BIO-333 Chapter 20 Guide 7e PDF

Name\_Isabel Hernandez Carrillo\_ BIO-333 Chapter 20 Guide 7e 1\. (pgs. 1163-1165, figs. 20-1, 20-2, and 20-3) Cancer is defined by two heritable properties, what are they? Define the following: benign, malignant, metastasis, carcinoma, sarcoma, leukemia, lymphomas, and adenoma. Familiarize yoursel...

Name\_Isabel Hernandez Carrillo\_ BIO-333 Chapter 20 Guide 7e 1\. (pgs. 1163-1165, figs. 20-1, 20-2, and 20-3) Cancer is defined by two heritable properties, what are they? Define the following: benign, malignant, metastasis, carcinoma, sarcoma, leukemia, lymphomas, and adenoma. Familiarize yourself with figure 20-2. - Heritable properties: - Reproduce in defiance of normal restraints on cell growth and division. - Invade and colonize territories normally reserved for other cells. - Benign- Self-limiting in growth and noninvasive. - Malignant- Invasive and/or able to undergo metastasis. Malignant tumor= cancer. - Metastasis- Secondary tumors, at sites in the body additional to that of the primary tumor; they result from cancer cells breaking loose, entering blood/lymphatic vessels, and colonizing separate environments. - Carcinoma- Cancer of epithelial cells. Most common form of human cancer. - Sarcoma- Cancer of connective tissue/muscle cells. - Leukemia- Cancer of WBC. - Lymphomas- Cancer of lymphocytes, in which the cancer cells are mainly found in lymphoid organs. - Adenoma- Benign epithelial tumor w/a glandular organization. - Figure 20-2: Most common cancers are those of the digestive organs (including colon, pancreas, and liver), respiratory system (primarily lung and bronchus), reproductive tract (prostate and uterine), and breast. Skin cells not included because almost all are cured easily. A graph with green and blue bars Description automatically generated  **Figure 20-3: Benign vs malignant tumors.** 2\. (pgs. 1165-1166, figs. 20-4 and 20-5) Explain why cancer is considered clonal. How does CML demonstrate clonicity? What are somatic mutations? Describe carcinogenesis, and its two classes of external agents. - Clonal because they develop from a single cell that multiplies abnormally. - Chronic myelogenous leukemia (CML) demonstrates clonicity by the Philadelphia chromosome they carry. - Philadelphia chromosome is a shorter version of chromosome 22→ 22q-. - Somatic mutations- One or more detectable abnormalities in the DNA sequence of tumor cells that distinguish them from the normal somatic cells from which the tumor was derived. - Body cells not in the germ line. - Carcinogenesis- Generation of cancer that is linked to mutagenesis (production of a change in the DNA sequence). - Chemical carcinogens- Cause simple changes in nucleotide sequence - Ex: Round up - Radiation- Cause chromosome breaks and translocations/specific DNA base alterations. - Ex: X-rays, UV light **Figure 20-5: Translocation between chromosome 9 and 22 responsible for CML** 3\. (1166-1168, figs. 20-6, 20-7, and 20-8) List the statistics on the rate of mutations in humans. If these statistics are so high, why is cancer so infrequent? Why does it take time for tumor-progression? - Statistics: - Estimated average-size human cells= 3.7 X 10\^13 - Cell divisions= 10\^16 - Mutations= 3 per cell divisions (10\^-6 mutations per gene per cell division) - Every single human gene will undergo mutation \~10\^10 separate occasions - Infrequent because development of cancer requires that a substantial number of independent, rare genetic, and epigenetic accidents occur in the lineage that emanantes from a single cell. There is an increase in incidence as people get older (40-80 yrs) but there is a decline among the very elderly (85-100 yrs). This is because cell proliferation (division) decreases providing fewer opportunities for mutation. - Tumor-progression- An initially mildly disordered cell behavior gradually evolves into a full-blown cancer by the selection of cell proliferation. - Takes time because as the tumor grows progression accelerates. Only the offspring of the best-adapted cells continue to divide and will eventually produce the dominant clones in developing lesion.  A collage of different types of cells Description automatically generated 4\. (pgs. 1168-1170, figs. 20-9, 20-10, and 20-11) How does natural selection influence the success of cancer cells? Describe the instability of the chromosomes and genes of cancer cells. How do defects in chromosome segregation lead to aneuploidy and/or chromothripsis? - Influence of natural selection in cancer: Original cancer cell lineage can diversify to give many genetically different subclones of cells. They can coexist in the same mass of tumor tissue or migrate and colonize separate environments suited to their individual quirks. Different subclones can gain advantage and come to predominate only to be overtaken by others/outgrown by their own sub-clones. - Genetically unstable- Abnormally increased spontaneous mutation rate. - Cancer cell karyotype severely disordered and disrupted genomes indicating that catastrophic events have occurred due to defects in chromosome duplication or segregation during mitosis. - Chromothripis- Isolation of a single chromosome in one of the daughter cells withing a micronucleus where it is prone to massive DNA damage and chromosomal rearrangement. - Aneuploidy- Similar to chromothripis but instead of damaging it, it gains or loses individual chromosomes.  