Carcinogenesis .pdf

Pathology Concepts 1.04 Carcinogenesis Dr. Hurnik BMS 100 Week 9 Today’s Overview Pre-learning: Definitions & tumour characteristics Risk factors In class: Model of carcinogenesis Tumor progression Oncogenes Ras, PI3 K, Myc, Cdks & cyclins Tumour suppressor genes RB, p53, CKIs, APC APC/Beta-...

Pathology Concepts 1.04 Carcinogenesis Dr. Hurnik BMS 100 Week 9 Today’s Overview Pre-learning: Definitions & tumour characteristics Risk factors In class: Model of carcinogenesis Tumor progression Oncogenes Ras, PI3 K, Myc, Cdks & cyclins Tumour suppressor genes RB, p53, CKIs, APC APC/Beta-catenin review Hallmarks of cancer Warburg effect Limitless replicative potential Carcinogens Assignment - HPV Molecular basis of cancer • Carcinogenesis is a multistep process resulting from the accumulation of multiple mutations § Mutations that results in the attributes of malignant cells - excessive growth, local invasion, distant metastasis Pathologic Basis of Disease(Robbins and Cotran) 10th ed. Figure 7.19. Page 282 Types of mutations • Initiating mutation – found in all progeny, begins the process towards malignant transformation § Essentially the first driver mutation § Often include loss-of-function mutations in genes that maintain genomic integrity • Leading to genomic instability • Driver mutation – mutation that increases malignant potential of the cell • Passenger mutation – mutation with low malignant effect Classes of mutated genes • Driver mutations fall into 4 main categories: § Proto-oncogenes • Gain-of-function mutations => oncogenes § Tumour suppressor genes • Generally loss-of-function mutations § Genes regulating apoptosis • Can be gain- or loss-of function § Genes responsible for DNA repair • Generally loss of function • Affected cells acquire mutations at an accelerated rate (aka genomic instability) Tumour progression • Once established, tumours evolve genetically based on survival/selection of the fittest § Mutations are acquired at random • Resulting in tumour cells being genetically heterogenous Pathologic Basis of Disease(Robbins and Cotran) 10th ed. Figure 7.20. Page 283 Tumour progression - continued • Once established, tumours evolve genetically based on survival/selection of the fittest § Tumour subclones compete for access to nutrients with fittest subclones dominating tumour mass • As a result , tumour become more aggressive over time (tumour progression) § This also explains changes in tumour behaviours following therapy • Tumours that recur after therapy are almost always found to be resistant to the initial treatment Mutation class - Oncogenes • Promote excessive cell growth, even in absence of normal growth-promoting signals § created by mutations in proto-oncogenes (unmutated cellular counterparts) § Encode oncoproteins that participate in signaling pathways driving cell proliferation • Can include: § growth factors or their receptors, signal transducers, transcription factors, or cell cycle components • We will consider the role of the following proto-oncogenes in more details § § § § Ras PI3 K Myc Cyclins and cdks Select Oncogenes • All FYI except Ras, Myc, Cyclin D and cdk4 Pathologic Basis of Disease(Robbins and Cotran) 10th ed. Table 7-5. Pg. 285 Oncogenes: Ras • Ras § Downstream component of receptor tyrosine kinases signaling pathways § Point mutation of RAS family genes is the single most common abnormality of proto-oncogenes in human tumors • FYI - Approximately 15% to 20% of all human tumors contain mutated versions of RAS § Eg. 90% of pancreatic adenocarcinomas and cholangiocarcinomas § 50% of colon, endometrial, and thyroid cancers § 30% of lung adenocarcinomas and myeloid leukemias § Important downstream signaler for lots of growth factors • EGF, PDGF, and CSF-1 • Review: how were growth factors involved in the cell cycle? Review: Ras pathway Molecular Biology of the Cell (Alberts et al) 6th ed. Figure 15-47. Page 855 Oncogenes: PI3K • PI3 family § Also very common in certain cancers • FYI - Eg. 30% of breast carcinomas