BIOL 2202 F2024 Cancer Past Paper PDF

BIOL 2202 F2024 CH. 20 – Part II Cancer  Cancer Multi-cellular organisms have bodies that operate as a society or ecosystem Self sacrifice, as opposed to survival of the fittest, is the rule Cells are committed to collaboration Molecular disturbances that upset thi...

BIOL 2202 F2024 CH. 20 – Part II Cancer  Cancer Multi-cellular organisms have bodies that operate as a society or ecosystem Self sacrifice, as opposed to survival of the fittest, is the rule Cells are committed to collaboration Molecular disturbances that upset this harmony mean trouble in the multi-cellular society Cancer is an appropriate topic to end a CMB course because cancer results from the breakdown of the regulatory mechanisms that govern normal cell behavior Cancer cells may be considered to be “selfish” – they display non- cooperative behavior 2  Cancer as a Microevolutionary Process The human body contains >1013 cells, with billions experiencing mutations every day Although DNA is replicated with great accuracy, some mutations occur Most of these mutations are repaired, but a few escape the cell repair processes Every single gene is likely to have acquired a mutation on more than 109 separate occasions in any individual The problem of cancer seems to be not why it occurs, but why it occurs so infrequently A mutation may give one cell a selective advantage, allowing it to grow and divide more vigorously and survive more readily than its neighbors, becoming a founder of a growing mutant clone Such selfish behavior can jeopardize the future of the entire organism Over time, repeated rounds of mutation, competition and natural selection operating within the population of cells can lead to success of one (or several) clone of cells and ultimately to cancer 3  4 Main Families of Cancer There are over 200 distinct types of cancer, but they are grouped into 4 main categories: Carcinomas (~30% of all human cancers) Are from epithelial cells Sarcomas (rare in humans) Arise from connective tissue (including bone and cartilage) or muscle cells Leukemias and Lymphomas Arise from blood cells and their precursors (hemopoietic cells) Neoplastic Neuromas Arise from cells of the nervous system (neurons and neuroglia) 4  2 Major Traits of Cancerous Cells Hyperplasia (excessive growth and proliferation) Cells proliferate to form a tumor Metastasis Individual cancer cells detach themselves from their primary location and travel via blood or lymphatic vessels to new locations in the body to establish secondary tumors (metastases) Tumors that do not metastasize are called benign tumors (not cancerous) Tumors capable of metastases are called malignant (cancerous) See Movie 20.7 5 Cancer Develops by an Accumulation of Somatic Mutations In order for a single abnormal cell to give rise to a tumor, it must pass on its abnormality to its progeny It must be heritable Somatic mutations occur in somatic body cells (not in germ line cells) The abnormality may be caused by: A genetic change (mutation/alteration of DNA sequence) OR An epigenetic change (an inherited pattern of gene expression without a change in the DNA sequence) E.g. heterochromatin gene silencing or DNA methylation 6 A Single Mutation is Not Enough to Cause Cancer Cancer is caused by an accumulation of random mutations in a single lineage of cells This is why the incidence of cancer increases with age It generally takes 10+ years to develop enough mutations in a cell line to become metastatic People with a genetic defect in their DNA repair mechanisms have cells that accumulate mutations at an accelerated rate, and show a strong disposition to develop cancer Will develop cancer at a younger age 7 Clonal Evolution of Cancer Cells Involves successive rounds of random inherited changes followed by natural selection Cells evolve from bad to worse At each stage, one cell acquires an additional mutation or epigenetic change that gives it a selective advantage over its neighbors The offspring of the best adapted cells continue to divide, becoming the dominant clone in the developing tumor 8  Tumor Progression in Cervical Cancer Layer of dividing cells Typically, at least 5 mutations must accumulate in a single lineage of cells to transform normal cells into cancer cells A multi-step process called tumor progression occurs over many years 9  Characteristics of Cancer Cells Genetically unstable Increased mutation rate due to defects in DNA replication/repair/segregation Defective control of cell death, cell differentiation or both Reduced dependence on signals from other cells for survival Abnormally invasive Lack adhesion molecules like cadherins Survive in abnormal locations