) gene Resulting hybrid gene produce chimeric protein with potent mitogenic tyrosine kinase activity Chromosome resulting from this reciprocal translocation is called Philadelphia chromosome Point mutations in JAK/STAT signaling pathway cause continuous stimulation of growth factors and cytokines
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Enlisting of Signal Transduction Proteins
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Transcription factors Growth autonomy occurs due to mutations affecting transcription factors regulating the expression of pro growth genes and Cyclins Transcription factors include MYC,MYB, JUN and FOS.
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MYC-Oncogene Master regulator of cell growth C-MYC: In Burkit's lymphoma, C-MYC is translocated from its normal place on chromosome 8 to chromosome 14 where it is placed close to the immunoglobulin heavy chain gene. In this new location, C-MYC in subjected to stimulation by the enhancer element of the immunoglobulin gene Following translocation, C-MYC protein is rapidly translocated to nucleus forms heterodimer with another protein (max) C-MYC /max complex activates transcription of several cell-cycle-related genes resulting in cellular proliferation N-MYC: amplified in Neuroblastoma L-MYC: amplified in Small cell lung cancer
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Nuclear Regulatory Proteins
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Cell Cycle regulators Orderly progression of various stages of cell cycle is under control of two classes of proteins, namely: cyclins (regulatory units) Cyclin dependent-kinases (catalytic units) CDKs are expressed continuously, but different cyclins are expressed periodically according to phase of cell cycle In mantle cell lymphoma, translocation t (11; 14) activation of PRAD1 gene overexpression of cyclin-Dl activates CDK-4 phosphorylation of Rb protein release of E2F which drives cell to enter S-phase (activates transcription of several genes whose products are essential for progression through S-phase
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Cancer Hallmarks Carcinogenesis results from the accumulation of supplementary mutations in stepwise fashion Driver mutations……contribute to the malignant phenotype Loss of function mutation….passenger mutations…..maintaining genetic integrity Darwinian selection……..outgrowth and progression of tumor cells Epigenetic aberrations……DNA methylation and Histone modification
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Main events of Carcinogenesis Self-sufficiency in growth signals Tumors can proliferate without external stimuli, usually as a consequence of oncogene activation. Insensitivity to growth-inhibitory signals Tumors may not respond to molecules inhibiting the proliferation of normal cells, such as transforming growth factor β (TGF-β) and direct inhibitors of cyclin-dependent kinases (CDKIs). Evasion of apoptosis Tumors may be resistant to programmed cell death due to the inactivation of p53 or the activation of anti-apoptotic genes Limitless replicative potential Tumor cells have unrestricted proliferative capacity, avoiding cellular senescence and mitotic catastrophe
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Sustained angiogenesis Tumor cells, like normal cells, are not able to grow without formation of a vascular supply to bring nutrients and oxygen and remove waste products. Hence, tumors must induce angiogenesis. Ability to invade and metastasize Tumor metastases cause most cancer deaths and depend on processes intrinsic to the cell or initiated by signals from the tissue environment. Defects in DNA repair Tumors may fail to repair DNA damage caused by carcinogens or incurred during unregulated cellular proliferation, leading to genomic instability and mutations in proto-oncogenes and tumor suppressor genes.
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Genomic instability Defects in the repair system lead to permanent DNA damage, causing genetic diseases
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Excision Repair pathways Base Excision Repair (BER) Nucleotide Excision Repair (NER) Mismatch Repair (MMR)
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Mismatch Repair (MMR) Mismatch repair deals with correcting mismatches of the normal bases; that is, failures to maintain normal base pairing (A･T, C･G) Recognition of a mismatch requires several different proteins including one encoded by MSH2. Cutting the mismatch out also requires several proteins, including one encoded by MLH1.
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Dysregulation of cancer-associated genes Chromosomal Changes Change in chromosome number (aneuploidy) and chromosomal instability may be the initiating events in tumor growth Two types of chromosomal re- arrangements that can activate proto- oncogenes: Translocations (more common) Inversions
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Mechanisms of activation by translocation Swapping of regulatory elements with those of another gene over- expression of proto-oncogene (e.g. lymphoid tumors - Burkitt’s lymphoma Recombination of unrelated sequences from two different chromosomes form hybrid fusion genes e.g. Philadelphia chromosome of CML; hemato- poietic tumors, sarcomas
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Deletions Second most common structural abnormality in tumor cells More common in non hematopoietic solid tumors Associated with loss of particular tumor suppressor genes e.g. Retinoblastoma (deletion of chr. 13q14
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Gene Amplification Reduplication and amplification of DNA sequences of proto-oncogenes  over-expression of products Examples: Amplification of N-MYC in Neuroblastoma ERBB2 amplification in breast cancers C-MYC, L-MYC, N-MYC amplification in small cell lung CA
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Epigenetic Changes Reversible, heritable changes in gene expression that occur without mutation Involve post-translational modifications of histones and DNA methylation Tumor suppressor genes are sometimes silenced by hypermethylation of promoter sequences rather than mutation Example: CDKN2A  codes for tumor suppressors p14/ARF and p16/INK4a  affect p53 and RB  inhibit two checkpoints BRCA 1 (breast cancer) and VHL (renal cell CA) Normal cells Majority of genes not expressed  silenced by DNA methylation and histone modification  heterochromatin formation Cancer cells Characterized by global hypo methylation and selective promoter-localized hypermethylation
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