have PI3K gain-offunction mutations Promotes cell proliferation • How? Inhibits apoptosis Molecular Biology of the Cell (Alberts et al) 6th ed. Figure 15-53. Page 860 Oncogenes: Myc • MYC (transcription factor) § Immediate early response gene • Induced by Ras/MAPK signaling (among others) § When activated: • Increases cell proliferation & growth § How was Myc involved in the cell cycle? • Contributes of other hallmarks of cancer § Warburg effect (eg. can upregulate glycolytic enzymes) § increased telomerase activity (contribute to endless replicative activity) § May also allow more terminally differentiated cells to gain characteristics of stem cells § Implicated in cancers of breast, colon, lung Oncogenes: Cdks & Cyclins • Which of the two cell cycle checkpoints regulated by cdk-cyclin complexes do you suppose is more important in cancer? • Gain-of-function mutations in cyclin D and Cdk4 • How would this affect progression through the G1/S checkpoint • FYI - Implicated in melanomas, sarcomas, glioblastomas Mutation class - Tumour suppressor genes • Products of tumor suppressor genes apply brakes to cell proliferation § Abnormalities lead to failure of growth inhibition § Many, such as RB and p53 recognize genotoxic stress • responds by shutting down proliferation • Activation of oncogenes aren’t enough for cancer induction, usually requires loss of tumour suppressor genes as well § We will discuss: • RB • P53 • CKIs Select tumour suppressor genes • Know the ones circled in red, rest are FYI Pathologic Basis of Disease(Robbi ns and Cotran) 10th ed. Table 7-7. Pg. 292 Select tumour suppressor genes • Know the ones circled in red, rest are FYI Pathologic Basis of Disease(Robbi ns and Cotran) 10th ed. Table 7-7. Pg. 292 Tumour suppressor genes: RB • RB: § Functions as a key negative regulator of the G1/S checkpoints • How? § What form do we normally find RB in a quiescent cell? § What form is RB in to facilitate passing through the G1/S checkpoint § Directly or indirectly inactivated in most human cancers • Directly – loss of function involving both RB alleles • Indirectly § Gain of function mutation upregulating CDK4 /cyclin D (slide 32) § Loss of function mutation of CKIs (p16 - coming up) Reminder Pathologic Basis of Disease(Robbins and Cotran) 10th ed. Page 294 Reminder Molecular Biology of the Cell (Alberts et al) 6th ed. Figure 17-61. Page 1013 Tumour suppressor genes: p53 • TP53 “ Guardian of the Genome” § Codes for p53 • What is p53? § Regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis § Most frequently mutated gene in human cancer • Loss of function mutation found in more than 50% of cancers § Including lung, colon, and breast – three leading causes of cancer death § Can include mutations in p53 or Mdm2 Tumour suppressor genes: p53 • How can mutated p53 contribute to carcinogenesis? § Hint: think about the functions of p53 Pathologic Basis of Disease(Robbins and Cotran) 10th ed. Figure 7.27. Pg. 296 Tumour suppressor gene: p53 • p53 functions in the presence of DNA damage: § Arrests the cell cycle until DNA can be repaired • How? § Stimulates DNA repair • If DNA repair is successful => cell cycle can resume • If DNA repair fails => p53 will activate pro-apoptotic pathways § p53 mutations are commonly responsible for genomic instability, driving tumour progression Tumour suppressor genes: p53 • Reminder Molecular Biology of the Cell (Alberts et al) 6th ed. Figure 17-62. Page 1015 Tumour suppressor genes: p53 • With loss of p53, DNA damage goes unrepaired & driver mutations accumulate in oncogenes & other cancer genes à malignant transformation Pathologic Basis of Disease(Robbins and Cotran) 10th ed. Figure 7.27. Pg. 296 Tumour suppressor genes: CKIs • CDKIs are frequently mutated or otherwise silenced in many human malignancies § p16 • Inherited mutations implicated in familial forms of melanoma • Acquired mutations detected in many cancers § Eg. Bladder cancers, head and neck tumours, ALL, cholangiocarcinoma • p16 can also be silenced by hypermethylation