Figure 20-11: Chromosome segregation defects can give rise to an aneuploidy and/or chromothripis 5\. (pgs. 1170-1171, figs. 20-12 and 20-13) Describe the phenomenon whereby some tumors rely on cancer stem cells for tumor growth. Why does this phenomenon add difficulty in treating cancer? - Cancer stem cells- Rare cancer cells capable of dividing indefinitely. - Stem cells produce transit amplifying cells - When tumor cells are genetically similar they may be phenotypically diverse. - Treatment can wipe out tumor cells in one state but will often allow survival of others that remain a danger. These are then able to resurrect the disease and actively divide again. A diagram of a cell Description automatically generated **Figure 20-13: Cancer stem cells can be responsible for a tumor's growth and yet remain only a small part of the tumor-cell proliferation.** 6\. (pgs. 1171-1173, figs. 20-14 and 20-15) Briefly, describe the six hallmarks for cancer progression. How does altered homeostasis (apoptosis vs. cell division) contribute to cancer? Describe contact inhibition and how this influences cancerous cells. - Six hallmarks for cancer progression: - Altered homeostasis that results in cell growing and dividing at a faster rate than they die - Bypass of normal limits to cell proliferation - Evasion of cell-death signals - Altered cellular metabolism - Manipulation of tissue environment to support cell survival and to evade a deleterious immune response - Escape of cells from their home tissues and proliferation in foreign sites (metastasis) - Altered homeostasis: Mutation/epigenetic change can increase the rate at which a clone of cells proliferations/by enabling it to continue proliferating when normal cells would stop/die because of failure in apoptosis. - Transformed cells will often divide even if held in suspension and doesn't require all of the positive signals from their surroundings that normal cells require. They also fail to recognize some negative influences that prevent them form moving and dividing. Therefore, they start to pile up layer upon layer in a culture dish. - Transformed- Cell w/an altered phenotype that behaves in many ways like a cancer cell (unregulated proliferation and anchorage independent growth in culture medium).  A diagram of a cell division Description automatically generated 7\. (pgs. 1173-1175, figs. 20-16 and 20-17) Describe replicative cell senescence. Do tumor cells undergo apoptosis? Why do cells undergo senescence? What are the two ways in which cancerous cells avoid senescence? Here is a link to a great video on cell senescence and cancer: - Replicative cell senescence- Phenomenon observed in primary cell cultures in which cell proliferation slows down and finally irreversibly halts. - Depends on the progressive shortening of the telomeres at the ends of chromosomes that eventually change their structure. Telomeres shorten every cell division and their protective caps deteriorate creating DNA damage signal because unprotected chromosome ends resemble double-strand breaks. Altered chromosome ends trigger a permanent cell-cycle arrest/cause the cell to die. - Cancer cells must accumulate changes that disable normal safety mechanisms like apoptosis. However, they do have an alternative cell-death, necrosis. - Cells undergo senescence as a protective mechanism to prevent replication of damaged cells. - Two ways cancerous cell avoid senescence: - Mutation in tumor suppressor genes p53 or pRb. - "Bypassing" senescence through mechanisms like epithelial-to-mesenchymal transition.  A microscope view of a purple and white cell Description automatically generated **Figure 20-17: Interior is deprived of oxygen and nutrients** 8\. (pg. 1175, fig. 20-18) How is sugar metabolism different in cancerous cells? What is the Warburg effect? - Normal cells: Fully oxidize carbon in glucose they take up to CO2 that is exhaled by lungs as waste product. - Cancer cells: Import glucose from blood at 100x higher than neighboring normal cells. Only a fraction of imported glucose is fully oxidized to CO2 by mitochondrial oxidative phosphorylation. However, metabolism of carbon atoms from glucose is rewired to support production of raw material for synthesis of proteins, nucleic acids, and lipids that enable cellular proliferation under oxygen-poor environments. - High glucose uptake allows tumors to selectively be imaged. - Warburg effect- Tendency of tumor cells to de-emphasize oxidative phosphorylation even when oxygen is plentiful, while at the same time taking up large quantities of glycose, is necessary for rapid proliferation of many cancer cells.  **Figure 20-18: Warburg effect in tumor cells reflects a dramatic change in glucose uptake and sugar metabolism.** 9\. (pgs. 1175-1176, fig. 20-19) Describe the tumor stroma. Why is it necessary for the tumor and the stroma to evolve together? - Stroma- 1) "Bedding": Connective tissue in which a glandular/other epithelium is embedded. Stromal cells provide the environment necessary for the development of other cells w/in tissue. 2) Larger interior space of a chloroplast, containing enzymes that incorporate CO2 into sugars. - Cancer cells induce changes in a stroma by secreting signal proteins that alter behavior of the stromal cells and proteolytic enzymes that modify the ECM. Stroma cells secrete signal proteins that stimulate cancer cell growth and division and proteases that further remodel ECM. - Stroma provides a framework for the tumor. 10\. (pgs. 1176-1178, fig. 20-20) Describe the process of metastasis. Why is it so rare? - Metastasis- Spread of cancer cells from their site of origin to other sites in the body. - First cancer cells invade local tissues and vessels, move through circulation, leave the vessels, and then establish new cellular colonies at distant sites. - Rare because some cells die immediately after entering foreign tissue or fail to proliferate.  **Figure 20-20: Steps in the process of metastasis.** 11\. (pgs. 1178-1180, fig. 20-21) With regards to oncogenes and tumor-suppressor genes, identify whether they are considered a gain-of-function or loss-of-function mutation, whether they are dominant or recessive. - Proto-oncogenes: Normal gene usually concerned w/regulation of cell proliferation that can be converted into a cancer-promoting oncogene by mutation. - Oncogenes: Altered gene whose product can act in a dominant fashion to help make a cell cancerous. It is a mutant form of a normal gene (proto-oncogene) involved in the control cell growth/division. - Dominant - Gain-of-function - Tumor-suppressor genes: Gene that appears to help prevent formation of a cancer. Loss-of-function mutations in such genes favor the development of cancer. - Recessive 12\. (pgs. 1180-1181) How can retroviruses cause cancer? What is the importance of *Ras* in cancer - how do mutations in this gene cause cancer? What class of cancer-causing genes is *Ras*? How often is mutated *Ras* found in human cancers? - Retroviruses- RNA-containing viruses that replicated in a cell by first making an RNA-DNA intermediate and then double-stranded DNA molecule that becomes integrated into the cell's DNA. - Ras oncogenes isolated from human tumor contain point mutations that create a hyperactive Ras protein that can't shut itself off by hydrolyzing its bound GTP and GDP. - Makes protein hyperactive, its effect=dominant. Only one of the cell's 2 gene copies needs to change to have an effect. - One or another of the 3 human Ras family members is mutated in about 30% of all human cancers. 13\. (pgs. 1181-1182, figs. 20-22 and 20-23) Describe the different ways a proto-oncogene can get converted to an oncogene. - Different ways a proto-oncogene→oncogene: - Small change in DNA sequence (ex: point mutation or deletion) that produces a hyperactive protein when it occurs w/in a protein-coding sequence or lead to protein overproduction when it occurs w/in regulatory region for that gene. - Gene amplification events, such as those that can be caused by error in DNA replication, may produce xtra gene copies. - Leads to overproduction of protein - Chromosomal rearrangement (breakage and rejoining of DNA helix) may either change protein-coding region, resulting in a hyperactive fusion protein, or alter the control regions for a gene so that a normal protein is overproduced. - Examples of protein: - Epidermal growth factor (EGF) can be activated by a deletion that removes part of its extracellular domain→ active even in absence of EGF. Mutant EGF receptor produces inappropriate stimulatory signal. - Myc protein (nucleus) stimulates cell growth and cell division. Contributes to cancer by overproducing in its normal form.  **Figure 20-22: Types of accidents that can convert a proto-oncogene into an oncogene.** Diagram of a diagram showing the growth factor trigger points Description automatically generated **Figure 20-23: Mutation of EGF receptor can make it active even in the absence of EGF and consequently oncogenic.