2 1.Heart Diseases685,089 28.0 2.Cancer556,902 22.7 3.Cerebrovascular diseases157,689 6.4 4.Chronic lower respiratory diseases126,382 5.2 5.Accidents (Unintentional injuries)109,277 4.5 6.Diabetes mellitus 74,219 3.0 7.Influenza and pneumonia 65,163 2.7 8.Alzheimer disease 63,457 2.6 1.Nephritis 42,453 1.7 10.Septicemia 34,069 1.4 RankCause of Death No. of deaths % of all deaths US Mortality, 2003
3 2006 Estimated US Cancer Cases* *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2006. Men 720,280 Women 679,510 31%Breast 12%Lung & bronchus 11% Colon & rectum 6% Uterine corpus 4%Non-Hodgkin lymphoma 4% Melanoma of skin 3% Thyroid 3%Ovary 2% Urinary bladder 2% Pancreas 22%All Other Sites Prostate33% Lung & bronchus13% Colon & rectum10% Urinary bladder6% Melanoma of skin5% Non-Hodgkin 4% lymphoma Kidney3% Oral cavity3% Leukemia3% Pancreas2% All Other Sites18%
4 2006 Estimated US Cancer Deaths* ONS=Other nervous system. Source: American Cancer Society, 2006. Men 291,270 Women 273,560 26%Lung & bronchus 15%Breast 10%Colon & rectum 6%Pancreas 6%Ovary 4%Leukemia 3%Non-Hodgkin lymphoma 3%Uterine corpus 2%Multiple myeloma 2%Brain/ONS 23% All other sites Lung & bronchus31% Colon & rectum10% Prostate9% Pancreas6% Leukemia4% Liver & intrahepatic4% bile duct Esophagus4% Non-Hodgkin 3% lymphoma Urinary bladder3% Kidney3% All other sites 23%
5 Overview of Genetic Recombination Two types of recombination processes alter genes. – gene transfer - one chromosome or genome donates a segment to another chromosome or genome – reciprocal recombination - two chromosomes trade segments
6 Gene Transfer What is a Plasmid? – Found in prokaryotes – Circular bit of DNA – Extrachromosomal – About 5% of bacterial DNA What is a transposon? – A DNA sequence capable of moving around What is transposition? – a random(?) movement of transposable elemenes (genes) which results in genetic recombination
7 Gene Transfer Plasmid creation – All cells have recombination enzymes that can cause double duplexes to undergo reciprocal exchange. loop is freed from rest of DNA and becomes a plasmid Integration – Region of plasmid DNA involved in original exchange, recognition site, aligns with matching sequence on main genome.
12 Gene Transfer Transposition – Transposons encode transposase enzyme that inserts transposon into the genome at a random site. causes insertional inactivation facilitates gene mobilization – Transposition can rapidly generate composite plasmids (resistance transfer factors). antibiotic resistance How could transposition cause cancer?
15 Mutations What is a mutation? – Mutations are changes in the hereditary message of an organism.
16 Mutations What is a mutation? – Mutations are changes in the hereditary message of an organism. What kinds of mutations are most significant in regards to heredity? – Only mutations in the germ line (cells that form gametes) are passed to subsequent generations. What is the difference between somatic cells and germ-line cells?
17 Mutations What is a mutation? What kinds of mutations are most significant in regards to heredity? – Only mutations in the germ line (cells that form gametes) are passed to subsequent generations. What is the difference between somatic cells and germ-line cells? – Somatic cells are normal body cells and germ line cells are sex cells.
18 Mutations Mutations in somatic cells may have a large effect on the individual, as they are passed on to other cells in the same individual. Why is this so?
19 Mutations Altering DNA Sequence Base substitution Chemical modification DNA breaks Slipped mispairing Triplet expansion
21 Mutations Arising from Gene Position Changes Chromosomal rearrangement – translocations - segments of one chromosome become part of another chromosome – inversions - orientation of a portion of chromosome is reversed – aneuploidy - genes or chromosome segments are added or deleted – polyploidy - entire sets of chromosomes added
24 Mutations Arising from Gene Position Changes Insertional inactivation – Transposons are capable of moving to different locations in the genome. select new locations at random may cause insertional inactivation
25 DNA Repair Mismatch repair - locate replication errors and correct daughter (non-methylated) strand – Where have we heard of methylated DNA before? – dam mutations (deficient in adenine methylation) Specific repair systems – UVR photorepair system animationanimation – Uracil-N-glycosylase Excision repair - Post-replication repair -
26 DNA Repair Mismatch repair - Specific repair systems Excision repair - excise damaged region and fill in gap using repair polymerase – Non specific Post-replication repair – Can handle double stranded DNA breaks – recombinational repair Why talk about DNA Repair mechanisms in a chapter about Cancer?
