BMS100 Pathology Concepts 1.04 Carcinogenesis Fall 2022 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-catenin...

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.