Secretion of proteases that degrade the ECM Absence of cell senescence Proliferate indefinitely due to reactivation of Telomerase enzyme Altered responses to DNA damage and stress No apoptosis Tumors are heterogeneous Different clones in the tumor contain different combinations of mutations 10  Cancer Cells are Genetically Unstable They accumulate genetic changes at an abnormally rapid rate Many are unable to repair DNA damage or correct replication errors Others fail to maintain the number or integrity of their chromosomes Often contain mutations in DNA maintenance genes Karyotypes of 2 colon cancer patients – one with gross chromosomal abnormalities and one with invisible defects caused by mismatch repair defects 11 Genetic instability results from mutations that interfere with the accurate replication and maintenance of the genome and thereby increase the mutation rate itself 12 Increased cell division and/or decreased apoptosis can lead to cancer progression by increasing the number of cells available for mutation 13  Cancer Stem Cells Most of the specialized (differentiated) cells that need continual replacement are themselves unable to divide The cells that replace terminally differentiated cells that are lost (damaged or died) are generated from a stock of proliferating precursor cells, which are themselves derived from a much smaller number of self- renewing cells called stem cells Stem cells are not terminally differentiated and can divide without limit Each daughter cell has a choice: Remain a stem cell Become terminally differentiated Cancers originate from cancer stem cells, which are capable of unlimited division Cancer stem cells can arise from normal stem cells that have obtain mutations OR from differentiated cells that have undergone changes that give them stem cell properties 14  Absence of Cell Senescence Cell senescence – Normal cells have a built-in limit to the number of times they can divide before they enter apoptosis Has to do with shortening telomeres Cancer cells do not stop when they hit this limit: Genetic and epigenetic changes disrupt cell cycle checkpoint controls E.g. mutations that inactivate the p53 pathway Mutations that maintain telomerase activity 15 Steps in Metastasis Most of the molecular mechanisms involved in these stages are not yet clear 16 Two Types of Cancer-Critical Genes There are 2 sets of cancer-critical genes that regulate the cell cycle Proto-oncogenes: Code for proteins that are required for normal cell proliferation Mutants called oncogenes are overactive and promote excessive proliferation Many oncogenes are directly encoded by DNA viruses (E.g. HPV, Epstein Barr virus, Hepatitis–B virus, etc.) Tumor Suppressor genes: Code for proteins that prevent excessive cell proliferation Mutants contain inactivated genes and thus excessive proliferation occurs 17 Oncogenes and Tumor Suppressor Genes Dominant mutation – only one mutated copy needed for change in phenotype Recessive mutation – two mutated copies needed for change in phenotype 18 Proto-oncogene can be Converted into an Overactive Oncogene Gene activation of a proto-oncogene leads to cancer Can mutate the coding sequence of the protein or the regulatory regions that control gene expression E.g. Many Ras oncogenes isolated from human tumors contain a point mutation that makes the Ras protein hyperactive Important cell signaling GTPase – the mutant cannot shut itself off – the proliferation pathway is always “on”, even without an external mitogen stimulus 19 Loss of Tumor Suppressor Gene Functions Lead to Cancer Often involves both genetic and epigenetic changes in gene expression 2nd mutation occurs frequently because of hypermutability characteristic of cancer cells (10-20X higher) E.g. p53 gene may be the most important gene in preventing cancer (See movie 20.9) Has multiple roles in cell cycle control, apoptosis and maintenance of genetic stability Almost all human cancers contain mutations in this gene or in one of the pathways it regulates 20 NOT the same as APC/C from cell cycle 22 Cancer-Causing Mutations Cluster in a Few Fundamental Pathways p53 regulates all 3 pathways!!! 