27 What is Cancer? Cancer is a growth disorder of cells. – uncontrolled and invasive growth results in tumor may metastasize – can be caused by mutagenic chemicals or possibly viruses cell division never stops in a cancerous line, and are thus essentially immortal
28 Carcinoma of the lung Connective tissue Lymphatic vessel Smooth muscle Metastatic cells Blood vessel Blood vessel What is Cancer ? – Fig 20.11
29 Causes of Cancer Sarcomas - arise in connective tissue or muscle Carcinomas - arise in epithelial tissue – Carcinogens are agents thought to cause cancer. Ames test – Carcinogenic chemicals are all mutagenic.
30 W hat is epithelial tissue? Structure covers the whole surface of the body. cells closely packed and ranged in one or more layers. tissue is specialized to form the covering or lining of all internal and external body surfaces. Epithelial tissue that occurs on surfaces on the interior of the body is known as endothelium. cells are packed tightly together, with almost no intercellular spaces and only a small amount of intercellular substance. usually separated from the underlying tissue by a thin sheet of connective tissue; basement membrane.
33 Causes of Cancer – Table 20.3 – Common Exposure
34 Causes of Cancer – Table 20.3 – Uncommon Exposure
35 Common Carcinogens in the Home Consumer products Deodorant, a bar of soap, toothpaste, hair spray, detergent... All of these products can contain carcinogens and many do. While each product may only contain a small amount of cancer-causing agents, most of us use these products every day. Making an informed, healthy choice starts by becoming aware of these products and choosing to use products made by companies that do not use harmful ingredients. The list below consists of common consumer products that contain carcinogenic materials. This is just a start -- please add to it and share information about other products that you know of so we can all live more healthy lives.companies that do not use harmful ingredients.
36 Common Carcinogens in the Home Bath and beauty products Dove Beauty Bar: It's 99% water, but watch out for that other 1%. It includes quaternium 15 and formaldehyde, known carcinogens, as well as irritants to the skin, eyes, and mucous membranes.mucous membranes Johnson's Baby Shampoo: Contains carcinogens quaterium 15, FD&C RED 40, which can cause dermatitis.dermatitis Crest Tarter Control Toothpaste: This best selling toothpaste contains saccharin and phenol fluoride. Talcum powder: Talc, the main ingredient, is a carcinogen that increases the risk of ovarian cancer. Use corn starch instead.ovarian cancer Cover Girl Replenishing Natural Finish Make Up (foundation): This makeup includes BHA, talc, titanium dioxide, triethanolamine. These interact with nitrites to form nitrosamines and lanolin, which is often contaminated with DDT and other carcinogenic pesticides.
37 Common Carcinogens in the Home Household cleaning products Tide & Cheer Laundry Detergent: Our favorite detergent contains trisodium nitrilotriacetate, a carcinogen. Lysol Disinfectant: While it makes the air sweet smelling, it contains the dioxin. Food products Oscar Meyer beef hot dogs: Labeled ingredients in this American favorite include nitrite, which interacts with meat amines to form nitrosamines. Tests have also found other carcinogens such as benzene hexachloride, dacthal, dieldrin, DDT, heptachlor, hexachlorobenzene, and lindane. If you have to eat hot dogs, look for ones without nitrates in them. Whole milk: Certain containers contain DDT, dieldrin, heptachlor, hexachlorobenzene, recombinant bovine growth hormone and Igf-1. All of these increase the chances of getting breast, colon and prostate cancers. Look for RBGH-free organic milk.breastcolonprostate cancers
38 Common Carcinogens in the Home Pet products Zodiac flea collars: These dog collars include the labeled carcinogen propoxur. Try Trader Joe’s herbal flea collars instead. Other products Carpets: Some carpets are made or finished with petrolatum-based chemicals. These chemicals can "outgas" into the home. Petrolatum is believed to a human carcinogen.
39 Cancer and the Cell Cycle Oncogenes - genes that when introduced into normal cells cause them to become cancerous – Originally discovered by transfection - nuclear DNA from tumor cells is isolated and cleaved into random fragments, and tested for ability to induce cancer
41 Cancer and the Cell Cycle Proto-oncogenes are genes encoding proteins that stimulate cell division. – Mutated proto-oncogenes become cancer- causing genes (oncogenes). Mutated alleles of many oncogenes are genetically dominant.
42 Table 20.4 Some Genes Implicated in Human Cancers
43 Tumor suppressors “Guardian(s) of the genome” Often involved in maintaining genomic integrity (DNA repair, chromosome segregation) Mutations in tumor suppressor genes lead to the “mutator phenotype”—mutation rates increase Often the 1 st mutation in a developing cancer
44 Tumor-Suppressor Genes Tumor suppressor genes encode proteins that turn off cell division in healthy cells. – Cancer may be initiated by the inappropriate activation of proteins that regulate the cell cycle, or by the inactivation of proteins that normally suppress cell division.