rather than mutation § This is an example of a epigenetic change § Occurs in some cervical cancers Tumour suppressor genes: p16 • Reminder of p16 function § Inhibits Cdk4Cyclin D complex (G1cdk complex) needed for progression through the cell cycle Pathologic Basis of Disease(Robbins and Cotran) 10th ed. Figure 1.19. Page27 Thinking Question • What do you notice about the common oncogenes and tumour suppressor genes we have discusses? § Hint: where do they all affect the cell cycle? Thinking Question • What do you notice about the common oncogenes and tumour suppressor genes we have discusses? § Hint: where do they all affect the cell cycle? • Loss of normal cell cycle control is a major contributor to malignant transformation § At least 1 of the 4 key regulators of the cell cycle is dysregulated in the significant majority of all human cancers • p16, cyclin D, Cdk4, RB Tumour suppressor genes: other • Remember β-catenin? § APC • Very commonly mutated in colorectal cancers • Part of Wnt-B-catenin pathway § E-cadherin • Loss of function mutations can contribute to loss of contact-inhibition in tumours and metastasis Pathologic Basis of Disease(Robbins and Cotran) 10th ed. Figure 7.28. Page 298 Hallmarks of cancer • All cancers display 8 fundamental changes in cell physiology: § 1. Self-sufficiency in growth signals § 2. Insensitivity to growth-inhibitory signals § 3. Altered cellular metabolism § 4. Evasion of apoptosis § 5. Limitless replicative potential § 6. Sustained angiogenesis § 7. Ability to invade and metastasize § 8. Ability to invade the host immune system Altered cellular metabolism • Warburg effect § Cancer cells take up high levels of glucose and demonstrate increased conversion of glucose to lactate • Even in the presence of ample oxygen • Also called aerobic glycolysis § Why do you suppose a cancer cell is relying on glycolysis alone for ATP production? • Hint: embryonic tissues also use on aerobic glycolysis Altered cellular metabolism • Warburg effect § Why do you suppose a cancer cell is relying on glycolysis alone for ATP production? • Provides rapidly diving tumour cell with metabolic intermediates needed for synthesis of cellular components § Mitochondrial oxidative phosphorylation does not! Limitless replicative potential • Normal human cells divide 60-70 times and then become senescent § Senescent = cell permanently exits the cell cycle & never divides again • Cancer cells can evade senescence § Likely due to loss of functions mutations in p53 and p16 § Allows cell to pass through G1/S checkpoint Limitless replicative potential - continued • Cancer cells have also demonstrated the ability to express telomerase • Remember telomerase is only very minimally expressed in most somatic cells § Allows cancer cells to continue replicating indefinetly Causes of mutations Chemical Carcinogens (FYI) Pathologic Basis of Disease(Robbins and Cotran) 10th ed. Table 710. Page 321 Causes of mutations - Radiation Carcinogenesis • Radiation is mutagenic and carcinogenic § UV radiation • Associated with squamous cell carcinoma, basal cell carcinoma, and melanoma of the skin § Ionizing radiation • Medical X-rays • Occupational exposure • Nuclear plant accidents Causes of mutations - Microbial Carcinogenesis • Many RNA and DNA viruses have been proven to be oncogenic § RNA Viruses: • Human T-cell Leukemia Virus Type 1 (HTLV-1) § Associated with Leukemia § DNA Viruses • • • • • HPV – Human Papillomavirus EBV – Epstein Barr virus HBV (& HCV) – Hepatitis B virus Merkel cell Polyomavirus HHV8 – Human herpesvirus 8 Study questions • Build a table comparing oncogenes and tumour suppressor genes § What is the basic difference between the two categories § List the common mutated genes in each category • Diagram how they fit into the cell cycle (ie how are they contributing to carcinogenesis References • Alberts et al. Molecular Biology of the Cell. Garland Science. • Betts et al. Anatomy and Physiology (2ed). OpenStax • Pathologic Basis of Disease(Robbins and Cotran) 10th ed.