** 14\. (pgs. 1182-1183, fig. 20-24) Describe retinoblastoma and its genetic background. Is this a loss-of-function or gain-of-function mutation? Why is tumor development more common in both eyes rather than only one? - Retinoblastoma: Rare type of human cancer arising from cells in the retina of the eye that are converted to a cancerous state by an unusually small \# of mutations. Studies of retinoblastoma led to discovery of first tumor suppressor gene. - Occurs in childhood and tumors develop from neural precursor cells in immature retina. - Heredity→ MULTIPLE tumors usually arise independently affecting BOTH EYES - Loss-of-function mutation present in one copy of Rb gene in every somatic cell - Nonhereditary→ Only ONE EYE affected and by only ONE tumor - Deletion of specific band on chromosome 13 predisposes and individual to the disease. - Require 2 independent events that inactivate the same gene on 2 chromosomes in a single retinal cell lineage. - Noncancerous cell= No defect on Rb gene  **Figure 20-24: Genetic mechanisms that cause retinoblastoma.** 15\. (pgs. 1183-1184, fig. 20-25) Describe the multiple ways cells can lose their wildtype copy of a tumor-suppressor gene. Describe the pathways leading to loss of tumor-suppressor gene function (genetic and epigenetic). - Ways cells can lose their WT copy: - First copy→Small chromosomal deletion/inactivation by point mutation due to a random error in DNA replication - Second copy→Commonly eliminated by a less specific mechanism that is likely to occur in cells progressing toward cancer that have become genetically unstable - Ex: Lost from cell/damage due to errors in chromosome segregation - Mitotic recombination- Normal gene along w/neighboring genetic material replace by mutant version - Epigenetic changes: C nucleotide in CG sequences in its promoter may become methylated in a heritable manner→ irreversibly silencing gene in cell and in all of its progeny. - Figure 20-25: Defective cells in only 1 of its 2 copies of a tumor-suppressor usually behaves as a normal cell. A diagram of different types of gene Description automatically generated **Figure 20-25: 6 ways of inactivating the remaining good copy of a tumor suppressor gene through changes in DNA sequence/an epigenetic mechanism.** 16\. (pgs. 1184-1186, figs. 20-26, 20-27, and 20-28) Using figure 20-26, understand why these particular types of mutations are found in oncogenes and tumor-suppressor genes. Understand that many cancers have very disrupted genomes (including aneuploidy and epigenetics). What are cancer-critical genes? - Figure 20-26: A) Oncogenes mutations can be detected by the same nucleotide change is repeatedly found among the missense mutations in a gene. B) Tumor suppressor genes missense mutations that abort protein synthesis by creating stop codons predominate. Only a few of the possible mutations in a protein-coding sequence are likely to activate, while inactivation can be consequence of missense, nonsense, and frameshift mutations. - Cancer-critical genes- Genes whose alteration contributes to the causation/evolution of cancer by driving tumorigenesis. - Disrupted genomes: - Aneuploidy- Change in chromosome karyotype from the normal \# (46). - Epigenetics- 1) Precede characteristic oncogenic mutations and lead them→ silencing of genes required for repair of DNA damage acts to increase mutation rates. 2) Accidental changes in DNA sequence can disrupt chromatin and epigenetic regulation. A diagram of a gene sequence Description automatically generated with medium confidence Figure 20-26: Distinct types of DNA sequence changes found in oncogenes compared to those in tumor suppressor genes. 17\. (pgs. 1186-1187) Describe "drivers" and "passengers". What percent of our genome would be considered cancer-critical? - Divers- Mutations that are causal factors in development of cancer. - Seen repeatedly - Passengers- Mutations that occurred in same cell as driver mutations but which are irrelevant to development of the cancer. - Encountered only rarely - \% of genome considered cancer-critical= \~1% 18\. (pgs. 1188-1189, fig. 20-30) Describe how mutations in the PI3/Akt/mTOR pathway could contribute to cancer. - PI3/Akt/mTOR pathway: Transmit signals for cell growth and cell division from outside the cell to the cell interior - In cancer pathway is activated by mutations so that the cell can grow in the absence of extracellular signal proteins. - Abnormal activation of protein kinases Akt and mTOR to stimulate protein synthesis and increase glucose uptake as well as the production of acetyl CoA in the cytosol. - Occurs early in the process of tumor progression. - Loss of phosphate and tensin homolog (PTEN) phosphatase that counteracts pathway is seen in cancer cells. - Working PTEN suppress pathway by dephosphorylating PI(3,4,5)P3 molecules that PI3K generates. - PTEN= commonly mutated in tumors  **Figure 20-30: Cells require 2 types of signals to proliferate.