23 Modes of Action of p53 Tumor Suppressor Gene p53 is a cellular stress sensor In response to stress, p53 levels in the cell rise and cause cells to undergo cell cycle arrest, apoptosis or cell senescence Cells defective in p53 fail to show these p53-dependent responses As a result, the cell may die or even worse – survive and proliferate with a corrupted genome – leading to loss of other tumor suppressors or activation of P53 is a gene regulatory protein oncogenes 24 Why Are at Least 5 Mutations Needed for Cancer to Develop? Large multicellular organisms have evolved a complex set of regulatory mechanisms to keep their cells in check Lots of redundant (back up) pathways Thus, many different regulatory systems must be disrupted before a cell can throw off its normal restraints and behave as an antisocial cancer cell 25 Development of Colorectal Cancer At least 5 random mutations must accumulate in a single lineage for cancer to develop Mutation of the APC gene has been identified as one of the central ingredients for colorectal cancer (80%) APC regulates genes involved in adhesion and proliferation Cells lose cell-cell adhesion properties; increase stem cell properties and increase genetic instability Most human cancers contain mutations in p53, Ras and/or Rb 26 Different Colorectal Cancer Patients will have Different Combinations of Mutations Molecular Biology of the Cell, 4th ed. (2002), B. Alberts et al., pg. 1355. Different cell abnormalities = different response to treatment 27  Current Cancer Treatments Prevention – avoid known carcinogens E.g., asbestos, cigarette smoke, etc. Early and precise detection/diagnosis is key to successful outcomes E.g. pap tests, mammograms, prostate exams, etc. Treatments: Many traditional treatments target cancer cells Surgery by damaging DNA – normal cells stop dividing in Radiation order to fix the damage or induce apoptosis Chemotherapy Various drugs Cancer cells continue to divide – they die Immunotherapy because of their extensive DNA damage – they Gene therapy contain mutations that prevent repair of the damage 28  Multidrug Treatments Tumors are constantly mutating and evolving As a result, they develop resistance to drugs If single drugs are given sequentially, the tumors can easily develop resistance, one-by-one If 2 drugs are given simultaneously, the cells would have to simultaneously develop 2 mutations to gain resistance (highly improbable) 29 New Cancer Therapies Try to take advantage of some molecular abnormality of cancer cells that distinguish them from normal cells As we become increasingly able to pinpoint the specific alterations in cancer cells that make them different, we can design therapies that kill the cancer cells without harming neighboring cells Custom tailoring treatments based on the specific gene expression profile of the patient’s cancer E.g. Some cancers contain a mutated tyrosine kinase that acts as an oncogene – leading to increased proliferation The anti-cancer drug Gleevec binds to and inhibits the tyrosine kinase, preventing the proliferation of the cancer cells 30 At-Home Exercise (20-15) Leukemias, cancers arising through mutations that cause excessive production of white blood cells, have an earlier average age of onset that other cancers. Propose an explanation for why this might be the case. At-Home Exercise (20-17) Heavy smokers or industrial workers exposed for a limited time to a chemical carcinogen that induces mutations in DNA do not usually begin to develop cancers characteristic of their habit or occupation until 10-20+ years after the exposure. Suggest an explanation for this long delay. At-Home Exercise (20-19) Is cancer hereditary? Explain. At-Home Exercise (20-21) One major goal of modern cancer therapy is to identify small molecules (anti-cancer drugs) that can be used to inhibit he products of specific cancer-critical genes. If you were searching for such molecules, would you design inhibitors for the products of oncogenes or the products of tumor suppressor genes? Explain why you would (or would not) select each type of gene. THE END of BIOL 2202!!!! iClicker Q1: A malignant tumor is more dangerous than a benign tumor because ____________________. A. its cells are proliferating faster. B. it causes neighboring cells to mutate. C. its cells attack and phagocytose neighboring normal cells. D. its cells invade other tissues. iClicker Q2: Which of the following genetic changes cannot convert a proto-oncogene into an oncogene? A. A mutation that introduces a stop codon immediately after the codon for the initiator methionine. B. A mutation within the coding sequence that makes the protein hyperactive. C. An amplification of the number of copies of the proto-oncogene, causing overproduction of the normal protein. D. A mutation in the promoter of the proto-oncogene, causing the normal gene to be transcribed at an abnormally high level. iClicker Q3: Which of the following statements is false? A. Mutations in proto-oncogenes are dominant B. Mutations in tumor suppressor genes are recessive C. p53 is a tumor suppressor gene D. APC is a proto-oncogene iClicker Q4: Which day will you write the BIOL 2202 final exam? A. Dec. 1, 2024 B. Dec. 19, 2024 C. Dec. 25, 2024 D. Jan. 1, 2025