45 p53—a classic tumor suppressor “The guardian of the genome” Senses genomic damage Halts the cell cycle and initiates DNA repair If the DNA is irreparable, p53 will initiate the cell death process What is the name of the cell death process?
46 Rb—a classic tumor suppressor Rb binds to a protein called E2F1 and inhibits its function E2F1 initiates the G1/S cell cycle transition Thus, Rb is a crucial cell cycle checkpoint
47 Some Genes Implicated in Human Cancers Table 20.4
50 Cancer and the Cell Cycle Cells control proliferation at several checkpoints. – All these controls must be inactivated for cancer to be initiated. Induction of most cancers involves mutations of several genes. explains why most cancers occur in people over 40 more time for individual cells to accumulate multiple mutations
52 The Stages of the Cell Cycle 1. Click on picture for cell cycle animation – will go to www.cancerquest.org)www.cancerquest.org 2. Use alt-tab keys to go between website and power point presentation. 3. Click on blank space to proceed to next slide.)
53 There are several factors that regulate the cell cycle and assure a cell divides correctly. 1.Before a cell divides, the DNA is checked to make sure it has replicated correctly. (If DNA does not copy itself correctly, a gene mutation occurs. DNA replication animation:click on DNA picture
54 2. Chemical Signals tell a cell when to start and stop dividing. (Target cells animation: click on go sign)
55 Neighboring cells communicate with dividing cells to regulate their growth also. ( Normal contact inhibition animation: click on petri dish)
56 Cancer is a disease of the cell cycle. Some of the body’s cells divide uncontrollably and tumors form. Tumors in Liver Tumor in Colon
57 While normal cells will stop dividing if there is a mutation in the DNA, cancer cells will continue to divide with mutation.
58 Due to DNA mutations, cancer cells ignore the chemical signals that start and stop the cell cycle. 2 animations of cancer cells dividing: click on picture
59 Due to DNA mutations, cancer cells cannot communicate with neighboring cells. Cells continue to grow and form tumors. (cancer cells dividing: click on picture.) Skin cancer
60 SUMMARY Normal Cell Division DNA is replicated properly. Chemical signals start and stop the cell cycle. Cells communicate with each other so they don’t become overcrowded. Cancer Cells 1. Mutations occur in the DNA when it is replicated. 2. Chemical signals that start and stop the cell cycle are ignored. 3. Cells do not communicate with each other and tumors form.
62 Chromosomal Instability as seen in karyotypes What is the main difference between these images?
63 Smoking and Cancer About one-third of all cancer cases in the United States are directly attributable to cigarette smoking. – Smoke contains many mutagenic chemicals, and places them in direct contact with lung tissues. damages genes of epithelial cells lining the lungs
66 Potential Cancer Therapy Targets Preventing the Start of cancer (1-6 )
67 Preventing start of cancer Many therapies work on the cell division initiation pathway 1. receiving signal to divide – mutations that increase number of receptors on cell surface amplify the division signal – Block signals or use immune system to attack protein signaling molecules
68 Preventing the start of Cancer 2. relay switch – passage of signal into the cell’s interior relay switch stuck in “ON” position Block on signals Turn off the switch
69 Preventing the start of Cancer 3. amplifying the signal amplification of signal within cytoplasm occurs naturally Disrupt amplification pathway
70 Preventing the start of Cancer 4. releasing the brake used to restrain cell division normally Rb blocks E2F E2F enables cell to copy DNA when Rb is inhibited DNA copying begins when Rb is mutated it cannot be inhibited
71 Preventing the start of Cancer 5. checking readiness ensures DNA is undamaged and ready to divide p53 inspects the integrity of DNA when mutated, DNA checking cannot occur
72 Preventing the start of Cancer 6. stepping on the gas normally “gas tank is nearly empty” restore telomerase inhibitors Cells normally can divide about 30 times, cancer cells have lost this inhibition
73 Preventing the spread of cancer 7. tumor growth angiogenesis inhibitors angiostatin & and endostatin 8. metastasis cells break off and migrate
74 Benign vs. Malignant Tumors Benign Tumors Benign tumors are not cancerous. They: can usually be removed do not come back in most cases do not spread to other parts of the body and the cells do not invade other tissues
75 Benign vs. Malignant Tumors Malignant Tumors Malignant tumors are cancerous. They: can invade and damage nearby tissues and organs metastasize (cancer cells break away from a malignant tumor and enter the bloodstream or lymphatic system to form secondary tumors in other parts of the body)