** 19\. (pgs. 1189-1190, fig. 20-31) What scenarios activate p53? How could mutations in this gene contribute to cancer? - p53: Transcription regulatory protein that is activated by damaged to DNA and is involved in blocking further progression through the cell cycle until the damage can be repaired. - Activation: - Hyperproliferative signals - DNA damage- Risk from faulty genome - Telomere shortening -- Dangerous to integrity of genome - Hypoxia- Deprives cell of O2 need to maintain mitochondrial respiration - Osmotic stress - Oxidative stress- High levels of reactive free radicals - Functioning p53 goes through apoptosis or temporary/permanent arrest of cell cycling - Mutated p53 leads to necrosis, continuation of cell division, and proliferation. - Necrosis leads cells to burst and spill its contents into the extracellular space inducing inflammation. A diagram of a person\'s life cycle Description automatically generated **Figure 20-31: Modes of action of the p53 tumor suppressor.** 20\. (pgs. 1194-1197, figs. 20-35 and 20-36, Table 20-1) Describe the physiological steps involved with colorectoral cancer. Describe the genetics that influence FAP. Describe the genetics that influence HNPCC. Describe the sequence of genetic changes that underlay the development of colorectoral cancer. - Colorectal cancer: Cancer arising from the epithelium lining the colon (large intestine) and rectum (terminal segment of the gut). - Renewal depends on stem cells that lie in deep pockets of the epithelium called intestinal crypts. - Adenomatous polyps= precursors of colorectal cancer - Progression is slow (\~10 yrs before malignant) - 3 main genes related to colorectal cancer: Proto-oncogene K-Ras, p53, and Apc - Loss of Apc= excess of free B-catenin leading to uncontrolled expansion of stem-cell population. - Familial adenomatous polyposis coli (FAP)= Hereditary predisposition - Hundreds to thousand polyps develop along the colon - FAP have inactivating mutations/deletions of one copy of the Apc gene and show loss of heterozygosity in tumors (both copies lost/inactivated) - Hereditary nonpolyposis colorectal cancer (HNPCC): Probability of colon cancer increase w/out any increase in \# of colorectal polyps - Tumors have gross chromosomal abnormalities with multiple translocations, deletions, other aberrations, and many more chromosomes than normal. - Sequence of colorectal cancer: See figure 20-36 - Inactivation of Apc gene (benign polyps) - Activating mutations in K-Ras gene - Inactivating mutations of p53 Close-up of a brain and a close-up of a brain Description automatically generated  21\. (pgs. 1207-1209, figs. 20-42, 20-43, and 20-44) Describe how a small molecule is used to treat CML. Familiarize yourself with figure 20-44. - Chronic myelogenous leukemia (CML): Associated w/particular chromosomal translocation visible as the Philadelphia chromosome. - Imatinib (Gleevec) inhibits the activity of tyrosine kinases. - Early stages - Late stages (blast crisis) relapse even with imatinib because secondary mutations in the Bcr-Abl gene disrupts its ability to bind to Brc-Abl kinase. A diagram of a translocation Description automatically generated  A diagram of a cell line Description automatically generated 22\. (pgs. 1209-1212, figs. 20-45 and 20-46) Describe how the immune system could be directed to target cancer cells. Explain how the immunosuppressive environment can be removed from T-cells in an effort to direct them to tumor cells - why could this be potentially dangerous? - Ex: Breast cancer- Trastuzumab (Herceptin) binds to Her2 inhibiting its function and slows growth of human breast cancers that overexpress Her 2. - Antibodies against proteins abundant on the surface of a particular type of cancer cell but rare on normal cells can be coupled to a toxin to kill cells that the antibody binds to. - Amino acid change from either passenger/drive mutations have potential to produce cell-surface neoantigens that can be recognized as foreign by T cells→ cancer cell death - Cytotoxic T cells kill infected host cells - T cell activation requires T cell to physically interact w/antigen-presenting cells (dendritic cells). - Dendritic cells= Highly migratory and pick up pathogens on their products at sites of infection and deliver them to neoantigens to T cells. - Some cancer cells inhibit this process by preventing dendritic cells from interacting with their acquiring their neoantigens.  **Figure 20-45: Tumor-specific antigens are recognized by immune system.** Diagram of a cell membrane Description automatically generated **Figure 20-46: Immune system interaction w/cancer.**