BIO211 General Biology Lecture 7: Cancer PDF

BIO211 (General Biology) Lecture 7: Cancer Robert Belshaw [email protected] © McGraw Hill 1  The short story: Cell cycle and cancer Cell cycle is regulated by signals that inhibit or...

BIO211 (General Biology) Lecture 7: Cancer Robert Belshaw [email protected] © McGraw Hill 1  The short story: Cell cycle and cancer Cell cycle is regulated by signals that inhibit or promote cell cycle Cancer may result from imbalance in these signals Cancer is a disease of the cell cycle in which cellular reproduction occurs repeatedly without end. Cell division has gone wrong (uncontrolled) © McGraw Hill 2  In 1960’s there was a debate over what caused cancer 1) Pathogens (viruses) 2) Inherited 3) Environment © McGraw Hill 3  1) Found a cancer-causing virus https://explorebiology.org/summary/genetics/the-genetic-basis-of-cancer © McGraw Hill 4  2) Also some inherited form of cancer https://basicmedicalkey.com/in-familie © McGraw Hill https://explorebiology.org/summary/genetics/the-genetic-basis-of-cancer5  3) Also environmental causes of cancer In the UK in the nineteenth century child chimney sweeps developed testicular cancer: ‘Chimney Sweep Cancer’ Siddhartha Mukherjee (2010) The Emperor of All Maladies: A Biography. Scribner https://www.chimneysolutions.com/blog/child-chimney-sweeps/ © McGraw Hill 6  Several other early environmental causes of cancer Painting watch faces with Smoking causes ~16-fold radioactive radium. Licking the increase in risk of lung brushes caused cancers in female cancer. Established in workers in the 1920’s 1940’s https://en.wikipedia.org/wiki/Radium_Girls © McGraw Hill 7  How could cancer be caused by 3 different things? © McGraw Hill 8  Resolution: 1) In 1970’s they found a cancer-causing gene in the virus: v-src = ‘viral src’ (pronounced ‘sarc’, short for sarcoma) Src caused division when inserted into cell cultures Naming genes and proteins Gene name = src (italics) https://explorebiology.org/summary/genetics/the-genetic-basis-of-cancer Protein name = Src (not italics and first letter is upper case) © McGraw Hill 9  Found src gene also in the chicken: c-src (‘cellular’ src genes) LMCQCWRKDPEERPTFEYLQAFLEDYFTSTEPQYQPGENL c-src – in chicken LMCQCWRKDPEERPTFEYLQAFLEDYFTSTEP - - - - - - - - - v-src – in Rous sarcoma virus.. and in humans (a few amino acid differences, in red) LMCQCWRKDPEERPTFEYLQAFLEDYFTSTEPQYQPGENL c-src – in chicken LMCQCWRKDPEERPTFEYLQAFLEDYFTSTEP - - - - - - - - - v-src – in Rous sarcoma virus LMCQCWRKEPEERPTFEYLQAFLEDYFTSTEPQYQPGENL c-src – in human © McGraw Hill 10  Reminder: concept of cell signaling pathway Inactive Active Important: Like the Na/K pump and Kinesin, these proteins go back to their original shape © McGraw Hill 11  Many pathways affect the cell cycle cell membrane nuclear membrane E2F binds to Rb https://www.easybiologyclass.com Alberts et al. (2002) Molecular Biology of the Cell. New York: Garland Science © McGraw Hill 12  Src protein is involved in many pathways including promoting cell division. This is how the normal Src protein (a tyrosine kinase) works (details not important) Okada (2012) Regulation of the SRC family kinases by Csk. Int J Biol Sci. 8:1385-97. © McGraw Hill 13  v-Src was different: it lacked one amino acid that was necessary to inactivate it (switch off) Tyr (Y) at position 527 is missing in v-src LMCQCWRKDPEERPTFEYLQAFLEDYFTSTEPQYQPGENL c-Src - chicken LMCQCWRKDPEERPTFEYLQAFLEDYFTSTEP - - - - - - - - - v-Src - rous sarcoma virus LMCQCWRKEPEERPTFEYLQAFLEDYFTSTEPQYQPGENL c-Src - human © McGraw Hill 14  Therefore v-Src is always ‘on’ (active) Effect of Src is similar to Myc shown in detailed pathway above Increases Cell division Inactive Active This is blocked In 1969, Huebner and Todaro proposed the ‘oncogene’ hypothesis of cancer Huebner RJ and Todaro GJ. (1969). Proc. Natl. Acad. Sci. USA, 64, 1087–1094 © McGraw Hill 15  Actually, src was not the first oncogene to be discovered In the 1970’s, injected pieces of DNA from human tumors into cell cultures to see what causes their proliferation First human oncogene discovered was ras. This is a kinase that was found to be locked permanently ‘on’ in cancer (involved in perhaps 30% of human cancers) ras is shown in Pathways PPT © McGraw Hill 16  2) Discovered a cancer-causing gene in Retinoblastoma patients The Rb protein normally binds to EF2 and prevents transcription of genes necessary for the cell to progress through the cell cycle Many different ‘knock-out’ mutations stop Rb from doing this. This defective gene is inherited (called a ‘tumor suppressor’) Remember checkpoints from cell division lecture？ © McGraw Hill 17  Tumor Suppressor gene RB1 (= Rb, RB) Mutations in gene prevent the protein working (new allele) https://cyberleninka.org/article/n/1099576/viewer © McGraw Hill 18  Remember: Mutations are often substitutions of one nucleotide for another (in addition to deletions as in v-src) https://en.wikipedia.org/wiki/Silent_mutation © McGraw Hill 19  Rb is inactivated (= always ‘off’) Inhibits Cell division Inactive Active Active © McGraw Hill 20  3) Discovered that patients with cancers caused by environmental factors also had mutations in such oncogenes and tumor suppressors healthy tumor suppressor (‘on’ proto-oncogene and ‘off’) (‘on’ and ‘off’) DNA damage mutated tumor suppressor (only oncogene (only ’on’) ‘off’) https://www.rndsystems.com/resources/articles/dna-damage-response © McGraw Hill 21  Cigarette smoke contains chemicals that cause mutations (= carcinogens) https://www.compoundchem.com/2014/05/01/the- chemicals-in-cigarette-smoke-their-effects/ https://www.researchgate.net/figure/Chemicals-adducted-to-guanine-and- mispairing-with-thymine-in-this-case-causes-a-G-to-A_fig2_303507593 © McGraw Hill 22  So, all 3 causes of cancer were due to mutations in key genes Mutated oncogene in virus Inherit mutated Tumor Supressor Agent in environment mutates Tumor Supressors and Proto- oncogenes © McGraw Hill 23  These Driver Mutations turn proto-oncogenes into oncogenes and inactivate tumor suppressors e.g. src e.g. Rb https://explorebiology.org/summary/genetics/the-genetic-basis-of-cancer © McGraw Hill 24  Not all mutations that cause cancer are within genes Translocation between chromosomes 22 and 9, resulting in the Philadelphia chromosome is common in chronic myeloid leukemia (CML). Fuses two parts of different genes making a dangerous oncogene (BCR-ABL). The pink cells in this micrograph are rapidly dividing white blood cells © McGraw Hill (b): ©Jean Secchi/Dominique Lecaque/Roussel-Uclaf/CNRI/Science Source 25  The mutation may just produce more copies of the oncogene (same effect) – overexpression ER+ are breast cancers with elevated expression of ER (Estrogen Receptor) PR+ are breast cancers with elevated expression of PR (Progesterone Receptor) https://www.verywellhealth.com/hormone-receptor-status-and-diagnosis-430106 © McGraw Hill 26  Another oncogene example: FLT3 30 of patients with Acute Myeloid Leukemia (AML) have mutated FLT3 Mutations leave receptor permanently ‘on’ Mutations also creates an autocrine (in same cell) loop leading to increased RNA expression of FLT3 Litzow (2005). More flitting about FLT3. Blood 106:3331-2 gene © McGraw Hill 27  Tumor supressors can have many effects, e.g. PTEN (details not important) PTEN is a phophatase: removes phosphate groups from proteins, and this can activate or inactivate them Repairing Activation DNA damage Inhibition https://www.jci.org/articles/view/121277/figure/1 MAPK/ERK pathway activates cell division © McGraw Hill 28  The most important tumor suppressor is p53 ‘Guardian of the Genome’ p53 (also called TP53) is a transcription factor that activates many genes involved in many functions Mutations in p53 are seen in at least 50% of all human cancers DNA damage leads to increased levels of p53 p53 helps apoptosis and slows down the cell cycle (leading to DNA repair) http://www.p53.at/main.asp?kat1=45&kat2=388&kat3=&Text=1788 © McGraw Hill 29  In some cases, only one mutation appears to be necessary: observation in retinoblastoma Bilateral Unilateral Tend to be in Tend to be in families with a families without a history of the cancer history of the cancer (familial) (sporadic) https://entokey.com/retinoblastoma-and-simulating-lesions-2/ https://www.researchgate.net/figure/Distribution-of-retinoblastoma-by-laterality-and-age-at-diagnosis_fig1_51702476 © McGraw Hill 30  Knudson’s 2-hit hypothesis Mutant allele In the first year (often both eyes and multiple tumors) Healthy allele Around 2-5 years old (one tumor in only one eye) © McGraw Hill 31  Summary of the two forms of Retinoblastoma https://basicmedicalkey.com/in-families/ © McGraw Hill 32  For most cancers need more than 2 hits; in different genes (oncogenes and tumour supprerssors) Healthy Healthy Healthy Cancer 1st hit 2nd hit 3rd hit 4th hit 5th hit 6th hit 7th hit Young Old © McGraw Hill 33  Maths: How they discovered it was typically 7 and not for example 9 or 5 driver mutations that cause cancer inference from observed relationship between incidence and age is that Incidence = Age6 This can be interpreted that cancer requires 7 events (mutations) to occur Led to somatic mutation theory of cancer (1980’s). Current paradigm. Proposes that successive DNA mutations in a single cell cause cancer (monoclonality) Incidence = age6 Incidence of cancer Observed Incidence of cancer Incidence = age4 Incidence = age2 0 Age (years) 80 © McGraw Hill 34  The original data Nordling, CO (1953) A New Theory on the Cancer-inducing Mechanism. Br J Cancer 7: 68–72 © McGraw Hill 35  The long story: Cancers are actually more complicated Form tumors — excessive division and do not respond to inhibitory signals Do not undergo apoptosis Undergo metastasis (cells travel to start new tumors) and angiogenesis (form new blood vessels to nourish themselves) Benign — tumor contained within a capsule. Not a Cancer Malignant — tumor invasive (spread around the body). Cancer © McGraw Hill ©Nancy Kedersha/Immunogen/SPL/Science Source 36  What is cancer? The long story One cell (red) acquires a mutation for repeated cell division New mutations arise, and one cell (green) has the ability to start a tumor Gradually The tumor grows at its place of aquiring more origin. One cell (purple) mutates driver further mutations Cells have gained the ability to invade underlying tissues, e.g. by producing a proteinase enzyme Cancer cells now have the ability to invade lymphatic and blood vessels New metastatic tumors are found some distance from the original tumor. These usually kill the patient © McGraw Hill 37  In 2 important reviews, Hanahan and Weinberg argued that cancers need to acquire a series of traits in order to develop They called these Hallmarks of Cancer (originally 6, extended to 10) * * Drugs that target * * hallmarks * * * Original 6 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013 © McGraw Hill 38  Example of multiple drivers: AML (Acute Myeloid Leukemia) (details here not important) Mutated genes in red Sustained Proliferation: NMP1, FLT3 Evades apoptosis: TP53, NPM1 Angiogenesis: TP53 Increased Growth Signals: FLT3 Limitless replication (blocking maturity): Runx1 Deregulated splicing (more mutations) © McGraw Hill 39  There are counter-acting pathways (make networks) (details here not important) Generally, Myc is an 2. Myc increases p19ARF oncogene 3. p19ARF inhibits But Myc leads to 1. Mdm2 Mdm2 inhibits activation of p53 p53 (=TP53), which leads to arrest (stopping) of cell cycle or to apoptosis So mutated Myc will only promote cell division if p53 is mutated Alberts et al. (2002) Molecular Biology of the Cell. New York: Garland Science © McGraw Hill 40  Reminder: pathways are complex Signal molecules Affect the cell cycle https://upload.wikimedia.org/wikipedia/commons/b/b4/MAPKpathway.jpg © McGraw Hill 41  Many mutations occur during cell division Large animals have more cell division so they should have more cancer The Blue Whale should not exist! This is called Peto’s Paradox (A paradox is a contradiction or something that should not exist) https://elifesciences.org/articles/21864 © McGraw Hill 42  Peto’s Paradox: More copies of p53 (‘Guardian of the Genome’) in the elephant Mutations in p53 are seen in at least 50% of all human cancers https://sitn.hms.harvard.edu/flash/2015/the-elephant-in-the-room-gene-copy-number-and- cancer/ © McGraw Hill 43  Cancer is always from a single cell New clones appear following appearance of a new Driver Mutation, which helps the cancer https://researchblog.duke.edu/2020/01/23/the-evolution-of-a-tumor/ © McGraw Hill 44 Mutations mostly hapen during DNA copying: The more cell divisions in a tissue; the commoner is cancer is that tissue Correlation coefficient = 0.81 Tomasetti and Vogelstein (2015) Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347(6217): 78–81. © McGraw Hill 45